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Exhibit B provides an accurate and complete breakdown of all Inventory as of November, 2015 of the Compounds specifically identified in Exhibit B. All of the Inventory: (a) is of such quality and quantity as to be usable by Purchaser in the ordinary course of business; and (b) is free of any defect or deficiency to the knowledge of Sellers. Except for the Inventory not included in the Selected Inventory as of the Effective Date, the Purchased Assets constitute all of the rights, property and assets that are owned by either Seller or any of its Affiliates as of the Effective Date and that are necessary or reasonably useful for the research, development or commercialization of any Compound or Product. Sellers and their Affiliates do not own any patents or patent applications that disclose or claim the composition of matter, manufacture or use of any Compound or Product. There are no pending, and to the knowledge of Seller, no threatened, adverse actions, claims, investigations, suits or proceedings against a Seller or any of its Affiliates, at Law or in equity, or before or by any Governmental Authority, involving the Purchased Assets or any Compound or Product. No Seller or Affiliate of a Seller has any obligations to [***] or its Affiliates that prohibit or place any limitations on a Sellers or its Affiliates ability to research, develop, manufacture or commercialize any Compounds or Products or to enable or grant rights to others to do so. Purchaser is a corporation duly organized, validly existing and in good standing under the laws of the State of Delaware and has all requisite power and authority and all necessary governmental approvals to own, lease and operate its properties and to carry on its business as now being conducted. The execution and delivery of this Agreement and the other Transaction Documents by Purchaser and the consummation by Purchaser of the Acquisition have been duly and validly authorized by all necessary action of the Purchaser and its board of directors, and no other proceedings on the part of Purchaser are necessary to authorize this Agreement or to consummate the Acquisition. This Agreement and the other Transaction Documents have been or when executed and delivered will be duly executed and delivered by Purchaser and, assuming the due authorization, execution and delivery by the other Parties hereto, each such agreement constitutes a legal, valid and binding obligation of Purchaser, enforceable against Purchaser in accordance with its terms, subject to the Exception. The execution and delivery of this Agreement by Purchaser do not, and the performance by Purchaser of its obligations hereunder and the consummation of the Acquisition will not: (a) conflict with or violate any provision of the Organizational Documents of Purchaser or (b) conflict with or violate any Law or Order applicable to Purchaser or by which Purchaser is bound or affected. Purchaser is not required to give any notice to, make any filing with, or obtain any Consent or Permit of any Governmental Authority or other Person in order to consummate the transactions contemplated by this Agreement. Purchaser is not party to any Contract as a result of which a broker, finder or agent could hold any payment obligation against Sellers with respect to the transactions contemplated by this Agreement. The Purchaser is not party to any Proceedings pending or, to Purchasers knowledge, threatened in writing by a Third Party challenging, or that would have the effect of preventing, delaying, making illegal or otherwise interfering with, the transactions contemplated hereby. Sellers hereby agree, without further consideration, to execute and deliver following the Effective Date such other instruments of transfer and take such other action as Purchaser (or Purchasers counsel on behalf of Purchaser) may reasonably request in order to [***] in accordance with this Agreement. Sellers shall transfer and deliver to Purchaser all Assigned Know-How and Selected Inventory within thirty (30) calendar days of the Effective Date, at Purchasers expense for shipping and handling costs, to the locations, and in accordance with the instructions, specified by Purchaser. Sellers will, to the extent any such Assigned Know-How exists in a form suitable for electronic transfer, make such transfer to Purchaser electronically. At any time during the first twelve (12) months following the Effective Date (the First Year ), Purchaser shall have the right to request the transfer by Sellers of further Compounds and/or Products from the Inventory, at Purchasers expense for shipping and handling costs, to the locations, and in accordance with the instructions, specified by Purchaser. Sellers shall provide such further Compounds and/or Products within thirty (30) days of such request. In the event that Orca Ltd undertakes any such internal research, Orca Ltd shall promptly disclose to Purchaser any and all intellectual property (including patentable inventions), Know-How, data and results generated through the conduct of such research (collectively, the Research Results ), and Sellers shall and hereby do assign to Purchaser all right, title and interest in and to the Research Results, including the sole right to apply for any patents and patent applications that disclose or claim any inventions included in the Research Results (the Research Patents ). At Purchasers reasonable request and expense, Sellers shall, and shall ensure that their employees and consultants, take all actions necessary or useful to demonstrate or perfect Purchasers ownership of the Research Results and Research Patents or to facilitate the filing, prosecution, maintenance, defense or enforcement of any Research Patent. If the Purchaser and Orca Ltd do not enter into [***] prior to [***], Purchaser shall not have any obligations to Orca Ltd, and Orca Ltd. Each of the Parties hereby waives compliance with the notification and all other requirements of the bulk sales laws in force in the jurisdiction in which such laws are applicable to the Purchased Assets or the transactions contemplated by this Agreement. Purchaser may issue a press release announcing this Agreement promptly after the Effective Date, subject to the mutual agreement by the Parties of the content and form of such press release. For clarity, all non-public information included in the Purchased Assets shall be deemed Confidential Information of Purchaser, and Sellers shall be deemed the receiving Party of such Confidential Information. In the event that such protective order or other remedy is not obtained or the other Party waives compliance with the provisions of this Section 5. In the event a Party is required to file a Form 8-K, such Party shall provide the other Party with a copy of such Form 8K and such other Party agrees to promptly review such disclosure within one (1) Business Day of receipt of such Form 8-K. In addition, such Party shall prepare a proposed redacted version of this Agreement to request confidential treatment for this Agreement, and the other Party agrees to promptly (and in any event, no less than seven (7) days after receipt of such proposed redactions) give its input in a reasonable manner in order to allow the Party seeking disclosure to file its request within the time lines specified by applicable Law. If both Parties determine that they are required to disclose this Agreement and its terms and conditions in securities filings as described in the first sentence of this Section 5. Each of the Parties shall bear its own expenses incurred in connection with the preparation, execution and performance of this Agreement and the Acquisition, including all fees and expenses of its representatives. Sellers shall indemnify and hold harmless Purchaser and its Affiliates and their respective Representatives (the Purchaser Indemnified Parties from and against any and all Damages incurred by any Purchaser Indemnified Party in connection with any claim, demand, action, proceeding, or investigation relating to or arising from: (i) any breach by a Seller of any warranty or the inaccuracy of any representation of such Seller contained in this Agreement, the Transaction Documents or in any other agreement or instrument contemplated by this Agreement; (ii) any breach by a Seller of any of such Sellers covenants contained in this Agreement, the Transaction Documents or in any other agreement or instrument contemplated by this Agreement; or (iii) the practice of the license set forth in Section 5. Purchaser shall indemnify and hold harmless Sellers and their respective Representatives (the Seller Indemnified Parties from and against any and all Damages incurred by any Seller Indemnified Party in connection with any claim, demand, action, proceeding, or investigation relating to or arising from: (i) any breach by Purchaser of any warranty or the inaccuracy of any representation of Purchaser contained in this Agreement, the Transaction Documents or in any other agreement or instrument contemplated by this Agreement; 16 (ii) any breach by Purchaser of any of Purchasers covenants contained in this Agreement, the Transaction Documents or in any other agreement or instrument contemplated by this Agreement; (iii) any Assumed Liability; and (iv) any third-party claim to the extent Damages resulting therefrom are (i) as a result of the use of, or the research, development, manufacture, commercialization, use or sale of, any Compound or Product by or on behalf of Purchaser or any of its Affiliates or Sublicensees after the Effective Date and (ii) not Damages for which the Purchaser Indemnitees are entitled to seek indemnification pursuant to Section 6. If any action at law or suit in equity is instituted by or against a third party with respect to which any Purchaser Indemnified Party or Seller Indemnified Party (the Indemnified Party believes is reasonably likely to result in Damages under this Section 6. Indemnifying Party shall, promptly and in no event later than five (5) days after receipt of the notice, notify such Indemnified Party whether Indemnifying Party elects to conduct and control such action or suit, but only after confirming in writing to such Indemnified Party that it accepts responsibility to indemnify such Indemnified Party for all Damages arising from such action or suit. If Indemnifying Party provides the foregoing notice, Indemnifying Party shall have the right to conduct and control, at its sole expense and with counsel of its choice (which counsel must be reasonably satisfactory to such Indemnified Party), such action or suit, and such Indemnified Party shall reasonably cooperate in connection therewith; provided that Indemnifying Party shall not settle such action or suit without the prior consent of such Indemnified Party (not to be unreasonably withheld, conditioned or delayed), unless the third-party claimant and Indemnifying Party provide to such Indemnified Party an unqualified release from all liability in respect of such action or suit and such settlement, compromise or judgment does not involve any nonmonetary penalty or admission of fault or liability on the part of such Indemnified Party or its Affiliates. Such Indemnified Party may participate in the defense of such action or suit that is defended by Indemnifying Party with counsel of its choice; provided, however, that the fees and expenses of such Indemnified Partys counsel shall be paid by such Indemnified Party unless (i) Indemnifying Party has agreed in writing to pay such fees and expenses or (ii) such Indemnified Party shall have reasonably determined based on the advice of counsel that a conflict or potential conflict exists between Indemnifying Party and such Indemnified Party that would make such separate representation advisable or there are one or more factual or legal defenses available to such Indemnified Party that are different or in addition to those that are available to Indemnifying Party. Notwithstanding anything to the contrary in this Agreement, and without prejudice to any other right or remedy it has or may have, Purchaser may set off or recoup any indemnification payments owed to it by Seller pursuant to Section 6. By signing this Agreement, each Party agrees to conduct the business contemplated herein in a manner which is compliant with all Laws, including the U. Specifically, each Party agrees that it has not, and covenants that it, its Affiliates, and its and its Affiliates directors, employees, officers, and anyone acting on its behalf, will not, in connection with the performance of this Agreement, directly or indirectly, make, promise, authorize, ratify or offer to make, or take any action in furtherance of, any payment or transfer of anything of value for the purpose of influencing, inducing or rewarding any act, omission or decision to secure an improper advantage; or improperly assisting it in obtaining or retaining business for it or the other Party, or in any way with the purpose or effect of public or commercial bribery. Each Party further represents, warrants and covenants that all books, records, invoices and other documents relating to payments and expenses under this Agreement are and shall be complete and accurate and reflect in reasonable detail the character and amount of transactions and expenditures. Each Party must maintain a system of internal accounting controls reasonably designed to ensure that no off-the-books or similar funds or accounts will be maintained or used in connection with this Agreement. In addition, each Party agrees to ensure that all such employees participate in and complete mandatory compliance training to be conducted by each Party, including specific training on anti-bribery and corruption, in accordance with such Partys standard operating procedures with respect to training. All notices or other communications required or permitted to be given hereunder shall be in writing and shall be delivered by hand or sent by facsimile or email or sent, 18 postage prepaid, by registered, certified or express mail or overnight courier service and shall be deemed given when so delivered by hand or facsimile, upon receipt of confirmation if sent by email, or if mailed, three (3) Business Days after mailing (one Business Day in the case of express mail or overnight courier service), to the parties at the following addresses, facsimiles or email addresses (or at such other address, facsimile or email address for a Party as shall be specified in a notice given in accordance with this Section 6. This Agreement shall be binding upon and inure to the benefit of the Parties named herein and their respective personal representatives, heirs, successors and permitted assigns. No Party may assign either this Agreement or any of its rights, interests or obligations hereunder without the prior written consent of the other Party; provided, that each Party may assign (a) any or all of its rights, interests or obligations hereunder to one or more of its Affiliates or (b) all of its rights, interests and obligations hereunder to its successor in interest in connection with a merger, acquisition or similar transaction or the sale of all or substantially all of its stock or assets. Any permitted assignee shall assume all assigned obligations of its assignor under this Agreement. The terms and conditions of this Agreement shall be binding upon, and shall inure to the benefit of, the Parties and their respected successors and permitted assigns. This Agreement is for the sole benefit of the Parties and their successors and permitted assigns and nothing herein expressed or implied shall give or be construed to give to any Person, other than the Parties and such successors and assigns, any legal or equitable rights hereunder. The courts of the State 19 of Delaware shall have jurisdiction with respect to any dispute between the Parties arising under or in connection with this Agreement, and the Parties submit to the jurisdiction of those courts 6. Any final decision mutually agreed to by the said Executives shall be in writing and shall be conclusive and binding on the Parties. The descriptive headings contained in this Agreement are included for convenience of reference only and shall not affect in any way the meaning or interpretation of this Agreement. The Parties have participated jointly in the negotiation and drafting of this Agreement. In the event an ambiguity or question of intent or interpretation arises, this Agreement shall be construed as if drafted jointly by the Parties, and no presumption or burden of proof shall arise favoring or disfavoring any Party by virtue of the authorship of any provisions of this Agreement. This Agreement (including the Schedules and Exhibits attached hereto) and [***] executed in connection with the consummation of the [***], contain the entire agreement between the Parties with respect to the subject matter hereof and related transactions and supersede all prior agreements, written or oral, with respect thereto. The Parties agree that irreparable damage would occur in the event that any of the provisions of this Agreement were not performed in accordance with their specific terms or were otherwise breached or threatened to be breached and that an award of money damages would be inadequate in such event. Accordingly, it is acknowledged that the Parties shall be entitled to equitable relief, without proof of actual damages, to enforce performance of this Agreement in accordance with its terms, including an Order for specific performance, to prevent 20 breaches of this Agreement and to enforce specifically the terms and provisions of this Agreement, in addition to any other remedy under this Agreement. Each Party further agrees that neither the other Party nor any other Person shall be required to obtain, furnish or post any bond or similar instrument in connection with or as a condition to obtaining any remedy referred to in this Section 6. This Agreement may be amended, superseded, canceled, renewed or extended only by a written instrument signed by all of the Parties. B) or claims of foreign counterparts thereof, or claims of patents issuing thereof which are directed to subject matter specifically described in the patent applications listed in Appendix 1.

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Sexually transmitted diseases tend to occur more commonly in younger, more sexually active individuals. Coliform bacterial urethritis may be seen with complicated urinary fistulous disease or associated with anal intercourse. Rates are higher in men than in women, partially due to the fact that signs and symptoms in men are often more obvious. All patients should have a mid-stream clean-catch collection or catheter collected urinalysis with microscopic studies and urine culture prior to initiation of antimicrobial treatment. Urinary symptoms, pyuria, bacteriuria, and evidence of active inflammatory changes in the urine such as the presence of nitrite and leukocyte esterase may warrant empiric treatment prior to culture and sensitivity reporting. Urinary infection is less likely in the absence of pyuria and may require urine culture data for verification. Conversely, pyuria without bacteriuria may indicate 5 an atypical infectious aetiology such as genito-urinary tuberculosis, staghorn calculi, or other urinary stone disease. Finally, serum leukocytosis and positive blood cultures may indicate a complicated urinary infection in an acutely ill patient. Some helpful studies include intravenous urography, ultrasonography, computed tomography, and cystography. Ultrasonography may aid in the differentiation of epididymitis from testicular torsion. Fullness of the testicular tail with ipsilateral increased epididymo-testicular blood flow indicates the diagnosis of epididymitis. Once adherent, the bacteria may ascend or descend the upper or lower urinary tract. Upper tract infections may range from uncomplicated to complicated, with the former requiring close outpatient follow-up with oral antimicrobials and the latter requiring hospitalization, catheterization or operative care. Although lower urinary tract infections are often less problematic, all cases of symptomatic urinary infection require antimicrobial treatment regardless of the locus. These medications allow for excellent urinary coverage of most uropathogens and provide tissue penetration for parenchymal infectious diseases such as pyelonephritis and prostatitis. Trimethoprim-sulfamethoxazole is an alternative medication; in many cases, it is less effective and it has a high incidence of microbial resistance. Complicated infections with enterobacter species, pseudomonas or gram-negative bacilli may require combination therapy with aminoglycosides and ampicillin or broad-spectrum cephalosporins. Uncomplicated pyelonephritis usually requires fourteen days of therapy for complete resolution. In this scenario, urine cultures should be repeated after five to seven days of therapy to ensure adequate response. Lower urinary infections in men should raise suspicion of concomitant prostatic infection. In the case of prostatic infection, treatment should continue for 21 days or longer, ensuring negative urine cultures at the conclusion of therapy. Typically, gonococcal and chlamydial infections are found simultaneously in up to 50 per cent of patients presenting with urethritis subsequent to suspicious sexual encounters. For this reason, these patients should be covered for both diseases and screened for the others previously mentioned. Assurance of no idiosyncratic reaction to appropriate culture-driven antimicrobial therapy. In childhood, diminished renal function commonly serves as the presenting factor to diagnosis of an anomaly. In adulthood, urological evaluations for haematuria, infection and nephroureterolithiasis commonly uncover congenital cystic and renal anomalies. These anomalies may also be found incidentally on radiographic evaluations for other problems. They range from simple cysts and collecting system duplications to major anatomical problems that may cause end stage renal dysfunction and other systemic illness. They are commonly oval to round in shape, with a smooth outline bordered by a single layer of flattened epithelium and contain a clear or straw-coloured fluid. Simple renal cysts are commonly found in individuals during the third decade of life or later. Although the disease is characterized by dilation of the papillary ducts of the renal medulla, renal function is usually normal. Bilateral disease will nearly always be identified early in childhood, as commonly seen in autosomal recessive juvenile or infant polycystic kidney disease. It is an autosomally dominant acquired condition that commonly presents in later life. Other associated anomalies include hepatic, pancreatic, splenic, and pulmonary cysts as well as colonic diverticula, and mitral valve prolapse. Renal hypoplasia is defined as an absent or adult kidney that weighs less than 50 g. The other kidney may compensate so well by physiologic hypertrophy that the condition is undetectable except by radiographic imaging. This isthmus prevents normal renal ascent during development at the point of the inferior mesenteric artery. Complications of this congenital anomaly may include infection, stone disease and, later, arterial hypertension. Once the condition is identified, some references recommend routine screening for these complications. Complications may include kinking of ureters, obstruction of urinary flow, hypertension and pain. If there are no complications and the patient is asymptomatic with normal function of the kidney, the condition has little aeromedical significance. In most cases it has no aeromedical significance, but occasionally it may be associated with obstruction and stasis of urine. Anaemia or elevated serum creatinine may also be found during initial presentation. Intracerebral arterial haemorrhage may be a presenting sign for this disease, secondary to the hypertension seen in this population. Of the infants that survive, approximately 50 per cent are alive at age 10, and some of those are completely asymptomatic throughout their lives. Obviously, the natural history of this disease makes it a rare diagnosis for the aeromedical examiner. The other congenital anomalies mentioned are usually radiographically identified after clinical presentation of nephroureteral stone disease, haematuria, infection, hypertension, abdominal mass, or other symptoms. Using ultrasound, a common simple cyst reveals the absence of internal echoes, a sharply defined wall, good sound transmission through the cyst with acoustic enhancement behind the cyst, and a spherical or ovoid shape. Cysts may be found by the same technique in other organ systems such as the liver or pancreas. Symptomatic distension of the renal capsule, obstruction of the collecting system or infection may warrant percutaneous treatment, sclerosis or even laparoscopic or open operative excision. Hypercalciuria associated with the disease induces stone formation, and thus thiazides or inorganic phosphates are effective for lowering hypercalciuria and limiting stone formation. Phosphate administration may increase the risk of infectious stone development in the presence of urease-producing bacteria. Simple cystic disease is compatible with flight as long as the cysts do not result in mechanical compromise to the kidney, collecting system or renal vasculature. Pyelonephritis and nephrolithiasis are common, with potential sequelae including septicaemia and renal failure in symptomatic patients. Effective use of the drugs listed above decreases complications and increases the chance of resuming aviation duties. Adult polycystic kidney disease may threaten the safety of flight and so should only be considered with limitation to multi-crew operations. Any aeromedical disposition of an applicant or aviator with polycystic kidney disease should be done in consultation with a specialist and the medical assessor of the Licensing Authority. Normal renal function studies, absence of symptoms, and no evidence of infectious, obstructive or congenital disease are signs of a good prognosis. In such cases, unilateral agenesis and hypoplasia are of no clinical significance and are not at increased risk to interfere with aviation duties.


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Compounds that, following such Brickell Change of Control, are developed, made or otherwise acquired or controlled by the Successor without use of Brickells Confidential Information (as defined in the Agreement) shall not be deemed [***]. Unless otherwise specified in writing, the mailing addresses of the Parties shall be as described below: If to Brickell: [***] With a copy to: [***] If to Kaken: [***] With a copy to: [***] 3. This Amendment shall be effective as of the date of receipt by Brickell of the Development Milestone 1 Payment pursuant to Section 8. At the time Brickell issues the [***], Brickell shall also physically or electronically deliver to Kaken, or provide Kaken access via secure electronic data room (any such delivery method, make available, and made available shall have a corresponding meaning) all material data related to [***], including from such [***], that Brickell then possesses (the [***] ). Upon Brickells receipt of the [***], Kaken shall have a period of [***] with Brickell [***]concerning the terms of an [***]. At the time Brickell issues the [***], Brickell shall make available to Kaken [***]. Upon Brickells receipt of the [***], Kaken shall have a period of [***] (the [***]) to negotiate [***]. Nothing in this Section 2 shall restrict Brickell or its affiliates from negotiating with, soliciting proposals from, entering into agreements with, or providing information to, (x) its own actual and potential advisors, agents and representatives and/or (y) any third party contract research organization or contract manufacture or other service provider. Licensor and Licensee are each individually referred to herein as a Party and collectively referred to as the Parties. For purposes of this definition, control shall mean the ownership of at least fifty percent (50%) of the voting stock of such entity or any other comparable equity or ownership interest, or (a) in the absence of the ownership of at least fifty percent (50%) of the voting stock of a corporation, or (b) in the case of a non-corporate business entity, possession, directly or indirectly, the power to direct, or cause the direction of, the management and policies of such entity whether through the ownership or control of voting securities, by contract or otherwise. Licensor hereby grants to Licensee an [***], license under the Licensed Patents and Licensed Know-How in the Field within the Territory to [***] Licensed Product. Any sublicense granted by Licensee to any Sublicensee shall be subject to a written sublicense agreement that contains terms and conditions that (a) impose obligations that are comparable to the obligations applicable to Licensee under this Agreement including, but not limited to, the audit rights set forth in Section 3. Without limiting the foregoing, each such sublicense agreement shall provide that Licensor is a third party beneficiary of such sublicense agreement, with the right to enforce the terms thereof in the event that Licensee does not enforce its rights. Licensee shall notify Licensor in writing of the grant of any such sublicense within ten (10) days thereof, which notice shall identify the Sublicensee and shall be accompanied by a copy of the applicable sublicense agreement. The terms of such sublicense agreements, and the identity of all Sublicensees shall be Confidential Information (as defined below) of Licensee. Licensee shall use Commercially Reasonable Efforts to monitor the performance of any Sublicensee under any sublicense granted pursuant to this Section 2. Licensor shall not be permitted, and shall cause its Affiliates to refrain from the practice of any rights granted to Licensee under this Article 2 in the Field in the Territory during the Term of this Agreement. During the Term of this Agreement, Licensor shall not grant to any third party any right or license whatsoever under the Licensed Patents or Licensed Know-How in the Field. Any new Invention or discovery, whether patentable or not, made solely by Licensee or in combination with any third party, as a result of the exercise of this Agreement, shall be Licensees property. The Parties shall reasonably cooperate in any patent application procedures for inventions or discoveries made under this section at Licensees expense. Except as expressly set forth herein, this Agreement does not grant to Licensee any right, title, interest, ownership or license by implication, estoppel or otherwise, to any intellectual property rights of Licensor. Licensee shall use [***] at its own cost and expense to develop a Licensed Product, to conduct all development necessary to obtain regulatory approval to market such Licensed Product, and to commercialize such Licensed Product, according to the applicable completion date listed in the table below for the Licensed Product. Licensee will deliver to Licensor an annual updated development plan for the Licensed Product (the Development Plan no later than January 31 of each year during the Term. The Development Plan will include, at a minimum, the information listed in Exhibit B Exhibit B ). Where the Licensee fails to [***] the Licensed Product in accordance with the Development Plan and Diligence Events, and fails to diligently undertake actions to remedy any such deficiency, and where mediation has failed to accomplish a satisfactory resolution, the Licensor may consider such failure to be a material breach under this Agreement and shall have the right to terminate this Agreement pursuant to Section 4. On or before the Effective Date of this Agreement, Licensor shall provide Licensee with a copy of all tangible materials and information in its possession related to or involving the Licensed Patents. Such information and materials shall generally include but not be limited to all patent correspondence, patent searches, patent files, patent landscaping, inventor disclosures, and patent applications and schedules. Licensor shall provide and make available to Licensee all manufacturing information and data, all formulation information and data, and all clinical and pre-clinical data, including toxicity data, whether submitted or not, as part of any Investigative New Drug Application or New Drug Application filing of Licensor or its sublicensees or Affiliates with respect to a Licensed Product subject to provisions of confidentiality. Licensor agrees to use its reasonable efforts to identify and make available inventors and any key scientific personnel to discuss research, development and commercialization activities as reasonably required. Each Party will make available, at no cost, data and any reports, including but not limited to full study reports, of any non-clinical and/or clinical study in animals or humans, related to the Licensed Patents and Licensed Know-How, on a confidential basis within sixty (60) days of the generation of same, such that: (i) Licensor may share such data with any other party, on a confidential basis, as background information in respect of any other non-competing application outside of the Field and have the right to reference any or all such data, (ii) Licensee may share such data, on a confidential basis, as background information to its Affiliates, financing sources, and potential investors and have the right to reference any or all such data for 4 development of Licensed Product in the Field only, and (iii) Licensee shall utilize such data to ensure full compliance with the regulatory authorities and to inform future development of the Licensed Product, provided neither party shall be required to disclose internally developed information to any competitor without the permission of the developing party. As consideration for the rights and licenses granted by Licensor to Licensee hereunder, Licensee agrees to pay Licensor the following amounts at the following times: 3. Licensee shall pay to Licensor milestone payments (each, a Milestone Payment as set forth in the following table [***] if and when each Milestone Event is achieved. Licensee shall notify Licensor promptly in writing (but in each case within thirty (30) days) of its achievement of each Milestone Event. Each Milestone Payment (other than Upfront payments) shall be due within sixty (60) days following the achievement of the applicable Milestone Event. The activities undertaken and the results achieved from all clinical development efforts shall be made available to Licensor on a confidential basis and in a timely manner, subject to Section 2. Licensee will pay a royalty to Licensor [***] Patent Royalty or collectively, Patent Royalties ). During the term of this Agreement, should Licensee enter into any sublicense with an unaffiliated third party Sublicensee for the sale of Licensed Products Sublicensing Agreement ), the rate for Patent Royalties payable to Licensor shall be in accordance with the following schedule based on the patent royalty rate set forth in the Sublicensing Agreement (the Sublicensee Patent Royalty Rate ): 5 [***] [***] [***] [***] [***] [***] 3. The Royalty on Net Sales of Licensed Products shall be [***] upon a [***] to any [***]. After [***] by Licensee or Sublicensees of a Licensed Product for which a Patent Royalty is payable under this Article 3, Licensee shall make quarterly written reports to Licensor within forty-five (45) days after the end of each calendar quarter, stating in each such report the number, description, Gross Sales, and itemized Net Sales of such Licensed Product sold during the calendar quarter. Simultaneously with the delivery of each such report, Licensee shall pay to Licensor the Patent Royalty, if any, due to Licensor for the period of such report. Such reports shall be Confidential Information of Licensee subject to Article 5, herein. Where any currency conversion is to be made in connection with the calculation of any amounts hereunder, such conversion shall be made using the selling exchange rate for conversion of the foreign currency into U. In addition to any other rights and remedies of Licensor under this Agreement, any amounts owed to Licensor under this Agreement shall, if not paid when due, accrue interest at a rate that is the lesser of [***]. Licensee shall maintain, and shall cause its Sublicensees to maintain, complete and accurate books and records relating solely to Net Sales of the Licensed Product and any amounts payable to Licensor under this Agreement, which records shall contain sufficient information to permit Licensor to confirm the accuracy of any reports delivered to Licensor hereunder. Licensor shall have the right to inspect Licensees books and records as needed in Licensors reasonable discretion. The term of this Agreement shall commence on the Effective Date, and shall continue in full force and effect until either (i) termination by either Party in accordance with Section 4. For purposes of this paragraph, Cause shall mean any material breach of any material provision of this Agreement by Licensor that is not cured within sixty (60) days after receipt by Licensor of written notice thereof from Licensee or, in the event that cure is not possible within such sixty (60) day period, Licensor shall have taken reasonable steps to ensure that the breach is cured as soon as reasonably possible. Licensor may terminate this Agreement (i) for Cause or (ii) immediately upon written notice to Licensee if Licensee or any Sublicensee brings a patent challenge against Licensor, or assists others in bringing a patent challenge against Licensor (except as required under a court order or subpoena). For purposes of this paragraph, Cause shall mean any material breach of any material provision of this Agreement by Licensee that is not cured within sixty (60) days after receipt by Licensee of written notice thereof from Licensor or, in the event that cure is not possible within such sixty (60) day period, Licensee shall have taken reasonable steps to ensure that the breach is cured as soon as reasonably possible; provided, however, that if the material breach is non-payment to Licensor of amounts due, then Licensee shall have sixty (60) days to cure, except in circumstances where there is a good faith dispute between the Parties as to sums due and owing and the Parties are engaged in a dispute resolution process to determine the legitimacy of any demand for sums due and any undisputed amounts are paid in full. Either Party may, by written notice, terminate this Agreement with immediate effect if the other Party: (i) makes a general assignment for the benefit of creditors; (ii) files an insolvency petition in bankruptcy; (iii) petitions for or acquiesces in the appointment of any receiver, trustee or similar officer to liquidate or conserve its business or any substantial part of its assets; (iv) commences proceeding involving its insolvency, bankruptcy, reorganization, adjustment of debt, dissolution, liquidation or any other similar proceeding for the release of financially distressed debtors under the laws of any jurisdiction; or (v) becomes a party to any proceeding or action of the type described above in (iii) or (iv), and such proceeding or actions remains =dismissed or =stayed for a period of more than ninety (90) days. Licensee may terminate this Agreement without cause, upon providing sixty (60) days written notice to Licensor by certified mail. The foregoing shall be in addition to any other rights of Licensee against Licensor pursuant to this Agreement or applicable law. The foregoing shall be in addition to any other rights of Licensor against Licensee pursuant to this Agreement or applicable law and (ii) Licensee shall promptly return to Licensor all Licensor Confidential Information, and all other documentation in the possession of Licensee relating to the Licensed Products, including, without limitation, all studies, data, protocols, materials, results and regulatory filings. Licensee shall promptly return to Licensor all Licensor Confidential Information, and all other documentation in the possession of Licensee relating to the Licensed Products, including, without limitation, all studies, results and regulatory filings. 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Similar reductions have been reported in other studies,8911though Zigler et al used 3 months 29. The nine patients in the confidence intervals, the data are consistent with who withdrew after surgery experienced a reduction in a wide range of differences between the groups, includ- Oswestry score of 30. As there is no consensus based agreement of the surgical group we found a similar net back to how large a difference between groups must be to be of work rate as reported by Fritzell et al. Table 7 | Unplanned analysis in secondary outcomes in patients with low back pain and degenerative disc randomised to disc prosthesis surgery or rehabilitation. To our Self efficacy?? knowledge, there are no specific criteria to determine Baseline 3. It is still effect might be higher in the surgical group, although possible, however, that patients in the rehabilitation the possible placebo effect of rehabilitation over sev- group found themselves faced with more of the eral weeks with personal contact with a therapist same. We be argued that the patients included in the study wanted to avoid the postoperative treatment contain- wanted surgery, but the number of patients not want- ing elements from the rehabilitation programme. At ference in treatment effect between patients who did six weeks, however, patients could be referred if and did not believe in surgery,45and a recent study required to a physiotherapist at their home for func- found no significant relation between baseline tional mobilisation and general muscle training. The potential long term revision rate with a prosthesis has been at least equivalent higher complication rate on revisions needs to be Compared with multidisciplinary rehabilitation, improvement in disability and pain are considered. Some studies have Oswestry disability index and variables measuring disability and pain, although the examined these issues but more information is difference in Oswestry score between groups was lower than the study was designed to needed. A full multivariate analysis of good Furthermore, some surgical patients underwent a sec- outcomes will be published soon to answer these ques- ond operation but repeat rehabilitation was not consid- tions. Patients did not request a second chance for degeneration in the facet joints of the operated level. Another weakness in our study eration of the operated level in addition to a full health is the difference in compliance between groups and the economic analysis will be published later. This difference in adherence to the the total blood loss and operation time were higher protocol probably leads to an underestimate of the true in our study than in similar studies. The learning curve effect of surgery,especially in the intention to treat ana- might be quite flat, and perhaps the participating sur- lysis. In similar studies comparing surgery with rehabi- 639-41 geons should have carried out disc prosthesis surgery litation, the drop-out rates were similar to ours. Using a the patients we included in our study were highly surgeon to expose the disc (access surgeon), might also selected, with one or two level degenerative changes have reduced the blood loss and operation time. Thus, our results are valid menthal et al and Zigler et al performed one level sur- only in similar patients. Furthermore, we examined gery, while a third of our patients underwent two level several secondary outcome variables that could lead 89 surgery. This could explain some of the increased to the detection of differences by chance. Because we conducted several unplanned analyses (not of the complexity of the surgery and the risk of serious recorded in the original protocol), in common with complications, we think this kind of surgery should be similar studies, we consider it as an important asset to confined to a few specialist centres with experienced our data. Lately, similar studies have applied repeated 40 spine surgeons and available vascular surgeons. Using high quality rehabilitation programmeshould be avail- unplanned analysis could be considered a weakness, able. Nevertheless, Our study was not designed to evaluate specific caution should be used in interpreting the results of mechanisms of reduction of pain and disability. Even thoughwe didnot havea controlgroup, perioperative vascular injury rate for anterior lumbar the mixed causes of chronic low back pain, the associa- interbody fusion was 0-18% (mean 3%). No major differences and the considerable improvement in the rehabilita- in complication rates between insertion of a disc pros- tion group suggest that it is reasonable to consider a thesis and fusion have been found in a randomised rehabilitation programme before surgery. Although vascular complications lectures for the rehabilitation intervention; Hege Andresen at St Olavs Hospital,Trondheim,fordatacoordination;PerFarupatStOlavsHospital, are reported, serious consequences like amputation 43 Trondheim, for organising the web randomisation system; Astrid and mortality are rare. Recently Kurtz et al looked Woodhouse and Kirsti Vanvik from St Olavs Hospital for performing the at the rates of short term revision and mortality total two year control; and Lucy Hyatt for paid editorial assistance. Four retrospective studies have reported long (department of neurosurgery), and Franz Hintringer, Anita Dimmen term reoperation rates of up to 13%. Spine disorders, department of neurosurgery), Bjorn Skogstad, Janne Birgitte 2007;32:1155-62. Prospective, randomized, multicenter Food and Drug department of physical medicine and rehabilitation). Total disc Vibeche Iversen, Ellen H Haldorsen, Elin Karin Johnsen, Kristin Hannestad replacement compared to lumbar fusion: a randomised controlled (Outpatient Spine Clinic, department of physical medicine and trial with 2-year follow-up. Total disc replacement surgery for symptomatic Oslo University Hospital, Oslo (53 patients): Vegard Slettemoen, degenerative lumbar disc disease: a systematic review of the Kenneth Nilsen, Kjersti Sunde, Helene E Skaara (department of literature. The reproducibility of quantitative measurements Contributors: All authors had full access to the data, were responsible for in lumbar magnetic resonance imaging of children from the general study concept and design, and critically revised the manuscript for population. Spine Competing interests: All authors have completed the Unified Competing 2000;25:2940-53. Ethical approval: the study was evaluated and approved by the regional 22 Euroquol Group. EuroQol?a new facility for the measurement of committees for medical research ethics in east Norway and all health-related quality of life. Churchill Livingstone, evaluation of a scale to measure perceived self-efficacy in people 2004. Predicting who develops chronic low back pain in Pract Res Clin Rheumatol 2005;19:593-607. Back performance scale for 3 Fritzell P, Hagg O, Wessberg P, Nordwall A, for the Swedish Lumbar the assessment of mobility-related activities in people with back Spine Study Group. Toward uniformity in evaluating pain: a multicenter randomized controlled trial from the Swedish results of lumbar spine operations. The clinical importance of changes in Randomized clinical trial of lumbar instrumented fusion and outcomescoresaftertreatmentforchroniclowbackpain. EurSpineJ cognitive intervention and exercises in patients with chronic low 2003;12:12-20. Randomised controlled trial to compare surgical stabilisation of the 33 Nachemson A. Spine J yearfollow-upof surgicalversus non-surgicaltherapy forchroniclow 2004;4:27-35. A prospective, randomized, multicenter Food and Drug versus placebo for the treatment of chronic discogenic low back Administration investigational device exemptions study of lumbar pain. Vascular injury and complication in clinical, x-ray, and magnetic resonance imaging investigation. We would like to provide our perspective that might be helpful in evaluating your decision. Transesophageal echocardiographic diagnosis of left atrial appendage occluder device infection. Percutaneous closure of the left atrial appendage in atrial fibrillation: An alternative if standard treatment fails Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: A randomized non-inferiority trial. Left atrial appendage obliteration; Mechanisms of healing and intracardiac integration. The incidence and long-term clinical outcome of iatrogenic atrial septal defects secondary to transseptal catheterization with a 12F transseptal sheath. Percutaneous left atrial appendage closure for stroke prevention in patients with atrial fibrillation: An assessment of net clinical benefit. Viles-Gonzalez J, Kar S, Douglas P, Dukkipati S, Feldman T, Horton R, Holmes D, Reddy V. Left atrial appendage closure: A percutaneous transcatheter approach for stroke prevention in atrial fibrillation. Percutaneous left atrial appendage closure for stroke prophylaxis in patients with atrial fibrillation: 2. Percutaneous Left Atrial Appendage Closure vs Warfarin for Atrial Fibrillation: A randomized clinical trial. Left atrial appendage closure as an alternative to warfarin for stroke prevention in atrial fibrillation: a patient meta-analysis. We will restrict our comments to potential topic number 3 on your list Left Trustees for Life Frank J. Thank you once again for the opportunity to provide comments on these proposed list of topics.

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However, a recent cord, dorsal root ganglion, motor cortex, and 181 systematic review found that decompression deep brain stimulation, provides pain relief with fusion was not superior to decompression throughmodulationofthenervoussystem. Spi- alone for lumbar spinal stenosis and concluded nal cord stimulation, the most widely used neuro- that the efcacy of various surgical treatments stimulation technique, involves placement of remains uncertain. This technique scores at 2- to 4-year follow-up were similar exerts its analgesic effects by stimulating large, in patients randomized to undergo spinal fast-conducting sensory bers, thereby inhibiting fusion or cognitive behavioral-based pain the slower-conducting A-delta and C nociceptive 182,183 rehabilitation. In is associated with more preserved range of essence, conventional spinal cord stimulation motion than is spinal fusion and, in some acts by creating an area of paresthesia within contexts, may be superior to spinal fusion the anatomical distribution of pain, though 1712 Mayo Clin Proc. One of the most widely diagnostic imaging can potentially diminish the recognized indications for neurostimulation is re- risk of unnecessary resource utilization. Multiple fractory radicular pain in association with failed pharmacological trials exist for both axial and 187 back surgery syndrome. Although the evi- radicular pain; however, the long-term outcomes dence supporting neurostimulation for axial of commonly used drugs remain mixed. The in- including medications, injections, and physical dications for performing the various lumbar modalities. However, the referred to as pain pumps or morphine pumps, general indications for commonly performed op- administer medications directly to the intrathecal erations include spinal decompression for radic- 189 space. A broad array of subcutaneously to a programmable reservoir physical modalities and psychological treatments pump that is typically implanted in the subcu- can improve pain and functioning, but individual taneous tissues of the lower abdominal region. Classication and management of low back pain: Is dicators of serious underlying pathology are ac- this the right direction Chymopapain for the treatment of intervertebral chronic low back pain and does age play a role Recurrence of radic- the relationships between age, gender, and body mass index ular pain or back pain after nonsurgical treatment of symp- and the source of chronic low back pain. Prevalence of lumbar spinal stenosis: a longitudinal cohort study over a min- neuropathic pain among patients with chronic low-back pain imum of 10 years. Micankova Adamova B, Vohanka S, Dusek L, Jarkovsky J, ment of neuropathic symptoms and signs pain scale. The effect of decompression neuropathic back and leg pain: a cross-sectional study. The natural course of lumbar Assessment of Neuropathic Symptoms and Signs pain scale. Lumbar spinal stenosis: conservative or surgical man- pathic pain among patients suffering from chronic low back agement Lumbosacral transitional vertebrae: clas- Epidural steroids: a comprehensive, evidence-based review. Clinical signicance of congenital lumbosacral mal- pathic origin in the community. Lumbosacral transitional verte- disk-related sciatica in an urban population in Tunisia. Lumbosacral transitional risk factors for new-onset sciatica in Japanese workers: ndings vertebra in a population-based study of 5860 individuals: prev- from the Japan epidemiological research of Occupation- alence and relationship to low back pain. Biochemical and structural tients with recent onset low back pain in Australian primary properties of the cartilage end-plate and its relation to the care: inception cohort study. Disco- non-specic low back pain: a systematic review of prospective genic low back pain. Nonoperative treatment of herniated lumbar lumbar zygapophysial (facet) joint pain. Pathomechanism of loss of pain: a study in an Australian population with chronic low elasticity and hypertrophy of lumbar ligamentum avum in back pain. Pathomechanism of ligamen- from the lumbar zygapophysial joints: is the lumbar facet syn- tum avum hypertrophy: a multidisciplinary investigation drome a clinical entity Lumbar spinal stenosis in the elderly: predictors of screening lumbar zygapophyseal joint blocks: an overview. During physiolog- spinal muscle function, perception of lumbar position, and ical motions. Dynamic changes of elasticity, joint anesthesia: proposed criteria to identify patients with cross-sectional area, and fat inltration of multidus at painful facet joints. Clinical predictors of success and failure for in paraspinal muscles and their association with low back pain lumbar facet radiofrequency denervation. Trunk ble block and value of sacroiliac pain provocation tests in 54 muscle recruitment patterns in specic chronic low back pain patients with low back pain. Sacroiliac joint pain: a associated with narrower lumbar intervertebral discs, high fat comprehensive review of epidemiology, diagnosis and treat- content of paraspinal muscles and low back pain and disability. Correlation of clinical examina- ment Subcommittee of the American College of Physicians; tion characteristics with three sources of chronic low back American College of Physicians; American Pain Society Low pain. Diagnosis of back pain: a joint clinical practice guideline from the American sacroiliac joint pain: validity of individual provocation tests College of Physicians and the American Pain Society [pub- and composites of tests. Diagnostic validity of criteria for and screening for serious spinal pathology in patients present- sacroiliac joint pain: a systematic review. Red ags to syndrome: diagnostic criteria and treatment of a monocen- screen for malignancy and fracture in patients with low back tric series of 250 patients. Red ags to ophysiology of axial low back pain: disc, posterior elements, screen for vertebral fracture in patients presenting with low- sacroiliac joint, and associated pain generators. Myofascial low back pain: a re- criteria and treatment of discogenic pain: a systematic review view. Mondelli M, Aretini A, Arrigucci U, Ginanneschi F, amination for lumbar radiculopathy due to disc herniation in Greco G, Sicurelli F. Does this older adult study evaluating lateral branch radiofrequency denervation with lower extremity pain have the clinical syndrome of lum- for sacroiliac joint pain. Pathophysiology, diagnosis and treatment of domized, comparative cost-effectiveness study comparing 0, intermittent claudication in patients with lumbar canal steno- 1, and 2 diagnostic medial branch (facet joint nerve) block sis. The evidence for phar- ment results or decision making in patients with lumbosacral macological treatment of neuropathic pain. Curr Med Res care utilization and costs associated with adherence to clinical Opin. Biondi D, Xiang J, Benson C, Etropolski M, Moskovitz B, among workers with acute occupational low back pain. The efcacy and safety of pregabalin in the treatment care from the American College of Physicians [published of neuropathic pain associated with chronic lumbosacral rad- correction appears in Ann Intern Med. In- rect comparison of randomised clinical trials in chronic low jection therapy for subacute and chronic low back pain: an back pain. Factors associated with failure of vertebral bone edema (Modic type 1 changes): a double- lumbar epidural steroids. The use of intradiscal nercept, or saline in subacute sciatica: a multicenter, random- steroid therapy for lumbar spinal discogenic pain: a random- ized trial. Intradiscal etanercept, compared with dexamethasone for treatment steroids: a prospective double-blind clinical trial. Spine (Phila of sciatica in patients with lumbar spinal stenosis: a prospec- Pa 1976). Randomized,double-blind, discal etanercept in patients with chronic discogenic low back placebo-controlled, trial of transforaminal epidural etanercept for pain or lumbosacral radiculopathy. Exercise interventions for placebo-controlled trial of intradiscal methylene blue injection the treatment of chronic low back pain: a systematic review for the treatment of chronic discogenic low back pain. A systematic review [published online ahead of print methylene blue injection for the chronic discogenic low June 18, 2015]. The cal electrothermal therapy for the treatment of discogenic low effectiveness of Pilates exercise in people with chronic back pain. What are patient trothermal therapy versus placebo for the treatment of beliefs and perceptions about exercise for nonspecic chronic chronic discogenic low back pain. Massage for low controlled trial of intra-annular radiofrequency thermal disc back pain: an updated systematic review within the framework therapyda 12-month follow-up. Effectiveness of acupuncture for chronic low back pain in active-duty soldiers: 2-year follow- nonspecic chronic low back pain: a systematic review and up. Assessment: efcacy of transcutaneous replacement versus fusion for lumbar degenerative disc dis- electric nerve stimulation in the treatment of pain in neurologic ease: a meta-analysis of randomized controlled trials. Living with chronic low back pain: a pain and degenerative disc: two year follow-up of randomised metasynthesis of qualitative research. Multidisciplinary quency with spinal cord stimulation: burst and high- biopsychosocial rehabilitation for chronic low back pain. Mindfulness-based system for the treatment of chronic pain and ischemic dis- stress reduction for low back pain: a systematic review. Surgery versus conservative ference 2012: recommendations for the management of pain treatment for symptomatic lumbar spinal stenosis: a systematic by intrathecal (intraspinal) drug delivery: report of an interdis- review of randomized controlled trials.

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Only patients that meet the criteria described in the indications should be selected. Any patient in which implant utilization would interfere with anatomical structures or expected physi- 2. Patient conditions and / or predispositions such as those addressed in the aforementioned contrain- ological performance. Devices should be protected during storage especially from corrosive environments. The surgeon should be familiar with the various devices before use and should personally verify that all devices are present before the surgery begins. The size of device for the case should be determined prior to beginning the surgery. Adverse effects may occur when the device is used either with or without associated instrumentation. At all times, extreme caution should be used around the spinal cord and nerve roots. Foreign body reaction to the implants including possible tumor formation, auto immune disease, and/ 3. Breakage, slippage, or misuse of instruments or implants may cause injury to the patient or opera- or scarring. To assure proper fusion below and around the location of the fusion, autogenous bone graft must 5. When used via a posterior approach, supplemental posterior instrumentation is recommended. Posterior supplemental fixation is limited to Medtronic Sofamor Danek posterior instrumentation systems. Bone cement should not be used, because this material may make removal of these components 9. Loss of neurological function, appearance of radiculopathy, dural tears, and/or development of pain. The physicians postoperative directions and warnings to the patient and the corresponding patient com- 11. The patient must be warned that loosening, and/or breakage of the device(s) are complications which may occur as result of early or excessive weight-bearing, muscular activity or sudden jolts or shock to the spine. The patient should be advised not to smoke or consume excess alcohol, during period of the bone fusion process. The patient should be advised of the inability to bend at the point of spinal fusion and taught to com- pensate for this permanent physical restriction in body motion. It is important that immobilization of union is established and confirmed by roentgenographic examination. If a non-union develops or if the components loosen, migrate, and / or break, the devices should be revised and / or removed immediately before serious injury occurs. Any retrieved devices should be treated in such a manner that reuse in another surgical procedure is not possible. If a loaner or consignment system is used, all sets should be carefully checked for completeness and all components including instruments should be carefully checked to ensure that there is no damage prior to use. Cleaning and disinfecting of instruments can be performed with aldehyde-free solvents at higher temperatures. Cleaning and decon- tamination must include the use of neutral cleaners followed by a deionized water rinse. Note: Certain cleaning solutions such as those containing formalin, glutaraldehyde, bleach and/or other alkaline cleaners may damage some devices, particularly instruments; these solutions should not be used. Once the seal on the package has been broken, the product should not be re-sterilized. When supplemental fixation is used, refer to the package insert of the supplemental instrumentation for sterilization information. When filing a complaint, please provide the component(s) name and number, lot number(s), your name and address, the nature of the complaint and notification of whether a written report from the distributor is requested. Contact Customer Service or your Sales Representative for the most up-to-date version of the package insert. Instruction by a surgeon experienced in handling these products is highly recommended. Reprocessing, Care and Maintenance For general guidelines, function control and dismantling of multi-part instruments, please contact your local sales representative or refer to: emea. It is specially designed for small incision, resulting in a relatively atraumatic operation for the patient. Implants provide an adequate stability, restore height and lordosis to provide an optimized fusion. A specic goal in the spine is returning as much function as possible to the injured neural elements. Stable internal fixation Stabilization of the spinal segment to promote bony fusion. Early, active mobilization Minimization of damage to the spinal vasculature, dura, and neural elements, which may contribute to pain reduction and improved function for the patient. Use a standard transforaminal approach for inser- tion of 28 mm and 32 mm spacers (Figure 1). Use a traditional bilateral posterior approach for insertion of 24 mm spacers (Figure 2). Shavers and excision instruments for intervertebral discs can facilitate removal of the nucleus pulposus and the surface layers of the cartilaginous endplates. Note: Appropriate cleaning of the endplates is im- portant for the vascularisation of the bone trans- plant. Excessive cleaning however can weaken the endplates by removing bone under the cartilaginous layers. Removal of the entire endplate can cause subsidence and lead to loss of segmental stability. Gently impact on the end of the trial implant until the implant is positioned across the midline and 3mm?4mm from the anterior longitudinal ligament. When the trial implant reaches the appropriate depth, rotate 90? clockwise to distract and assess height adequacy (5). Repeat using the next larger size trial implant, sequen- tially distracting until adequate anterior height is ob- tained. Continue to impact on the end of the trial implant until the cage is positioned across the midline and 3 mm? 4mm from the anterior longitudinal ligament. With the segment fully distracted, the trial im- plant must t tightly and accurately inside the disc space. Provisionally tighten the construct on the contralateral side to ensure that the height in the anterior column is maintained. If removal of the trial implant requires too much force, the slide hammer can be used. While holding the handle of the trial implant with one hand, apply an upward force to the slide hammer with the other hand. Attach the knob to the distal end of the implant holder sleeve by turning the knob counterclockwise (1). Insert the shaft into the sleeve making sure to align 2 3 the arrows on the end of the shaft with those on the sleeve (2). Press the button on the distal end of the implant holder and push the shaft into the holder (3). Turn the knob at the distal end of the implant holder counterclockwise to open the jaws. Place the jaws over the posterior end of the cage making sure that the jaws base is rmly seated against the implant. Turn the knob on the end of the implant holder clockwise until the jaws of the implant holder have a tight grip on the cage. It is important to ll the implant until the lling material protrudes from its perforations in order to ensure opti- mal contact with the vertebral endplates. Use the cancellous bone impactor to pack the lling material into the implant cavities. The implant holder must be frmly attached to the implant in order to avoid damage to the implant holder. Orient the cage so that the lateral graft window is facing the vertebral endplate.

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Option 1: Use of the Reamer-Distractor One side of the working end has a smooth surface that may be applied to the endplates to distract the intervertebral space. The smallest reamer-distractor is inserted horizontally into the intervertebral space; the widest part of the instrument facing medial/lateral and the thinnest part facing superior/ Figure 8b - Turn instrument 90? to distract and scrape the endplates. When 20mm long Cages are to be used, it is recommended that the posterior wall of the vertebral body be fush with the 25mm mark on the reamer-distractor. For 25mm long Cages, it is recommended that the posterior wall of the vertebral body be fush with the 30mm mark on the reamer-distractor. For 30mm and 33mm long Cages, it is recommended that the posterior wall Figure 8c - Measure depth. Examination of the material removed with the reamer- distractor helps to determine whether the endplates have been suffciently prepared. If the material removed with the reamer-distractor is white (debris from the annulus fbrosus or cartilage), a larger reamer needs to be used to reach the subchondral bone. Figure 9 - Rotate reamer-distractor Figure 10 - Serial insertion of Reamer-distractors of progressively to scrape endplates. The fnal reamer-distractor is temporarily left in the vertical position on the contralateral side to maintain the disc space distraction. A small distractor is inserted horizontally into the intervertebral space and then turned 90? to distract it. The graduations on the instrument in- dicate the depth of the opening made in the disc. If using a 20mm long cage, it is recommended that the posterior wall of the vertebral body be fush with the 25mm mark on the distractor. For the 25mm long cage, it is recommended that the posterior wall of the vertebral body be fush with the 30mm mark on the distractor. For 30mm and 33mm long cages, it is recommended that the posterior wall Figure 12c - Measure depth. The fnal distractor is temporarily left in position to maintain the disc space distraction. This precautionary measure is taken to prevent contact of the cutting edges of the reamer with the dura mater or nerve roots. Examination of the material removed helps to determine whether the Figure 14a - Gentle impaction Figure 14b - Rotate clockwise to endplates have been suffciently without rotation. If the material removed from the reamer is white (debris from the annulus fbrosus or cartilage), a larger reamer needs to be used to reach the subchondral bone. Curettes may be used to complete the preparation of the parts of the endplates that are not accessible with the reamer. The cage is screwed onto the cage impactor and slipped into the cage support, where it is flled with pieces of autologous bone or other bone grafting material. The compacted graft should be fush with the upper and lower surfaces of the cage, to be in contact with the endplates. Option accessible, the contralateral distractor is left in place during the Cage placement. Option the Cage distracts the endplates, due in part to its bulleted ogival or wedge shape. The distractor is removed and the steps are repeated on the contralateral side of the intervertebral space. One marker is positioned horizontally at the end of the wedge nose, and the other marker is positioned vertically at the posterior aspect of the implant. On a true lateral fuoroscopic view of implants centered from left to right within the disc space, the vertical posterior markers and anterior horizontal markers will appear as depicted. Align the outter chamfered shaft with the contours of the implant and thread the internal shaft into the implant and remove it. The construct is then placed under compression to ensure proper contact between the vertebral endplates and the bone graft material inside of the Cages. Cages are intended to be used with supplemental spinal fxa- tion systems that have been cleared for use in the lumbosacral spine. Please refer to the surgical technique of any additional Stryker System before use. Description (height x length x lordosis-width) (height x length x lordosis-width) (height x length x lordosis-width) Without lordosis - 0? Lordosis - 4? Lordosis - 8? Width 09 mm - Length 20mm Width 09 mm - Length 20mm Width 09 mm - Length 20mm 6760090 Cage 9x20x0? - 9 6760074 Cage 7x20x4? - 9 6760098 Cage 9x20x8? - 9 6760100 Cage 10x20x0? - 9 6760084 Cage 8x20x4? - 9 6760108 Cage 10x20x8? - 9 6760110 Cage 11x20x0? - 9 6760094 Cage 9x20x4? - 9 6760118 Cage 11x20x8? - 9 6760120 Cage 12x20x0? - 9 6760104 Cage 10x20x4? - 9 6760128 Cage 12x20x8? - 9 6760130 Cage 13x20x0? - 9 6760114 Cage 11x20x4? - 9 6760138 Cage 13x20x8? - 9 6760140 Cage 14x20x0? - 9 6760124 Cage 12x20x4? - 9 6760148 Cage 14x20x8? - 9 6760150 Cage 15x20x0? - 9 6760134 Cage 13x20x4? - 9 6760158 Cage 15x20x8? - 9 6760160 Cage 16x20x0? - 9 6760144 Cage 14x20x4? - 9 6760168 Cage 16x20x8? - 9 6760154 Cage 15x20x4? - 9 Width 11 mm - Length 20mm Width 11 mm - Length 20mm 6760164 Cage 16x20x4? - 9 673090 Cage 9x20x0? - 11 67310098 Cage 9x20x8? - 11 673100 Cage 10x20x0? - 11 Width 11 mm - Length 20mm 67310108 Cage 10x20x8? - 11 673110 Cage 11x20x0? - 11 673094 Cage 9x20x4? - 11 67310118 Cage 11x20x8? - 11 673120 Cage 12x20x0? - 11 673104 Cage 10x20x4? - 11 67310128 Cage 12x20x8? - 11 673130 Cage 13x20x0? - 11 673114 Cage 11x20x4? - 11 67310138 Cage 13x20x8? - 11 67310140 Cage 14x20x0? - 11 673124 Cage 12x20x4? - 11 67310148 Cage 14x20x8? - 11 67310150 Cage 15x20x0? - 11 673134 Cage 13x20x4? - 11 67310158 Cage 15x20x8? - 11 67310160 Cage 16x20x0? - 11 67310144 Cage 14x20x4? - 11 67310168 Cage 16x20x8? - 11 67310154 Cage 15x20x4? - 11 Width 08 mm - Length 25mm Width 08 mm - Length 25mm 67310164 Cage 16x20x4? - 11 6765090 Cage 9x25x0? - 8 6765098 Cage 9x25x8? - 8 6765100 Cage 10x25x0? - 8 Width 08 mm - Length 25mm 6765108 Cage 10x25x8? - 8 6765110 Cage 11x25x0? - 8 6765074 Cage 7x25x4? - 8 6765118 Cage 11x25x8? - 8 6765120 Cage 12x25x0? - 8 6765084 Cage 8x25x0? - 8 6765128 Cage 12x25x8? - 8 6765130 Cage 13x25x0? - 8 6765094 Cage 9x25x4? - 8 6765138 Cage 13x25x8? - 8 6765140 Cage 14x25x0? - 8 6765104 Cage 10x25x4? - 8 6765148 Cage 14x25x8? - 8 6765150 Cage 15x25x0? - 8 6765114 Cage 11x25x4? - 8 6765158 Cage 15x25x8? - 8 6765160 Cage 16x25x0? - 8 6765124 Cage 12x25x4? - 8 6765168 Cage 16x25x8? - 8 6765134 Cage 13x25x4? - 8 Width 11 mm - Length 25mm Width 11 mm - Length 25mm 6765144 Cage 14x25x4? - 8 6730900 Cage 9x25x0? - 11 67315098 Cage 9x25x8? - 11 6765154 Cage 15x25x4? - 8 6731000 Cage 10x25x0? - 11 67315108 Cage 10x25x8? - 11 6765164 Cage 16x25x4? - 8 6731100 Cage 11x25x0? - 11 67315118 Cage 11x25x8? - 11 6731200 Cage 12x25x0? - 11 Width 11 mm - Length 25mm 67315128 Cage 12x25x8? - 11 6731300 Cage 13x25x0? - 11 6730904 Cage 9x25x4? - 11 67315138 Cage 13x25x8? - 11 67315140 Cage 14x25x0? - 11 6731004 Cage 10x25x4? - 11 67315148 Cage 14x25x8? - 11 67315150 Cage 15x25x0? - 11 67311104 Cage 11x25x4? - 11 67315158 Cage 15x25x8? - 11 67315160 Cage 16x25x0? - 11 6731204 Cage 12x25x4? - 11 67315168 Cage 16x25x8? - 11 6731304 Cage 13x25x4? - 11 Width 11 mm - Length 30mm 67315144 Cage 14x25x4? - 11 6731060 Cage 6x30x0? - 11 67315154 Cage 15x25x4? - 11 6731070 Cage 7x30x0? - 11 67315164 Cage 16x25x4? - 11 6731080 Cage 8x30x0? - 11 6731090 Cage 9x30x0? - 11 6731100 Cage 10x30x0? - 11 67311100 Cage 11x30x0? - 11 6731120 Cage 12x30x0? - 11 6731130 Cage 13x30x0? - 11 Width 11 mm - Length 33mm 6733060 Cage 6x33x0? - 11 6733070 Cage 7x33x0? - 11 6733080 Cage 8x33x0? - 11 6733090 Cage 9x33x0? - 11 6733100 Cage 10x33x0? - 11 67331100 Cage 11x33x0? - 11 6733120 Cage 12x33x0? - 11 6733130 Cage 13x33x0? - 11 19 Titanium Cage Instrument Reference Numbers Reference Numbers Ref. While rare, would preclude the potential beneft of spinal gin with degeneration of the disc conformed intraoperative fracture or breakage of instru- implant surgery, such as the presence of by history and radiographic studies. Instruments which have ex- tumors, congenital abnormalities, elevation patients may also have up to Grade I spondy- perienced extensive use or extensive force are of sedimentation rate unexplained by other lolisthesis at the involved level(s). Surgeons must dis- with supplemental spinal fxation systems that have acquired blemishes or latent compromise cuss the relative contraindications with the have been cleared for use in the lumbosacral of its integrity which would reduce its service patients spine. Particular discussion should systems because this is a technically demand- important. The operating surgeon must avoid be directed to the issues of premature weight ing procedure presenting a risk of serious in- notching or scratching the device. The surgeon must warn the patient plantation, patient weight, patient activity lev- the skin to the materials that make up the im- that the device cannot and does not replicate el, other patient conditions, etc. If fusion device must be performed only by expe- fully weighed against the patients overall eval- the patient is involved in an occupation or ac- rienced spinal surgeons with specifc training uation. Circumstances listed below may reduce tivity which applies inordinate stress upon the in the use of this device because this is a tech- the chances of a successful outcome: implant (e. Any abnormality present which affects the been shown to have an increased incidence of intervertebral body fusion device, which may normal process of bone remodeling non-unions. Surgeons must advise patients of require additional surgery, include: device including, but not limited to, severe osteo this fact and warn of the potential consequenc- component fracture, loss of fxation, pseudoar- porosis involving the spine, bone absorption, es. The surgical indication and the choice of im- use or extensive force, are more susceptible to. Patients having inadequate tissue coverage of plants must take into account certain impor- fracture depending on the operative precau- the operative site. Instruments must be examined for unsafe load level on the device during the that applies excessive loading upon the im wear or damage prior to surgery. An overweight or obese patient can ing, or muscle strain) may be at increased provided non-sterile and must be sterilized produce loads on the spinal system which can risk for failure of the fusion and/or the de prior to use. These conditions, among oth excessive loading through patient weight or and other minor surgical procedures have been ers, may cause the patient to ignore certain activity, and be taught to govern their associated with transient bacteremia. A condition of senility, mental illness, chemi must instruct patients to report any unusual stress shielding of the graft or fusion mass. These condi- changes of the operative site to his/her physi- this may contribute to failure of an adequate tions among others may cause the patients to cian. Where material sen Include but are not limited to: ture of bone graft or the intervertebral body sitivity is suspected appropriate tests must. Late bone fusion or no visible fusion mass above or below the level of surgery can be made prior to material implantation. Adverse effects may have been shown to have an increased inci- erotopic bone formation and neurovascular necessitate reoperation. Such patients must be compromise, including paralysis; advised of this fact and warned of the. While the expected life of spinal implant Adverse effects may necessitate reoperation potential consequences. The surgeon is respon- expected to indefnitely withstand the activ is not intended to be removed unless the man- sible for this choice which depends on each ity level and loads of normal healthy bone. Any decision by a phy- Patients who are overweight may be respon- matory phenomena; sician to remove the device should take into sible for additional stresses and strains on the. Allergic reactions to the implanted materials consideration such factors as: device which can speed up implant fatigue although uncommon can occur;. The risk to the patient of the additional surgi and/or lead to deformation or failure of the. Decrease in bone density due to stress cal procedure as well as the diffculty of implants. Once implanted, the implants are sub- heterotopic bone formation and neurovas tissue lesions.

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At 1 month, the tibial nerve block groups did not do as well as the non-tibial nerve block groups, but the matter was not discussed. There was no difference among the groups at 3 or 6 months, suggesting that benefit of steroid injection or drawback of tibial nerve block may be short term. In contrast, the other study demonstrated no short- term benefit at 3 weeks, but did demonstrate a long-term benefit at 6 months post injection. Heels were divided between placebo and 25mg hydrocortisone injection with no significant differences found at short- and long-term follow-up. This study has potential methodological flaws, including duration of plantar pain at initiation. There was no statistical analysis presented between the steroid and steroid-pad groups, but a trend towards better scores in the injection alone group was presented. Injection should be performed at the point of maximal tenderness by palpation rather than with ultrasound or other guidance techniques. Ruptures may have long-term sequelae, including longitudinal arch strain, lateral plantar nerve dysfunction, stress fracture, hammer toe deformity, and antalgia. Overall, corticosteroid injections are minimally invasive, are of moderate cost, and are recommended after other non-operative options have been tried for patients who have chronic or recalcitrant plantar fasciitis. Data lignocaine Local anesthetic patient comfort suggest hydrochloride plus tibial nerve from glucocorticostero given after a block: anaesthetizing id injection tibial nerve 5. No substance to comparisons not 1 or statistical analysis inject, but its provided. All both provided but author advantage subjects given heels states not over saline heel cups. Data suggest no benefit from 25mg hydrocortisone, which may have been a suboptimal dosage. Maudsley score at 6 Triamcinolone months: Group C, salt and dose excellent and good not specified. Plantar significant thickness, fat betamethason fascia, fat pad difference pad thickness). Strength of Evidence ? No Recommendation, Insufficient Evidence (I) Level of Confidence ? Low Rationale for Recommendation There are no quality trials for plantar fascia hyperosmolar dextrose injection. In a case series of 20 consecutive patients treated with sonographically guided injections of hyperosmolar dextrose and lidocaine in patients with plantar fasciitis of 6 months duration, 16 reported good or excellent results with 4 unchanged. Ultrasound guidance of injection was also described, although the necessity of this technique is also undefined. Therefore, there is no recommendation for or against the use of hyperosmolar dextrose injection into the plantar fascia. Evidence for the Use of Hyperosmolar Dextrose for Plantar Fasciitis There are no quality trials evaluating the use of hyperosmolar dextrose injections for plantar fasciitis. Recommendation: Platelet Rich Plasma Injections for Plantar Fasciitis There is no recommendation for or against the use of platelet rich plasma injections for treatment of plantar fasciitis. There is a case series report suggesting therapeutic efficacy, which suggests future trials of this intervention are indicated. Therefore, there is no recommendation for or against the use of platelet rich plasma injection into the plantar fascia. Evidence for the Use of Platelet Rich Plasma for Plantar Fasciitis There are no quality trials evaluating the use of platelet rich plasma injections for plantar fasciitis. Recommendation: Cryosurgery for Chronic Plantar Heel Pain There is no recommendation for or against the use of cryosurgery for treatment of chronic plantar heel pain. Recommendation: Cryosurgery for Acute or Subacute Plantar Heel Pain Cryosurgery is not recommended for treatment of acute or subacute plantar heel pain. Strength of Evidence ? Not Recommended, Insufficient Evidence (I) Level of Confidence ? Low Rationale for Recommendations There are no quality trials for percutaneous cryosurgery. A prospective case series reported 77% success in 137 feet at 3 weeks and 24 months in patients with chronic plantar heel pain. Although potentially promising, further studies are needed, thus there is no recommendation for or against its use to treat plantar heel pain. Evidence for the Use of Cryosurgery for Plantar Fasciitis There are no quality trials incorporated into this analysis. Strength of Evidence ? Moderately Recommended, Evidence (B) Level of Confidence ? Moderate Rationale for Recommendation There is one high-quality placebo-controlled trial performed as a pilot study that suggested pain relief and satisfaction compared with sham treatment in a small population of chronic plantar heel pain and radiographic spur. Author/Year Score Sample Comparison Results Conclusion Comments Study Type (0-11) Size Group Dogramaci 8. Strength of Evidence ? No Recommendation, Insufficient Evidence (I) Level of Confidence ? Low Rationale for Recommendation There are no quality trials for percutaneous bone fenestration. A prospective case series of 38 feet reported 100% success rates 12 months post-operatively in patients with chronic plantar heel pain. Although potentially promising, further studies are needed, and thus there is no recommendation for or against its use. Evidence for the Use of Percutaneous Bone Fenestration for Plantar Heel Pain There are no quality trials incorporated into this analysis. This technique involves application of radiofrequency cautery through 10 to 20 percutaneous sites into the superficial tissue and plantar fascia. Strength of Evidence ? No Recommendation, Insufficient Evidence (I) Level of Confidence ? Low Rationale for Recommendation There are no quality trials evaluating radiofrequency microtenotomy for plantar fasciitis. Although potentially promising, further studies are needed, thus there is no recommendation for or against its use. Evidence for the Use of Radiofrequency Microtenotomy for Plantar Fasciitis There are no quality trials incorporated into this analysis. Surgical Considerations Plantar fascia release is performed in 5 to 7% of patients treated for plantar fasciitis(199, 313) (Faraj 02, Davies 99) as a last resort when other therapies have failed. Recommendation: Surgery for Select Chronic Recalcitrant Plantar Fasciitis Surgical release is recommended for select chronic recalcitrant plantar fasciitis. Indications ? Moderate to severe chronic plantar fasciitis patients who have failed multiple non- surgical treatments and whose condition has lasted at least 6 to 12 months. Recommendation: Surgery for Acute or Subacute Plantar Fasciitis Surgical release is not recommended for treatment of acute or subacute plantar fasciitis. Strength of Evidence ? Not Recommended, Insufficient Evidence (I) Level of Confidence ? High Rationale for Recommendations ? Copyright 2016 Reed Group, Ltd. Plantar fasciotomy is reported to have a complete pain relief success rate of 44%,(313) (Faraj 02) 50%,(199) (Davies 99) 61%,(314) (Conflitti 04) 68%,(315) (Hogan 04) and 69%. Thus, while surgery appears to provide complete relief to about half of patients, it is not without significant risk of complication, expense, and lack of comparison data to other non-surgical interventions. Therefore, surgery is recommended as an intervention after at least 6 months of other non-operative treatments have been attempted and the patients symptoms are sufficient to warrant the risks of surgical intervention. Evidence for the Use of Surgery for Plantar Fasciitis There are no quality trials incorporated into this analysis. Foot Ulceration Foot ulcers that arise out of occupational trauma, burns, infection, or other occupational disease. Foot ulcers may be painless; but may be accompanied by pain, burning, or itching; and may be infected. Pressure ulcers develop as a result of pressure, force or friction concentrated on a small area over a bone of the foot. Treatment options for foot ulcerations include local wound care, surgical intervention and topical nerve growth factors. Initial Assessment Assessment of foot ulcer should exclude diagnoses that need aggressive or highly restrictive treatment, or involve inadequately treated underlying disease. The patient should be assessed for cardiovascular disease, diabetes, inflammatory disorders, peripheral neuropathy, systemic and localized infection. Ensure that the patient is free of fever and chills, compromise of skin in other areas than the affected foot, and sensory changes. Physical Examination the size, depth, and location of and condition of the area surrounding an ulcer should be recorded. Check for exudate, odor, tunneling, undermining, sinus tracts, necrosis or eschar formation, infection, and signs of healing (granulation and epithelialization). Assess the wound margins and areas around the wound, including for induration, and tracking of infection or inflammation. Sensation of the foot and bone and joint deformities should be carefully assessed. Evaluation of perfusion of the foot and ankle, including dorsalis pedis and posterior tibial pulses, and of capillary refill is helpful.


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Nkx family genes are mostly observed in mesodermal derivatives; in particular, Nkx2. This family of genes is composed of two independent functional domains: the T-box in the large N-terminal region and a transcriptional activation/repression domain in the C-terminal region. The Brachyury (or T) mouse mutant is characterized by a truncated tail and was discovered about 80 years ago. Until recently, 17 genes were identified as T-box family genes in vertebrates, and genetic analyses of individual genes have progressed significantly. These analyses indicate that T- box genes are widely involved in developmental processes of mesoderm specification (Naiche et al. In humans, mutations in T-box genes, including deletions, rearrangements, missense mutations, insertions, and truncation, lead to various genetic disorders (Packham and Brook, 2003). The phenotypes of T-box gene knockout mice can be compared with the phenotypes of several human genetic disorders. Tbx1-/- mice have a lethal phenotype in late gestation and display a wide range of developmental abnormalities including facial abnormalities, cleft palate, cardiac outflow tract defects, and hypoplasia of the thymus and parathyroid glands (Jerome and Papaioannou, 2001; Merscher et al. Tbx1 is located in a region spanning 3 Mb, but another genes are also located in this region. Tbx3-/- mice show a deficiency of mammary gland induction, genital abnormalities, and forelimb and hind limb malformations, and die during gestation(Davenport et al. Many similarities are exhibited in the phenotype, but gene dose sensitivities are different between humans and mice. Tbx4-/- mutants have problems with the allantoic connection to the placenta and die early in embryogenesis (Naiche and Papaioannou, 2003). Tbx5-/- resulted in early embryonic lethality due to severe defects in early heart formation (Bruneau et al. Holt-Oram syndrome is an autosomal dominant disorder that includes cardiac and upper limb malformations. Tbx5+/- mutants faithfully recapitulate the human phenotype, including cardiac defects and forelimb malformations. The Tbx22-/- mutation caused death within 24 hr after birth due to submucous cleft palate and ankyloglossia (Pauws et al. In humans, Tbx22 is a gene responsible for X-linked cleft palate and ankyloglossia (Braybrook et al. Developmental toxicants Teratology is the study of abnormal development and congenital malformations attributed to genetic factors, maternal factors, toxicants, or other factors such as environmental chemicals. These principles are still applied today and guide the investigation of teratogenic agents and their effects on the development of organisms. A wide variety of chemicals and environmental factors are believed to have teratogenic potential in humans and animals. These five categories (A, B, C, D, and X) have been considered a therapeutic advantage but they are only based on specific criteria and are not universal. Therefore, the number of these factors is likely higher than one thousand and is increasing daily. The teratogenic potentials of various chemicals and environmental factors are determined using animal models (e. In the past, observations of the characteristics of embryos from candidate-exposed pregnant animals were used as the main criteria, but current teratological evaluations need to include knowledge about the molecular mechanisms. In this section, six xenobiotics known to be developmental toxicants in humans were selected for further description. In adults, the role of the endocrine system in the maintenance of homeostasis is established and adults therefore have resistance against endocrine disruptors. However, in the fetus, infants, and children, resistance against these agents may be weak and they therefore can have irreversible impact on developmental functions such as organ formation. Hox Genes and Teratogenic Factors 9 Endocrine disruptors are found in low doses in products of daily use. Estrogen and androgen are sex steroids that are needed for the proper development of reproductive organs (Dupont et al. Each steroid binds to a specific nuclear-receptor and these receptors act as ligand-dependent transcription factors. Alterations in Hox gene expression induced by endocrine disruptors is thus considered to be a nuclear receptor- mediated mechanism. Exposed offspring also experienced a high incidence of pregnancy wastage and preterm labor. Under this rule, Hoxa9 is normally expressed in the oviduct and Hoxa10 in the uterus. However, reports of the teratogenic potency of thalidomide appeared in the early 1960s. In these reports, infants exposed to thalidomide during the early stages of pregnancy had multiple defects, such as malformations of the limbs, ears, eyes, internal organs and central nervous system. The most commonly observed defects were limb malformations including amelia (complete absence of the limb) and phocomelia (truncation or absence of the zeugopod). Thalidomide-induced limb defects are observed in humans, monkeys, rabbits and chicks, but these phenotypes are not observed in the mouse or rat (Vargesson, 2009). Thalidomide is a derivative of glutamic acid and contains two imide rings: glutarimide and phthalimide. Thalidomide has therefore been believed to act by causing biochemical alterations of glutamic acid, nucleic acids and vitamin B. Recently, the primary target of thalidomide was identified and parts of the molecular mechanism were revealed (Ito et al. Generally, the limb has three developmental axes: the proximal-distal axis, which runs from the base of the limb to the tip; the A-P axis, which runs parallel with the body axis; and the D-V axis, which runs from the back of the hand to the palm. Under the control of these three axes, various positional identities are specified by the concentration gradient of diffusible factors, such as Fgfs, Bmps, Wnt, and Sonic Hedgehog. The malformed fin or limb in knockdown Crbn zebrafish or the dominant negative form of Crbn expressing chicken, respectively, indicated the important role of the ubiquitin ligase pathway for morphogenesis through thalidomide, and clearly showed that the reduction of Fgf8 expression lead to the deformity of the limb. Although there is no information about the specific target molecule of Crbn, identification of this target molecule will allow a more effective use of thalidomide for the treatment of multiple myeloma and erythema nodosum leprosum and avoid its associated teratogenic risks. Retinoic acid is one of the morphogens that function during the formation of various organs such as the head, trunk, limbs, heart, and the central nervous system. Retinol and other retinoid compounds, which are precursors of retinoic acid, cannot be synthesized de novo and must therefore be ingested in food or supplements. After modification of ingested retinol by multiple enzymes, the resulting compounds bind to ligand-activated nuclear receptors, namely Rar (retinoic acid receptor) and Rxr (retinoid X receptor). Rar and Rxr are concurrently encoded by three family genes (,, and), and subtypes exist that are products of alternative splicing or different promoter usage. Some target genes have been identified and these genes function in the cell cycle, proliferation, and morphogenesis (Delacroix et al. Infants exposed during gestation have teratogenic syndrome including craniofacial abnormalities and defects of the Hox Genes and Teratogenic Factors 11 thymic, cardiovascular, and central nervous system. The teratogenic effect is observed in other animal models, such as mouse, rat, pig, rabbit, dog, chick, and monkey. The dosage and timing of gestational exposure profoundly influence the form of the birth defect and the lethality, but differences in the genetic background in mice also have an effect. The peak period of sensitivity for a given tissue appears to be during the development of the primordial structures. Rar and Rxr knockout mice were produced by several methods and these mice exhibited various phenotypes (Mark et al. However, their abnormalities were restricted to a subset of tissues normally expressing these receptors, probably reflecting the existence of functional redundancies between nuclear receptors. Dioxin is an environmental contaminant and is unintentionally generated as a by-product of industrial combustion. Differences in the exposure dosage determine the resulting phenotypes, which include cleft palate, hydronephrosis, and defects of sex organs. The molecular mechanisms of the xenobiotic dioxin pathway can be understood through the analyses of nuclear receptors. The toxicant and teratogenic effects of dioxin are thought to depend on the activation of the Ahr (aryl hydorocarbon receptor) pathway.

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Although the next session will focus on implementation of activities, suggest that they try to engage in at least one of their chosen activities before the next meeting. During Session 7, Veterans will solidify the activities that they wish to pursue and develop a concrete plan for implementation. In all activity scheduling, pacing should be used to maintain a balanced approach. If Veterans are still uncertain about activities that they would like to adopt, more time should be spent discussing the list of possibilities and any other considerations. Activities such as excessive television watching or computer activities are discouraged due to their passive or often solitary nature. Once two to three activities have been identifed, scheduling these activities into each week will increase the likelihood that Veterans will follow through with implementation. Remind patients of the benefts of increasing pleasurable activities such as improved mood and increased socialization, as well as a healthy distraction from pain. It is important that the activities chosen as well as the schedule devised is feasible for Veterans to achieve. Creating an unrealistic plan only sets the stage for lack of completion and the accompanying negative emotions. Remind Veterans to use pacing and discuss in detail how it may be applied to their chosen activities. Use the Pleasant Activities Schedule to plan how the selected activities will be implemented over the next week. Encourage Veterans to start with easily achievable activities in order to develop a sense of mastery, and move to more diffcult tasks after some profciency has been established. Veterans may feel motivated to expand the schedule of activities after initial successes have boosted mood and self-esteem. It may be helpful to provide a reminder that when adopting a new activity, the enjoyment may increase over time like with the guitar example from last session. Review not only the day or days of the week that will be best for the activity, but the time of day, location, frequency, and other relevant information. Being specifc will help Veterans visualize enacting the plan, which has several benefts. First, it will bring attention to barriers that may be encountered and these can be addressed in session. For example, if a Veteran wants to play basketball, what if it is raining and the outdoor court is not an option If Veterans have a clear picture when they leave session of what they will do and what to expect, they are more likely to implement activities as discussed. Therapist Manual 71 Scheduling activities helps improve daily functioning, so encourage patients to have something planned each day, balancing physical activity with leisure and recreational activity. Therapist:Consider the following exchange between Reggie and his therapist regarding creating a plan to engage in pleasant activities:From our discussions, you said that lately you spend most of your time sitting in the recliner. However, it appears that you have a lot of interests, like listening to music, going fshing, spending time with your grandchildren, attending church functions. Therapist: What are some of the reasons that you havent gone to your granddaughters games or coached her at the house Therapist: What are your thoughts about creating a plan for engaging in these activities I plan to start going to services again this weekend, I already told my wife and she told my kids so everyones expecting me. Anticipating Obstacles Discuss anticipated barriers to Veterans participation in scheduled activities and collaboratively brainstorm possible solutions or backup plans. These issues may arise during Session 6 while reviewing activity options or in Session 7 when discussing how Veterans will implement activities into their lives. Remind Veterans that having a positive distraction can help take their minds off of pain, even if temporarily. Discuss the importance of having pleasant activities to improve wellbeing and increase effectiveness in other areas. Encourage behavioral trials to test negative expectations and start with activities that are comfortable. Remind them of the biopsychosocial model, and the infuence of activity and mood on pain experience. Tell Veterans that pushing themselves to engage in the behavior, even when they dont feel like it, will improve their mood and overall motivation to try again. Once their plan is complete, request that they track their progress and note, not only when they participated in the scheduled activity but, when they did not and why. Remind patients that multiple attempts are common and provide reassurance that through collaboration with the therapist they will fnd an activity schedule that is realistic and enhances their lives. Session 8 focuses on understanding the dynamic interplay between thoughts and pain, and recognizing common cognitive distortions. This will help Veterans gain awareness about how their thoughts relate to pain or negative mood. Session 9 helps Veterans actively challenge negative thoughts with the use of a thought record and coping plan. As pain fails to improve over time, Veterans thoughts may become increasingly negative and exert a greater infuence on pain. Research shows that negative thoughts are directly associated with pain perception (Lawrence, Hoeft, Sheau, & Mackey, 2011). Often times, negative thoughts are automatic and outside of a persons awareness but may still signifcantly impact emotions and behaviors. Veterans will often recognize that with increased stress or negative emotions, they also notice an increase in pain Therapist Manual 73 intensity. While patients may be able to easily identify experiencing emotions such as anger or frustration, discuss that negative thoughts often accompany these feelings and may be a precursor. For example, while waiting at a doctors visit may increase irritability, negative thoughts associated with that experience impact the emotional response (e. Explain to Veterans that all human beings have automatic thoughts that may be negative or positive. The presence of pain, however, sets the stage for an increase in such distorted negative thinking since an uncomfortable stimuli is always present. It may be important to tell Veterans that this is not suggesting that their thoughts have caused their pain; some patients may be sensitive to this as they may feel they have been accused of exaggerating pain in the past. Assure them that while their pain is real, it is also accurate that unhealthy thoughts can negatively impact their pain experience in direct and indirect ways; conversely, having more adaptive thoughts can have a positive impact on their pain experience. Today we are going to talk about something different - how your thoughts can affect your pain and how changing them can help improve your satisfaction with life. Negative thoughts also get in the way of doing the things that we know help make pain better. For example, you may have thought, My pain is never going to get better, or I cant do anything with this pain. This chain reaction of negative, unhealthy thinking, feeling upset, avoiding others, and not using active coping skills is the cycle that we are trying to break! Ask Veterans for one or two negative thoughts they have in response to their pain. Discuss the downward spiral that can contribute to increased anxiety, tension, and pain followed by isolation and avoidance. In this session these will be introduced to Veterans through the use of the Pain Thoughts Handout, which includes all-or-none thinking, should statements, and emotional reasoning. While it is not necessary to review this entire list with Veterans, applying the appropriate labels to the examples on the handout and those provided by patients may be helpful. It is important to make note of one cognitive distortion in particular: catastrophizing. Catastrophizing, or believing the worst, is particularly salient in the treatment of pain as it has consistently been associated with important pain-related outcomes. Catastrophizing is characterized by the tendency to magnify the threat value of pain and to feel helpless in the context of pain. In addition to presenting the types of cognitive distortions, the Pain Thoughts Handout also provides examples of these unhelpful thoughts as well as alternatives that are more balanced and healthy. Clarify to Veterans that since many of these thoughts happen without conscious awareness, this initial process requires some effort. While they may occur at any time, they are most likely to occur during situations that are stressful, painful, or a combination of the two. Therapist: When you notice yourself experiencing a negative emotion ? you feel angry, depressed, anxious, or annoyed, that is a sign to pay attention to your thoughts.


  • https://www.health.gov.au/sites/default/files/documents/2020/03/coronavirus-covid-19-frequently-asked-questions_5.pdf
  • https://www.rxabbvie.com/pdf/humira.pdf
  • https://books.google.com/books?id=AY5nDwAAQBAJ&pg=PA861-IA1&lpg=PA861-IA1&dq=Liver+Enzymes+.pdf&source=bl&ots=WPBc6eNixE&sig=ACfU3U2AAwS_v7_-t6jIzn7oX-2zLm_15w&hl=en

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