Surgical meshes, in particular those used to repair hernias, have been in use since 1891. Since then, research in the area has expanded, given the vast number of post-surgery complications such as infection, fibrosis, adhesions, mesh rejection, and hernia recurrence. Researchers have focused on the analysis and implementation of a wide range of materials: meshes with different fiber size and porosity, a variety of manufacturing methods, and certainly a variety of surgical and implantation procedures. Currently, surface modification methods and development of nanofiber based systems are actively being explored as areas of opportunity to retain material strength and increase biocompatibility of available meshes. This review summarizes the history of surgical meshes and presents an overview of commercial surgical meshes, their properties, manufacturing methods, and observed biological response, as well as the requirements for an ideal surgical mesh and potential manufacturing methods. A hernia is defined as a protrusion or projection (prolapse) of an organ through the wall of the cavity where it is normally contained . There aHernias can be uncomfortable and are sometimes accompanied by severe pain, which worsens during bowel movements, urination, heavy lifting, or straining . OccasioHernia repair is one of the most common surgical procedures performed globally. It is estimated that there are over 20 million hernia repair procedures per year worldwide . The numThe use of hernia mesh products to surgically repair or reconstruct anatomical defects has been widely adopted: in fact, more than 80% of hernia repairs performed in United Sates use mesh products . HoweverCurrently, utilized surgical meshes exhibit many but not all of the desired characteristics . TherefoIn 1890, Theodor Billroth suggested that the ideal way to repair hernias was to use a prosthetic material to close the hernia defect . Many maIn 1955, Dr. Francis Usher focused his attention on the materials that could solve existing problems. Nylon, Orlon, Dacron and Teflon were studied and were observed to have a variety of shortcomings such as: foreign body reaction, sepsis, rigidity, fragmentation, loss of tensile strength and encapsulation . All of Today, many surgeons agree that use of a prosthetic mesh is the preferred way to repair hernias. It should be emphasized that in the past, the success of repair was evaluated based on the strength and permanency of the mesh itself, not on the degree of scar tissue or other factors, which subsequently develop in and around the mesh . The bioAlthough the only treatment is surgery, there are new surgical procedures that ameliorate postoperative side effects such as the laparoscopic approach. Open surgery repair is performed by making an incision in the abdomen to identify and dissect the hernia sac through the subcutaneous tissues and fascia. Once the hernia sac is dissected away from any adjacent structures and examined for contents (intestine or any other tissues), these are inserted back into the peritoneal space, and hernia repair is carried out. Repair can be executed in two ways: (1) primary repair and (2) patch or mesh. The first involves sewing the tissue of the abdominal wall using sutures, while the second technique relies in the placement of a mesh to cover the hernia defect and reinforce surrounding tissue, fixing it with fibrin glue, staples or sutures.In the case of a laparoscopic procedure, the surgeon starts by making several small incisions in the abdominal wall surrounding the hernia sac, in order to introduce surgical instruments and a laparoscope. In one of the incisions, carbon dioxide gas is introduced into the abdomen. The mesh or patch is then introduced, unrolled and fixed with staples or tacks. The procedure then continues with the release of the gas from the abdomen and closure of cutaneous incisions with sutures .Most surgical meshes used currently are chemically and physically inert, nontoxic, stable and non-immunogenic. However, none of them are biologically inert, a property related to the mesh physiology and its role into the hernia repair process . ImplantThe introduction of a foreign material into the body triggers a healing response characterized by one of three stereotypical reactions: (1) destruction or lysis, (2) inclusion or tolerance, and (3) rejection or removal. When an implant is introduced into the body, the immune system recognizes it as a foreign material and therefore attempts to destroy it ; immunosInflammation is the reaction of vascularized living tissue to injury and is the primary biological reaction to implanted medical devices. In the case of implanted meshes, the inflammatory response is presented in four stages that are related both temporally and hierarchically . ImmediaWhen the acute inflammatory response is unable to eliminate the injurious agent or restore injured tissue to its normal physiological state, the condition could progress into a state of chronic inflammation, known as second stage of inflammation. In this stage, monocytes that have migrated to the wound site during the acute inflammatory response rapidly differentiate into macrophages. In addition to macrophages, other primary cellular components such as plasma cells and lymphocytes actively contribute to the inflammatory process. Macrophages increasingly populate the area to consume foreign bodies as well as dead organisms and tissue .In most of the cases where chronic inflammation is related to a medical device or biomaterial, the inflammation process will lead to an immune response or foreign body reaction, corresponding to the third stage of inflammation, where chronic inflammation macrophages fuse into a foreign body giant cell as a response to the presence of large foreign bodies . ForeignThe fourth stage of inflammation occurs in the wound healing phase and is characterized by the replacement of damaged tissue with various cells that specialize in secreting extracellular matrix materials to form a scar . Wound hFibroblasts are cells that mediate the wound healing phase. These cells enter the wound site two to five days after the injury occurs, typically once the inflammatory phase has ended. Fibroblasts proliferate at the wound site, reaching peak levels after one to two weeks. The main function of fibroblasts is to synthesize extracellular matrix and collagen to maintain the structural integrity of connective tissues; at the end of the first week, these are the only cells in charge of collagen deposition. Cells involved in the regulation of inflammation, angiogenesis (formation of new blood vessels from preexisting vasculature) and further connective tissue reconstruction attach to, proliferate, and differentiate on the collagen matrix laid down by fibroblasts .From a histological standpoint, the interaction between prosthesis and organism is characterized by three main aspects: size of tissue reaction; cell density; and fibroblastic activity. As mentioned, fibroblastic activity peaks one to two weeks post-wounding, usually on the 8th day for the intraperitoneal plane and on the 10th day for the extraperitoneal plane. The optimum quantity of fibroblasts needed for a successful integration of the mesh is achieved approximately two weeks after wounding. Further accumulation of fibroblasts will cause an inflammatory phase with increased fibrosis and faster prosthesis integration associated with paresthesia and pain. Furthermore, the inflammatory process could cause contraction and shrinkage of the mesh, resulting in adhesions and fistulas, leading to prosthesis rejection and eventually explantation .The wound repair process described above creates a mesh integration due to the conformational changes of the proteins. This integration is progressive, starting from the prosthesis implantation that is accompanied by the foreign body reaction followed by the inclusion of the prosthesis, which occurs within the first two weeks. The process is finalized as the overall strength increases gradually, which last about 12 weeks and results in a relatively less elastic tissue that has only 70–80% of the strength of the native connective tissue .Although integration and collagen deposition that result from the inflammatory response provide long-term strength, as pointed out, an aggressive integration could also be harmful to the tissue that surrounds the wound site causing a severe body reaction, inflammation, fibrosis, infection, and mesh rejection . The fibResearch in abdominal wall repair has provided valuable information on the parameters, properties, and design of the meshes that influence the immune reaction of the body to the prosthesis as well as the optimal parameters to reduce fibrosis ,39. ThesA deterioration of the tensile strength of the mesh or a strained mesh could potentially lead to hernia recurrence or a poor functional result. Hence, materials employed in surgical meshes must possess the minimum mechanical properties necessary to withstand the stresses placed on the abdominal wall. The maximum intra-abdominal pressure generated in a healthy adult occurs when coughing or jumping and is estimated to be approximately 170 mmHg. Given this information, the mesh used to repair abdominal hernias must withstand at least 180 mmHg (20 kPa) before failing .2 as the maximum pressure to be experienced in the intra-abdominal wall), and 32 cm as the longitudinal diameter of the abdominal wall 50], e-PTCommonly, the monofilaments used for surgical meshes have diameters in the range of 100–300 microns . MultifiDuring the knitting process, fibers or yarns are curved to follow a meandering path and not oriented unilaterally as in weaving; therefore, the resulting fabric tends to be much more flexible and elastic than woven fabrics. The basic structure of a knitted fabric consists of courses and wales. Courses are rows running across the width of the fabric, while wales are columns running across the length of the fabric. When the wales are perpendicular to the course of the fiber/yarn, this is called weft knitting. When the courses and wales are approximately parallel to the direction of the fiber/yarn, the process is known as warp knitting . Figure Warp knits and weft knits have been generated for use as implantable meshes to repair specific tissue sites and organs, such as those needed in hernia repair. Because of the looped stitches, the knitted structure is soft, flexible, and stretchable. It easily adapts to the movement of the human body , and hasThe most commonly used systems in the knitting manufacturing process are the Tricot  and RascIn principle, the Tricot knitting machine is very similar to the Raschel knitting; the only difference is the use of spring beard or compound needles instead of the latch needles used in the Raschel knitting machine. In addition, Tricot sinkers not only performed the function of holding down the loops whilst the needles rise as Raschel sinkers, but also support the fabric loops. The small angle of fabric take-away and the type of knitting action in Tricots creates a gentle and lower tension on the knitted fabric, ideal for high-speed production of fine gauge .A double Raschel warp knitting machine (DR 16 EEC/EAC) has 16 guide bars and enables the production of textiles with different yarn materials and counts. The machine is equipped with two different gauges, E18 and E30. This system allows the design of a mesh configuration that could be adjusted to match given design parameters such as size, shape, Young modulus, and porosity . The ultDespite the clinical success and vast body of knowledge that has been gained regarding manufacturing of surgical meshes, material properties, and surgical procedures, it is obvious that the ideal mesh has not been developed. It is well known that meshes still suffer from contraction and/or infection after implantation . FurtherA variety of biocompatible and biodegradable natural and synthetic polymers are being investigated. Extensive research focuses in the development of a bi-layer composite hernia mesh in order to minimize the risk of infections and reduce adhesions on the visceral side ,72. Mate2). The following Most of the recently published literature still presents PP surgical meshes as the “gold standard” though with surface modifications made with materials mentioned in In general, the new composite meshes show highly improved performance regarding peritoneal regeneration and visceral adhesion . These sNanofiber systems made from a large variety of materials have been explored extensively in the last decade. Scaffolds for tissue regeneration are strongly deemed as a potential application of these systems . MimickiNanofibrous structures present several advantages, such as high specific surface area for cell attachment, higher microporous structure and a 3D micro environment for cell–cell and cell–biomaterial contact, these being associated with unique physical and mechanical properties. These structures when compared with commercial surgical meshes possess higher porosity and smaller pore size. These properties make nanofiber systems suitable for biomaterials used in wound care, drug delivery, and scaffolds for tissue regeneration ,44,91.Scaffolds for tissue engineering must possess a porous structure able to facilitate cell migration, a balance between surface hydrophilicity and hydrophobicity for cell attachment, mechanical properties comparable to natural tissue, and biocompatibility. Studies have shown that the abovementioned characteristics are also highly influenced by average diameter of the fibers and pore size. Effective cell attachment and proliferation has been observed in fiber systems with average diameters smaller than 1 µm and average pore size of 14 µm . In commThe application of nanofiber systems has been hampered due to its poor mechanical properties and nanofiber availability. Most of the available studies have focused on nanofibers prepared through solution processes. The properties of the developed fibers can be controlled by different parameters such as utilized solvent, concentration of polymer, processing methods, and ambient conditions. For example, in the case of nanofibers made of polypropylene , decahydronaphthalene  and cyclohexane have been used as preferred solvents. Polypropylene nanofibers prepared with cyclohexane exhibited a rougher surface when compared to the fibers prepared with decalin, suggesting that the surface morphology of the nanofibers depend on the boiling point of each solvent . When st® (FS) [Regarding nanofiber availability, there are several methods to prepare nanofiber systems. These methods include wet chemistry, Electrospinning (ES)  and Forc® (FS)  techniqu® (FS) ,97.Nanofiber systems are certainly showing a strong potential to be used in the next generation of surgical meshes, the increased availability (FS process) will certainly promote the development of practical applications. Nanofiber developed through the FS system have shown promising results regarding adhesion, growth, metabolic activity, proliferation, and viability of 3T3 cells ,102. It In summary, this review synergistically complements recent reviews made in this important area. Surgical meshes have become the system of choice for hernia repair. Even though it is not the optimum method, so far it is the one that has shown a lower rate of recurrence. Currently, there are more than 70 types of meshes commercially available. These are constructed from synthetic materials  and animal tissue. Despite reducing rates of recurrence, hernia repair with surgical meshes still faces adverse effects such as infection, adhesion, and bowel obstruction. Most of these drawbacks are related to the chemical and structural nature of the mesh itself.An optimum integration with the abdominal wall and negligible adhesion on the visceral side are the most important after sought features for the “ideal” mesh. A surgical mesh will trigger one of three different responses from the body: it may be integrated, encapsulated or degraded. In order to have a minimal inflammatory response to better integrate it to the body, it is highly important to improve biocompatibility.To overcome this obstacle, researchers are actively exploring methods to improve biocompatibility, with the goal of developing a mesh that can be effectively incorporated with minimal inflammation and/or infection. Nanofibers have been recently considered as a strong potential intermediary structure to be used as a coating, given their ultralightweight quality, which could contribute to minimize the inflammatory response from the body and given its functional porosity, which could promote cell adhesion and proliferation.


The foremost aim of medical education is improvement of health for all human beings. This is the goal of the World Federation for Medical Education (WFME). The WFME is an international organization representing all medical doctors and teachers, as well as teaching institutions. Along with publishing its workbook, the WFME aims to implement the highest ethical and scientific standards in medical teaching and to encourage the advancement of new instructional tools, learning methods, and innovative management of medical teaching. The worldwide focus of the WFME is on the evaluation of medical trainees, with a concentration on validity, reliability, and fairness of assessment tools .A growing number of publications have stressed the necessity of worldwide evaluations of medical trainees. However, despite the existence of various governmental and non-governmental institutions for certifying and evaluating ophthalmology residents, international consensus and universally accepted standards for this purpose do not yet exist. Nevertheless, as the only international council that conducts medical-specialty examinations, the International Council of Ophthalmology (ICO) investigated the curricula used for ophthalmology trainees in a number of countries. This investigation was designed and reviewed by a working party in order to establish a curriculum for residency training.Currently, there is high global demand for qualified ophthalmologists committed to vigilance and rehabilitation of vision. This need is especially evident in developing countries that lack well-trained specialists. To meet this need, the ICO has established several examinations on topics including basic science, optics and refraction, instrument use, and clinical sciences. Any individual who passes these three-step examinations or any similar examination may attend the advanced ICO examination . These IHowever, to date there are no uniform criteria for evaluation among ICO society members. For instance, the evaluation of residents  is carried out every two years in Malawi, while in Germany a 30-minute oral exam is considered the final assessment exam after a training period of 60 months . Determining the measurable scale to use is the first step in resolving this problem, which by itself is considered a major challenge in creating any international policies. However, if the ICO plans to launch a uniform assessment style among its member societies worldwide, it should establish global policies both for providing clear society databases and contact details and for ensuring the commitment of those societies to the implemented roles. In other words, stakeholders should respect ICO strategies and recognize its exams as equivalent to their national exams. Societies need to appreciate that no real borders exist in the current fast-growing scientific realm. To allude to this fact, we would like to cite a 2010 report in the journal Lancet : “all heIn summary, we believe that the major authorities in the field of ophthalmology should implement uniform, fair, and strict universal standards for the evaluation of ophthalmology residents worldwide. Following implementation of those standards, a continuous quality control and auditing approach should be used. In addition, evaluation of each program in view of its advantages and disadvantages should be performed in parallel to promote quality and betterment of that specific program. This approach would provide us with a better and more applicable plan for the continuance of this uniform assessment style. We who have set out on this mission should appreciate this fact. Synchronous globalization in all fields of science is rapidly growing and will definitely affect medical education. Once international standards are adopted, we should respect them, although local barriers, such as market forces and resistance from powerful lobby groups, may be anticipated in advance. Possible approaches for the enforcement of the adopted standards should then be proposed, as some obstacles at the national level may still exist for young ophthalmologists who are entering practice.


Pharmaceutical drug shortages (DSs) are a global problem which presents challenges to countries around the world. Shortages of pharmaceutical products may have a direct detrimental impact on public health and patients’ wellbeing by causing delayed, or even lack of, treatment. Moreover, DSs may force both patients and caregivers to use unfamiliar drugs, which could lead to medication errors. The objective of our study was to analyze DSs in Israel during the years 2013–2015, assessing their etiology and exploring the steps taken for their mitigation and prevention.The database of the Israeli Ministry of Health (MoH) on drug shortages contains all the DSs recorded in Israel since 2013, detailing the cause of the DS, its duration, steps taken in its’ management and the availability of generic or therapeutic alternatives. Selected examples of DSs from the database are described in this paper in order to identify the causes of DSs, the scope of the problem and possible solutions. Additionally, we have reviewed the recent activities performed by European Medicine Agency (EMA) and the American Food and Drug Administration (FDA) in their efforts to minimize this problem.Several factors contributing towards DSs in Israel were identified, including quality problems in both the final drug product and in the raw materials, upgrades and improvements of the manufacturing process required by the MoH, manufacturing by a sole supplier, dramatic price decrease in off-patent medications causing the manufacturer to discontinue the distribution of the product in Israel, just-in-time inventory control, and others.One of the most important steps in managing drug shortages was identified to be early notification of the shortage by the Marketing Authorization Holder (MAH) to the MoH. In 2013, the Israeli MoH updated the regulation on drug shortages instructing MAHs on their obligation of early notification to the MoH.Furthermore, various steps dealing with marketing withdrawal of drugs and temporary drug shortages are being implemented in Israel, such as suspending any further reductions in drug prices below 17 new Israeli shekels, instructing all MAHs to maintain no less than 1 month supply of all registered and non-registered drugs in Israel and allowing an expedited registration pathway for well-established use/grandfather drugs.Drug shortages pose significant public health hazards worldwide. Early notification to the MoH and open dialog with MAHs are essential for managing DSs and mitigating their impact. Despite the efforts carried out by health regulatory authorities worldwide, DSs still pose a significant threat to public health. A drug shortage (DS) is defined by the Food and Drug Administration (FDA) as a situation when: “the total supply of all clinically interchangeable versions of a FDA-regulated drug product is inadequate to meet the current or projected demand at the patient level” .DSs are a global problem relevant to countries regardless of size. In the United States (US), the number of prescription DSs more than tripled between 2005 and 2010, increasing from 61 in 2005 to 178 in 2010 [As an additional step in coping with the DS challenge in the US, the FDA recently established the Drug Shortage Assistance Award program aiming to provide public recognition to drug companies and manufacturers who have worked in cooperation with the FDA and have implemented strategies to help ensure a steady supply of necessary drugs. Award letters posted on the FDA website recognize these companies for making a substantial contribution to preventing or alleviating a DS. Advocates of this initiative hope that these public letters will serve as an incentive for other companies to maintain a stable drug supply and avoid DSs by working together with the regulator.Furthermore, a publicly available database of DSs was established on an FDA website, keeping all the stakeholders updated on new entries and resolved shortages .Data from the European Union (EU) is relatively lacking compared to the US and most DSs are dealt with at a national level. Nevertheless, the European Medicine Agency (EMA) is concerned with DSs as well, focusing mainly on shortages associated with quality defects affecting many EU countries. In November 2012, the EMA published a position paper on medicinal product supply shortages caused by manufacturing problems . SubsequIn 2014 the Organization of Economic Co-operation and Development (OECD) released a report from the Global Forum on Competition that focused on the distribution of pharmaceuticals . ShortagThe Business and Industry Advisory Committee to the OECD (BIAC) has suggested that the economic crisis has forced deep price cuts to pharmaceutical products, as governments have attempted to reduce healthcare spending . The cauAt the beginning of 2016, the World Health Organization (WHO) released a new report on global drug shortages . The WHOShortages of pharmaceuticals can result in delayed treatment for patients and sometimes even deprivation of treatment due to lack of availability of the needed drug. When no appropriate alternative therapy is available, DSs could lead to a serious threat to public health.Moreover, DSs are often the cause of medication errors. Alternative drugs, unfamiliar to clinicians or patients, different brands or concentrations, altered presentations, all may cause medication errors, adverse events and decreased patient adherence.A recent paper by CL Ventola, emphasized the consequent mortality associated with DSs in the US . For exaNumerous studies and reviews have referred to the possible impact of DSs on public health. Exploring the problems and the negative outcomes of DSs, Clauder et al. have conducted a survey among pharmacy directors in North Carolina, South Carolina, Georgia, and Florida . RespondBesides affecting the quality and the safety of public health, DSs have a significant financial effect on health systems. For example, the financial burden of drug supply disruptions to hospitals in the US was estimated in 2011 to be $200 million annually, because of the need to purchase more expensive therapeutic substitutes. Another $216 million of indirect costs were estimated as a result of labor costs due to time spent by healthcare personnel in the management of DSs in hospitals , 13. TheIn this article, we will describe the current situation in Israel with reference to other countries emphasizing special circumstances relevant to the Israeli health system. Due to the lack of data on outpatient DSs worldwide, the analysis of the situation in Israel, and references to EMA and FDA, focuses mainly on inpatient DSs. Furthermore we will discuss approaches and solutions to overcome this phenomenon.Since 2013, The Israeli Ministry of Health (MoH) receives and documents notifications regarding supply shortages from MAH. We have searched this database to identify the scope of the problem and steps taken by the Pharmaceutical Division in the prevention and management of DSs. Furthermore, recent policies by EMA and FDA in the management of DSs are described.Based on the data collected by MoH, between 2013 and 2015, 677 DS notifications were received: 191 in 2013, 240 in 2014 and 246 in 2015. In the US, 117, 44 and 44 DSs were tracked in the years 2012, 2013 and 2014, respectively. The FDA helped to prevent 282 DSs in 2012, 170 shortages in 2013 and 101 shortages in 2014 [Figure The following case studies provide examples of the complexity of DSs as seen in Israel, some of which may be relevant to other countries as well.At the beginning of May 2013, the Israeli MoH received a notice of a possible shortage of phenytoin effective almost immediately and anticipated to last for a period of up to 6 months. Phenytoin is an anti-epileptic drug with narrow therapeutic range and non-linear metabolic elimination. Its therapeutic range is so limited, that cases of patients developing breakthrough seizures due to batch-to-batch variations are described in the scientific literature . In dealAnother example of a DS is Clomiphene citrate, a sole supplier drug used for induction of ovulation. Following intervention by the MoH, the MAH was able to allocate to the Israeli market a supply of the same drug manufactured in Israel for export, thus temporarily resolving the shortage.Additional imminent shortage of a topical preparation for treatment of burn wounds arose following rapid alert report received by the MoH in 2014 regarding possible cross-contamination with penicillin. Following risk assessment of drug shortage vs. possible side-effect as a result of cross-contamination, it was decided to add a special labeling to the drug’s package notifying the customers that this product should not be used in patients sensitive to beta-lactams. The distribution of the product was accompanied by a Dear Health Care Provider (DHCP) letter and a notice to the public made by MoH.In March 2014, a routine inspection of the manufacturing facility of oromucosal solution of midazolam, a drug indicated to stop sudden and prolonged convulsive seizures in children, was carried out. The inspection revealed failures in the quality management of the manufacturing process of the drug, raising concerns regarding a potential risk of cross-contamination with amsacrine, another medicine produced at the same site used for the induction and maintenance of remission in acute leukemia in adults. Tests did not find any residuals of amsacrine. As a precautionary step, the drug was recalled in Member States where suitable alternative treatments were available. Due to the lack of available alternatives, the product was classified as critical and it was decided to maintain its supply to the Israeli market.One of the major concerns in DSs worldwide is disruption in the supply of sterile injectables, resulting in severe impact on public health. During the years 2013–2015 in Israel, 27% of DSs were supply interruptions of injectables and approximately 20% of them were IV injections. Surprisingly, this was in contrast to the situation in the US, where a significantly higher incidence of shortages related to sterile injectable products was noted. For example, according to FDA data in years 2011–2012, sterile injectables accounted for about 70% of all DSs .Throughout 2014–2015, Israel experienced three major DS crises leading to disruption of drug supply; two of them involved local manufacturing sites. In one case, all the production of a MAH was moved to a new manufacturing plant. During the preparation for this major variation, following discussions between the MoH and the MAH, it was decided to increase the inventory of critical drugs to 6 months of use, taking into account the MAH being the sole supplier for these products. Unfortunately, due to unexpected production difficulties at the new facility, these efforts were insufficient, resulting in an immediate shortage of many critically important injectables such as midazolam, lidocaine and morphine. In another incident, one of the major pharmaceutical companies in Israel relocated the secondary packaging site of solid oral dosage form products, creating an ongoing temporary shortage in 90 of the company’s drugs (some of them with a single supplier). Another crisis, related to the transfer of the production of injectables to a new manufacturing facility abroad, is still having an impact on their supply chain, resulting in the need to import non registered alternatives. The MoH is working closely with the MAH, other manufacturers, importers and healthcare institutions to find a solution for this problem.Quality problems that are not limited to the final drug product, but often found in the raw materials, affect drug production and supply around the globe. Major challenges are quality problems with Active Pharmaceutical Ingredient (API) from emerging countries like India and China. Just recently, Good Manufacture Practice (GMP) approvals of several large global manufacturers of APIs have been revoked following inspections carried out by mature regulatory authorities. Failure of quality management in facilities that produce the finished dosage form of the drug was directly responsible for 56% of sterile injectable DSs in 2011 in the US .Disruption or delay in the supply of the raw or bulk material can affect multiple manufacturers and result in a country/regional/worldwide DS. For example, a shortage of the injectable antibiotic streptomycin was reported in 15 countries in 2010, with 11 more countries predicting their stock would run out before they could be replenished .Regulatory authorities’ requirements for improvement of the manufacturing process have become a complex and expensive effort for pharmaceutical companies. Many companies, especially, but not limited to small ones, are unable or unwilling to make capital investments to sufficiently upgrade the infrastructure required according to the updated GMP standards. Hence, manufacturers often choose to discontinue production of low priced off-patent drugs. The phenomena is further accentuated in a small country with strict regulations like Israel, where local manufacturers are sometimes required to implement changes in the manufacturing/validation process of drugs intended for a relatively small local market.The situation in Israel, with limited market size and number of competitors, results in many drugs being manufactured solely by one company. Therefore, in case of manufacturing or supply difficulties, the risk for a nationwide shortage constantly exists. Special emphasis should be drawn to sterile injectable products with revenues barely covering the costs of production. Currently in Israel, numerous old, well established and extensively used drugs in an ICU setting, like lidocaine, midazolam and dipyridamole, are manufactured and registered by a single company.Low prices of certain off-patent medicines may contribute to DSs and drive manufacturers of these medicines out of the market. Furthermore, in Israel, reference pricing policy is determined by referencing overseas countries, but not necessarily reflecting global and local market conditions. Fluctuations in currency exchange rates influence prices as well. This, in turn, may lead to situations in which the revenue of drugs will not cover the costs of production, resulting in permanent DSs.Just-in-time inventory control by manufacturers, medical product distributors and healthcare institutions reduces the possibility to cope with DSs at times of unexpected demand changes or supply disruption. In cases in which an MAH is the main or sole source for a medication on the market, a manufacturing/supply chain problem can often result in a DS affecting the entire country.The drug market in Israel is centralized and dominated by Health Management Organizations (HMOs) with large scale generic medication tenders. Therefore, all approved generics and innovative drugs of the same International Nonproprietary Name (INN) are perceived as switchable by the HMOs . Thus, the HMOs buy their drugs based almost entirely on pricing. This often leads to a situation, where an MAH that fails to win a tender discontinues manufacturing or local distribution of the drug, resulting in only one alternative with sole supplier on the market.The Israeli regulation currently mandates Certificate of Pharmaceutical Product (CPP) from a pre-determined limited set of “authorized countries” as stated in the legislation. This demand is a prerequisite for drug registration. Consequently, this limits the drugs submitted for registration in Israel.The etiology of DSs in Israel is similar to FDA and EU, being multifactorial and related to one or more of the following factors:Unfortunately, without supporting legislation, a regulatory authority cannot instruct a pharmaceutical company/MAH to produce a drug. It also has no capacity to influence a DS that occurs due to commercial agreements between manufacturers and healthcare institutions.While the root cause of DSs is usually outside the regulator’s control, some of the shortages can be managed and even prevented by activities promoted by the MAH and/or the regulator, especially when both parties collaborate effectively.One of the key steps in overcoming some of the DSs is ensuring that the regulator receives a notice of the upcoming shortage well in advance. Early disclosure of a shortage by the MAH can allow the regulator to find alternative solutions to overcome the crisis.In their attempt to prevent and mitigate DSs, the FDA implemented section 506 (c) of the Federal Food Drug and Cosmetic Act requiring MAHs to notify of any manufacturing discontinuance or interruption in manufacturing of the product at least 6 months prior to the date of the discontinuance or as soon as possible and in no case later than 5 business days after DS occurs. EMA requires MAHs to notify the Members State’s competent authority no less than 2 months before the expected interruption in the market.Until May 2013, the Israeli MoH required MAHs to notify only in cases of permanent marketing termination. The procedure for the notification process in event of drug shortage, also known as Procedure 104, was updated, requiring MAHs to notify the MoH of any permanent or temporary DS anticipated to last more than 2 weeks, at least 6 months prior to the estimated shortage start date. This notification requirement enables the Israeli MoH to monitor DSs in Israel, to receive early notifications of such incidents and to take risk mitigation measures. Additionally the procedure requires the MAH to discuss any future termination with the MoH in order to find acceptable solutions in view of public health considerations. The MoH reserves the right to instruct the MAH to continue distribution of a medicine under special circumstances.During the years 2013, 2014 and 2015, 58, 71 and 64% (respectively) of the DS notices were received immediately before the shortage (less than 1 month before the shortage came into effect). A decrease in immediate notifications was noted in the months following the update of the procedure. Nevertheless, in spite of the updated requirements, many MAHs still fail to provide the MoH with adequate notice on forthcoming shortages. The lack of compliance with the early notification requirements could be due to the fact that the MAH is not always aware in advance of future shortages and thus is unable to meet the requirement for 6 months notification. This is especially evident when the disruption of the drug supply is caused by global API shortage, quality issues requiring withdrawal from the market of one or more batches of the product, noncompliance with GMP requirements following regulatory inspection and others.The Israeli MoH developed a protocol for the management of DSs based on country specific experience. According to the protocol, following the MAH notification of the forthcoming shortage of drug with no generic alternatives, the MoH engages all the relevant stakeholders, including Health Care Professionals (HCP), HMOs and/or hospitals and drug importers, to identify a possible solution . In some cases, after careful risk evaluation, the MoH may expedite evaluation of drugs that are in shortage to allow the distribution of a drug with relatively minor defects, such as inappropriate labeling or packaging, etc. Cross-contamination of midazolam with the cytotoxic agent amsacrine, described above in this manuscript, is an excellent example of risk management by the Pharmaceutical Division. In another case, similarly to the decision taken by the FDA, a product containing glass particles was allowed to be distributed into the market accompanied by a filter and a DHCP letter instructing the HCP to use the filter to remove potential particles from the product.According to Procedure 104, it is the responsibility of MoH to notify the public regarding the forthcoming shortage. Furthermore, the MoH actively seeks alternative supply sources of the drug in shortage, to import either a registered or a non-registered drug. Israeli legislation allows for importation of non-registered drugs from authorized countries under article 29 C of the Pharmacist Regulations—Medicinal Products. This allows for a quick and effective way of obtaining drug supply in shortage.Another step taken by MoH once a shortage is imminent is to instruct the MAH to control more adequately the distribution of the drug in shortage, preventing excess purchase of large quantities by some of the customers and enabling all the stakeholders to receive appropriate restricted drug quantities. An additional strategy may be to instruct physicians, to prescribe the remaining product to defined patient populations and for specific clinical situations, where no appropriate alternatives are available, thus switching or initiating the remaining patients to other therapeutics alternatives.The presence of a generic drug is not always a guarantee for preventing DSs. The manufacturer may not have the flexibility to increase drug production to meet the national demand in a timely manner, especially at short notice. The MAH of an imported alternative may be unable to increase the supply of the drug into the country due to lack of finished product, previous commitments to other customers and delivery schedules at the manufacturing facility.In the effort to reduce the number of DSs occurring in Israel each month, the MoH has recently published Procedure 120 which introduces an expedited pathway for authorization of well-established/grandfather drugs. Such drugs were usually registered in Israel in the past or are similar to products registered and marketed for more than 10 years in authorized countries and are imported to Israel under article 29 C. This procedure is currently being evaluated for its impact on reducing the number of non-registered drugs imported to Israel.One of the causes for cessation of drug distribution in Israel is price reductions. The pricing reference model in Israel is based on overseas reference prices of drugs as well as currency exchange rates. Following the MoH decision on the reference price, HMOs, using an effective tender system may reduce the price even further. This pricing system may be problematic especially with old drugs and small pharma companies. Reference prices for old drugs may be so low that any further decrease makes the production and/or distribution of these important drugs non feasible. Additionally, small local pharma companies may find it difficult to cope with drug suppliers from abroad unwilling to accept the designated price. This challenge has generated important discussions within the Ministry on ways to preserve the availability of such drugs on the market. One of the strategies chosen to overcome this was to suspend any further reductions in drugs prices below 17 new Israeli shekels. The Pharmaceutical Division’s role as an important stakeholder overseeing DSs was an essential factor preventing further reductions below this price.Finally, as part of Israel preparedness to emergency scenarios , it was decided to instruct all MAHs to hold at any time at least 1 month’s supply of all registered drugs in Israel. This strategy was recently published and is monitored and enforced. This requirement is now applicable to both registered drugs and new molecules under evaluation for registration. HMO’s and medical institutions are obliged to ensure a 1 month’s supply of non-registered drugs which are part of the National Health Basket and are imported into Israel under article 29 C of the Pharmacist Regulations—Medicinal Products.In this paper, we have described the topic of DSs in Israel, with use of statistics for years 2013–2015. We have analyzed the etiology of DSs and utilized selected examples and the actions taken in their management.Despite all the steps taken by the Israeli MoH to prevent and manage DSs, their number continues to rise annually. As described in this paper, numerous steps are being taken in the management of DSs, including early notification, working closely with the MAH, preservation of prices for grandfather drugs, procedure 120 and the request for no less than 1 month drug supply in Israel at any time. In order to prevent the selection of one supplier/brand by HMOs due to generic/generic tenders, it was even considered to instruct the HMOs to maintain two suppliers for certain critical drugs, thus limiting the possibility of sole drug supplier on the market.The MoH periodically publishes a call for manufactures and importers to apply for registration of old well established (grandfather) drugs currently imported under article 29 C. This call was positively taken by potential MAHs.The MoH preemptively takes measures to overcome the challenge of DSs. A designated unit was established to deal with this ongoing and important task and all DSs are publicly available on the unit’s website. In spite of the time and efforts invested, this problem is yet to be solved. While cooperating with the MAHs is a key factor for this process, currently, there are no deterring measures set in legislation, including financial constraints for any MAH not complying with the requirements set by the MoH. Introducing these deterring measures could serve to minimize the frequency of DS.DSs pose significant public health hazard worldwide. Early notification and open dialog between the MAH and the regulator is essential for preventing and mitigating the impact of shortages. Further collaboration of all stakeholders, including international stakeholders, is required to overcome these substantial challenges.


Point-of-care (POC) tests have been useful in increasing access to testing and treatment monitoring for HIV. Decentralising testing from laboratories to hundreds of sites around a country presents tremendous challenges in training and quality assurance. In order to address these concerns, companies are now either embedding connectivity in their new POC diagnostic instruments or providing some form of channel for electronic result exchange. These will allow automated key performance and operational metrics from devices in the field to a central database. Setting up connectivity between these POC devices and a central database at the Ministries of Health will allow automated data transmission, creating an opportunity for real-time information on diagnostic instrument performance as well as the competency of the operator through external quality assessment. A pilot programme in Zimbabwe shows that connectivity has significantly improve the turn-around time of external quality assessment result submissions and allow corrective actions to be provided in a timely manner. Furthermore, by linking the data to existing supply chain management software, stock-outs can be minimised. As countries are looking forward to achieving the 90-90-90 targets for HIV, such innovative technologies can automate disease surveillance, improve the quality of testing and strengthen the efficiency of health systems. The recent availability of point-of-care (POC) technologies allows for a shift from a centralised to a decentralised model of testing. Such decentralisation of testing can offer a significant increase in access to much needed diagnostics for populations in peri-urban, rural and other hard to reach areas, which will be needed to achieve the UNAIDS 90-90-90 target.The wide deployment of POC tests at hundreds or even thousands of sites raises a big challenge for Ministries of Health to track instruments and monitor the quality of the test and the testing. In order to address these concerns, numerous connectivity (connected diagnostic) initiatives and interventions have been undertaken in an attempt to ensure that the implementing institution is able to keep track of, at minimum, key performance and operational metrics for devices in the field. These initiatives have had mixed success in implementation due to a variety of reasons. Companies are now either embedding connectivity in their new diagnostic instruments or providing some form of channel for electronic result exchange.Zimbabwe, for example, has placed 346 Alere Pima™ POC CD4 devices in hard to reach areas throughout the country. At present, 114 of these instruments are connected via Alere 3G modems to the Clinton Health Access Initiative’s in-country POCLabs platform in conjunction with the National Microbiology Reference Laboratory. The Ministry of Health has been receiving scant data from the devices, as is shown in the snapshot provided in 3 EQA for POC testing has the potential to provide a snapshot of quality, both in terms of the diagnostic instrument performance as well as the competency of the operator. The implementation of POC testing in rural and peri-urban settings, however, presents tremendous challenges in the organisation of an EQA programme. These challenges include:External quality assessment (EQA) is a critical component of a laboratory quality assurance and management system.The scale of providing EQA samples to hundreds of sites within a country, requiring the preparation or procurement of a large number of proficiency testing panels and the means to distribute them.POC tests are typically operated by non-laboratory staff who are not familiar with a laboratory ‘culture’ of quality or EQA.Poor response rates and delay in reporting weaken the value of EQA programmes.Connectivity for POC tests and other medical devices can be defined as an initiative that can improve patient flow, increase the quality of testing, and improve patient outcomes. Connectivity should be viewed as a complementary approach to EQA. It can provide continuous quality monitoring, as all of the data generated by the instrument can be analysed as an average of a series of aggregated, non-unique events, whereas EQA is a series of controlled events, with known inputs and known outputs. Connectivity can be used not only to monitor patient data such as diagnostic results and response to treatment, but it can also be used to capture operational data from the device and provide key performance and quality indicators.Most POC instruments now include methods to exchange data electronically. This can be via a port , or via embedded GSM/3G capabilities within the POC device. The diagnostics industry is beginning to take full advantage of these capabilities with a number of ecosystems being constructed around the consumption of this data. Various stakeholders have distinct, and well-defined needs for the different data sets and subsets. Broadly, the data can be categorised into clinical data, which includes patient-identifiable information, and operational data. Operational data is defined as a subset of the clinical data which is de-identified. These systems allow Ministries of Health to receive information and derive intelligence, in real-time, from any testing facility throughout a country into one central database. This allows Ministries of Health to have daily monitoring of the performance of the devices, the test results and the competency of the operators from each site. Furthermore, connectivity can help improve forecasting and prevent stock-outs based on the utilisation rate at each facility, as shown in 4 These informatics systems are continually expanding and innovating features as the ecosystems become better defined. One example is the automated detection and transmission of EQA samples from diagnostic devices which is made available, in near-real time, to the EQA providers for analysis.Operational data can be used by instrument manufacturers, Ministries of Health, funders, trainers, and supply chain managers. Diagnostic data can be used for patient management by nurses, clinicians and epidemiologists and stored in a laboratory information system and/or a central data warehouse.Historically, the Pima CD4 EQA programme in Zimbabwe requires a significant amount of hands-on time for both sample shipping, testing and reporting. The process, briefly, is as follows.EQA samples are shipped to a single, central, location for separation and distribution. This facility unpacks the samples and re-packages them for distribution by courier for delivery to the facility . After tOnce the EQA deadline closes, the central facility captures all of the received results, first on paper for central collection, and then via a web-form on the EQA provider’s informatics platform, for all participating sites. Once the EQA results have been captured and submitted, the EQA provider is able to analyse the results and report these, with any corrective action suggestions, back to the central facility. At this point, the central facility is, again, responsible for separating the individual performance reports for the facilities and re-distributing these, along with any corrective actions, back to the participants. This whole process usually takes at least 12 weeks.For connected devices, it is clear that a much simpler and more efficient workflow can be leveraged to optimise the EQA process. POC tests connected to an informatics system capable of distinguishing EQA from routine samples via the sample ID can dramatically help improve turnaround time for EQA results, thereby allowing for action to be taken if necessary. Furthermore, there will be significantly fewer transcription errors and data analysis will be simplified.An automated EQA proof-of-concept pilot for CD4 counts was conducted in November 2015 in Manicaland Province in Zimbabwe. Several issues had to be resolved among different partners before the proof-of-concept testing could be initiated. A standardised barcoding format had to be agreed upon for use as the sample ID for testing on the Pima CD4 instrument. The barcode standardisation was necessary so that the informatics systems would be able to differentiate EQA samples from patient results to ensure that no patient data is transmitted beyond the clinical boundaries defined in these structures .Alere, the developer of the Pima POC CD4 device developed an ‘EQA only’ data-store and interface for its centralised data warehouse, Data Point. This allows for authorised, external systems to query Data Point for samples that have been identified as EQA samples from the barcode. For this pilot, the EQA provider, Oneworld Accuracy, developed an application program interface for their informatics system, OASYS (Oneworld Accuracy System), which would automatically query Data Point every hour for any new data that has been identified as an EQA sample. All new data identified as EQA are then immediately received by OASYS for storage and processing (both of these application program interfaces have now been included in the production version of both Data Point and OASYS).The proof-of-concept study only involved one site, the Marange rural health centre. Three sets of EQA samples were delivered to Marange and run by the operator over a three-week period. Oneworld Accuracy received the results from the EQA samples within 60 minutes of these tests being performed on the Pima device, demonstrating that the automated system performed as expected. The next phase was to increase the number of sites to approximately 50 and EQA samples were distributed as part of the routinely-scheduled EQA assessment planned for the end of March 2016.® platform to the relevant EQA provider informatics systems. The proof-of-concept testing for this took place in April 2016 at four sites in Manicaland.Due to the perceived impact of this intervention, a similar process is currently being established to automate the reporting of EQA samples (identified by a barcode) from the Cepheid GeneXpertThe proof-of-concept pilot highlighted the potential for improvement in turn-around time from testing to reporting of EQA results, as well as reducing the overall administrative burden of these events. It is recommended that some standard barcoding identification be implemented for all EQA samples for both laboratory and POC instruments. The implementation of a standardised barcode structure for the identification of EQA samples would allow any informatics system , connected to any laboratory or POC instrument, to identify a sample as an EQA sample and transmit these results, in near-real time, to the relevant EQA provider for analysis and reporting.In the ideal case, the following workflow could become standard for EQA testing and reporting:The EQA provider sends out the sample to the test site.The test site receives the sample and tests the sample.The results are automatically uploaded to a server upon completion.The server identifies the result as an EQA result and forwards the result to the correct EQA provider.The EQA provider scores the result and generates the user report.This proposed workflow reduces the need for the paper transcription of results to be collected centrally, as well as the need for the collected results to be re-transcribed in an electronic format on the EQA provider’s informatics platform, thus reducing errors in both interpretation and transcription.The automation of the collection and analysis of EQA results from laboratories, especially for POC instruments, can help countries:Significantly improve the turn-around time of EQA result submissions and the impact of any prescribed corrective actions in a timely manner.Reduce the transcription error rate and improve the quality of the resulting process.Eliminate the time-consuming processes involved with EQA result collection, capture and re-distribution.Reduce the cost and improve uptake of EQA programmes for both laboratories and POC facilities.Additional expected outputs from this pilot are:Feasibility and acceptability from EQA providers to adhere to a standardised barcode format.Willingness for Ministries of Health to have this data (non-patient data) automatically shared between connected systems (and ecosystems) from the instrument to the EQA provider.Definition of the role the instrument manufacturer can play in helping countries successfully implement and monitor EQA programmes via manufacturer platforms.Connectivity has shown that it is possible for Ministries of Health to have up-to-the-hour information on testing and test results across the country. These results can also be accompanied by EQA results from laboratories, as well as each POC testing site across the country, so that corrective action and refresher training can be provided in a timely manner. These systems can also be twinned to supply chain management software to monitor supplies at each site, providing an automated system for alerts to avoid stock-outs. As countries are looking forward to achieving the 90-90-90 targets for HIV, such innovative technologies can automate surveillance, improve quality of testing and strengthen health systems.


Patients with congenital agenesis of the portal vein may develop hepatocellular tumors due to enhanced arterial blood flow. These tumors may be benign  or malignant . Liver resection can be proposed, and preoperative arterial embolization may decrease blood loss during surgery. Liver transplantation with PV reconstruction is also an option. Abernethy syndrome is a congenital disease characterized by the total or partial agenesis of the portal vein, creating a portosystemic shunt in the absence of portal hypertension or liver disease. This congenital absence of the portal vein (CAPV) is discovered during childhood in 80% of cases, but may also be diagnosed in adults, in a context of complications.This syndrome is rare and has been reported only about a hundred times since its description by John Abernethy in 1793 In normal physiological conditions, the portal vein is formed by the superior mesenteric vein and the spleen mesaraic trunk, which is itself made up of the inferior mesenteric vein and the splenic vein. The blood enters the liver for purification and the hepatic veins then penetrate into the inferior vena cava. In Abernethy syndrome, the liver is bypassed and the unpurified blood passes directly into the systemic circulation via the inferior vena cava.1a: the spleen mesaraic trunk and the superior mesenteric vein flow directly into the inferior vena cava1b: the spleen mesaraic trunk and the superior mesenteric vein join to form a trunk vein that then plunges into the inferior vena cavaTwo types of Abernethy syndrome have been described: type I, corresponding to a congenital absence of the portal vein, and type II, in which blood supply to the portal vein is partly preserved In type II Abernethy syndrome, a portal vein is present, but it is hypoplasic due to a predominant shunt between the portal vein and the inferior vena cava.Type I predominates in female subjects (61–78%) and includes multiple malformations, some of which may be lethal Liver transplantation appears to be the most effective treatment in children and young adults Mr. D., aged 72, had been followed for more than 15 years by hepatologists and nephrologists, for hepatorenal polycystic kidney (HRPK) disease associated with microbiliary hamartomas  . There were only two HVs, one on the right and the other on the left Fig. . The HCCThree days before surgery, preoperative embolization of the left hepatic artery was performed, and biochemical data were collected for the liver.An ultrasound scan of the liver was performed during surgery, to localize the two hepatic veins (left and right HVs) and their confluence and the junction with the inferior vena cava. The left HV passed through the tumor, and the right HV was located close to the tumor. The gastrohepatic ligament was opened and the hepatic pedicle was carefully explored: there was no portal trunk, the right liver artery was recovered and the left was embolized. A left hepatectomy was performed by an anterior approach, and biliary stasis was checked by cholangiography after the cholecystectomy. The hepatic section was in contact with the right hepatic vein. The transfusion of only two units of packed cells was required during surgery. The patient did not develop hepatocellular insufficiency. On D2, ALAT levels had almost returned to normal (114 U/mL), bilirubin concentration was 29 μmol/L and the patient had a prothrombin ratio of 69%. Laboratory test results returned to normal values by D10. The patient was discharged from the digestive medicine unit 10 days after surgery.The final pathology evaluation reported a well‐differentiated HCC with invasion of the channel section. Two types of lesions were also observed: biliary microhamartomas and arterial branch duplication, with an absence of venous branches in the portal spaces, and fibrosis Fig. .In adults, Abernethy syndrome type I, or CAPV, is often associated with large liver tumors, but it may also be associated with other, possibly lethal malformations Table  4.Encephalopathy with hyperammonemia due to an absence of blood detoxification resulting from the portosystemic shunt;Brain abscess;Hepatopulmonary syndrome, which causes chronic hypoxia with clinical signs, such as cyanosis, dyspnoea, and nail clubbing.It may also have diverse complications, which may lead to detection of the syndrome:The vein usually arises by selective involution of the peri‐intestinal vitelline venous loop during early embryogenesis. Excessive involution of this loop can cause congenital agenesis of the portal vein, with the development of a complete or partial mesocaval shunt, as reported here Moreover, about half the individuals with congenital agenesis of the portal vein also have benign or malignant liver neoplasms The high frequency of liver disease associated with congenital agenesis of the portal vein strongly suggests a relationship between the systemic deviation of portal flow and the development, hepatocellular function, and regenerative capacity of the liver parenchyma Imaging revealed a direct deviation of portal venous blood in our case, with the upper and lower mesenteric veins and the splenic vein emptying directly into the left renal vein, and a high level of liver arterialisation. No signs of portal hypertension were observed, but high levels of blood flow through the hypertrophic hepatic artery, associated with bile duct proliferation, were observed on pathology examination In our case, the liver was resected after chemical embolization, due to the large size of the tumor. The preoperative embolization of the left artery significantly decreased blood loss. We felt that mobilization of the tumor before liver resection was too dangerous, and an anterior approach therefore remained the only viable option.Portosystemic caval shunts can lead to abnormal liver development, function, and regeneration due to the absence of portal hepatotrophic factor, resulting in the development of hepatic tumors. These tumors are generally considered to be benign parenchymatous lesions, but with the potential for malignant conversion In young patients with immature intrahepatic portal veins, as in our case, liver transplantation (LT) may be required in young patients. Surgical reconstruction of the portal structures of the native liver could be proposed, but this method has yet to be clearly established.Two methods can be used to reconstruct the portal vein during LT LT for CAPV. In the first, the shunt is anastomosed end‐to‐end to the portal vein in the graft The other technique involves the anastomosis, end‐to‐side, of a venous interposition graft to the shunt via a partial side clamp, with the venous interposition graft anastomosed end‐to‐end to the portal vein in the graft However, it is important to check the feasibility of LT in cases of type I portocaval shunt, in which the portal vein is immature, as in our case. Indeed, it is necessary to analyze tumor size, histology, and residual liver volume. Embolisation significantly decreases the amount of blood lost and facilitates the resection. As suggested by Hua, we propose the use of a decision algorithm for the management of patients with CAPV Fig. .In conclusion, we describe a case of congenital agenesis of the portal vein diagnosed in a 72‐year‐old man, a much greater age at diagnosis than in previous studies, which have focused on the frequent association of liver damage with this congenital malformation. This vein agenesis seemed to be primarily a consequence of hepatic hyper arterialisation linked to the deprivation of portal blood flow. Surgery is the treatment of choice for this disease when associated with the formation of a liver tumor, as in this case. The decision as to whether to perform LT or liver resection‐chemoembolisation is based on the same criteria as for HCC.None declared.NC and ND: analyzed the data and wrote this clinical case. EC, AT, SDF, and DV: contributed to interpret the images and revised the clinical case. MM: designed, revised, and approved the final version of the clinical case.


Meta-analyses of telemonitoring for patients with heart failure conclude that it can lower the utilization of health services and improve health outcomes compared with the standard of care. A smartphone-based telemonitoring program is being implemented as part of the standard of care at a specialty care clinic for patients with heart failure in Toronto, Canada.The objectives of this study are to (1) evaluate the impact of the telemonitoring program on health service utilization, patient health outcomes, and their ability to self-care; (2) identify the contextual barriers and facilitators of implementation at the physician, clinic, and institutional level; (3) describe patient usage patterns to determine adherence and other behaviors in the telemonitoring program; and (4) evaluate the costs associated with implementation of the telemonitoring program from the perspective of the health care system , hospital, and patient.The evaluation will use a mixed-methods approach. The quantitative component will include a pragmatic pre- and posttest study design for the impact and cost analyses, which will make use of clinical data and questionnaires administered to at least 108 patients at baseline and 6 months. Furthermore, outcome data will be collected at 1, 12, and 24 months to explore the longitudinal impact of the program. In addition, quantitative data related to implementation outcomes and patient usage patterns of the telemonitoring system will be reported. The qualitative component involves an embedded single case study design to identify the contextual factors that influenced the implementation. The implementation evaluation will be completed using semistructured interviews with clinicians, and other program staff at baseline, 4 months, and 12 months after the program start date. Interviews conducted with patients will be triangulated with usage data to explain usage patterns and adherence to the system.The telemonitoring program was launched in August 2016 and patient enrollment is ongoing.The methods described provide an example for conducting comprehensive evaluations of telemonitoring programs. The combination of impact, implementation, and cost evaluations will inform the quality improvement of the existing program and will yield insights into the sustainability of smartphone-based telemonitoring programs for patients with heart failure within a specialty care setting. Currently, one of the greatest challenges for health care systems worldwide is the growing fiscal and social burden of preventing and managing chronic diseases . Heart fThere is mounting evidence that embedding self-care within existing health care services provides an effective model to meet these needs for a number of chronic diseases, including HF -7. AlthoIn HF, meta-analyses conclude that TM lowers the utilization of health services, improves HF health outcomes, and improves health-related quality of life (QoL) -20. HoweAlthough the ubiquity of mobile phones is believed to have the potential to make TM interventions more accessible and cost-effective ,28, addibring your own device model is planned, which would enable patients with smartphones to use their own devices by downloading the Medly app.An algorithm-based smartphone-based TM program for patients with HF, called the Medly Program, is being implemented as part of the standard of care at the University Health Network’s Ted Rogers Center of Excellence for Heart Function in Toronto, Canada (hereafter referred to as the HF clinic). The objective of the Medly Program is similar to other HF TM programs: improve patient self-management and decrease health care utilization . PatientIf there are signs of deteriorating health of a patient, the Medly algorithm generates an alert to a HF clinician who is part of the patient’s care team. The alerts are made available to clinicians in 2 formats. The first is through an automated email containing the latest weight, blood pressure, and symptoms along with the patient’s target ranges. In addition, the email contains the patients’ latest medication list and HF–related laboratory results, and contact information. Second, clinicians can choose to view the alerts by accessing a secure Web portal that presents a list of all the alerts triggered. Here, clinicians can review details of the latest alert and graphs showing historical weight, blood pressure, symptoms, and HF–specific laboratory results, which are visually contextualized according to the patient’s target ranges. The clinician will follow-up with the patient depending on the clinical need, documenting all actions and decisions taken in response to the alert in the hospital electronic medical record (EMR).The Medly Program is intended to be delivered as part of the standard of care; as such, the goal is for it to be seamlessly integrated within the existing workflows of the HF clinic. Before deployment, a service blueprint was created through ethnographic methods including observation and informal interviews with clinicians and support staff in the HF clinic. This helped identify areas where the processes of the Medly Program could be incorporated. In addition, an RCT of 100 patients with an embedded qualitative component was previously conducted in the HF clinic with an earlier version of the Medly system. This study concluded that patients receiving the intervention experienced improvements in QoL and self-care maintenance compared with a control group . LessonsTraining as to how to use the Medly app and associated devices is provided to patients at the time of enrollment into the Medly Program by a telehealth analyst. Clinicians monitoring patients through the Medly system participated in a formal training session approximately 1 month before program deployment. Both patients and clinicians are provided with a user manual to supplement the in-person training along with contact information of the telehealth analyst who offers technical support during normal business hours.The first objective is to evaluate the impact of the Medly Program on health service utilization, patient health outcomes, and their ability to self-care. Alerts sent to patients and clinicians will help identify periods of symptom exacerbation and volume overload. The impact of this is expected to permit earlier intervention for worsening conditions, thus avoiding trips to the emergency department (ED) and hospitalizations. For patients who are enrolled into the Medly Program on hospital discharge, the program is expected to reduce 30-day readmission rates. In addition, participation in the Medly Program is expected to improve patients’ ability to self-care, leading to improved clinical outcomes and QoL.The second objective is to evaluate the degree to which the Medly Program was implemented as intended and to identify the contextual barriers and facilitators of implementation. This objective will answer the following questions:To what extent did the HF clinic implement the Medly Program as intended?What contextual factors influence the implementation of the Medly Program?What adaptations were needed to implement and sustain the program within existing clinical workflows?The third objective is to describe patient usage patterns to determine adherence and other behaviors in the Medly Program. This objective will answer the following questions:To what degree do patients adhere to the Medly Program and how do adherence patterns change over time?What factors influence patient adherence?The fourth objective is to evaluate the costs associated with the implementation of the TM program from the perspective of the health care system , the hospital, and patients.Data for the 4 objectives will be collected using mixed-methods. This approach will include a multiple pre-and posttest design for the evaluation of patient-level impacts, patient adherence, and cost. Quantitative data will include data collected as part of the standard of care  and usage data from the TM system. Additional patient-level data will be collected using questionnaires at baseline, 1 month, 6 months, 12 months, and 24 months. The qualitative component will take the form of an embedded single case study . The 2 eRepresentatives from all stakeholder groups involved in the implementation of the Medly Program will be recruited for participation.Patients can be enrolled into the Medly Program provided they (1) are 18 years or older, (2) have been diagnosed with HF and are followed by a cardiologist at the HF clinic, (3) can speak and read English  to adequately understand the text prompts in the Medly app, and (4) are able to comply with using Medly . As the Medly program is being implemented as part of the standard of care, there is no explicit exclusion criteria for participating in the program and its evaluation. The duration of program participation will be decided by patients and their treating cardiologist on an individual basis.Upon enrollment into the Medly Program, patients will be presented with the option of answering questionnaires and participating in interviews related to the program evaluation. Patients will be asked to sign a written consent form before participating in the evaluation.All members of the Medly Program staff will be asked to participate in semistructured interviews. These include clinicians providing care for patients with HF in the HF clinic (n=7), telehealth analyst (n=1), project manager (n=1), and members of the implementation team (n=2). These individuals will be asked to sign a consent form before their first interview.The primary outcome for evaluating the impact of the Medly Program is the number of hospitalizations because of HF in the 6 months before versus the 6 months after enrollment. Secondary impact outcomes comparing 6-month to baseline values are described below.The number of hospitalizations , 30-day readmission rate, days in hospital , number of ED visits , visits to family doctor , number of HF–related outpatient visits, and changes to medication will be recorded.The following HF–specific clinical parameters will be collected: left ventricular ejection fraction (LVEF), brain natriuretic peptide (BNP), creatinine, sodium, potassium, hemoglobin, and uric acid levels.Patient mortality will be tracked. In addition, the Seattle Heart Failure Model (SHFM) will be calculated at program entry. Projected SHFM survival versus actual survival will be compared . The calPatients will be asked to describe their level of breathlessness using a visual analogue scale for dyspnea on a scale ranging from 0 (no shortness of breath) to 10 (shortness of breath is the worst it can be).The EQ-5D-5L is a measure of generic health status and will be administered to all patients as a measure of QoL ,35. ThisThe self-care of HF index asks respondents to respond to 22 items on a 4-point Likert scale to assess their ability to self-care across 3 subscales . The tool has undergone validity and reliability testing involving patients with HF .Demographic information will also be collected using a questionnaire, which includes questions on the following: age, sex, income, native language, living arrangements , whether or not they have a caregiver , and type of living areas . In addition, patient comorbidities will be tracked. Finally, questions will be asked to assess the patient’s experience and comfort level with technology and smartphones, including frequency of use.Data collection will occur at baseline, 1 month, 6 months, 12 months, and 24 months, or until the patient exits the program. Data collected in addition to the primary evaluation period (baseline to 6 months) will provide an opportunity for post-hoc analyses aimed at quality improvement, including recommended duration of use. For example, the 1-month time point was included to determine if the bulk of changes to self-care and QoL occur immediately after enrollment. Similarly, longitudinal data will help determine whether patient-level impacts are sustained or change when using the system long term.Health service utilization, laboratory results, mortality, prediction of survival, and select demographic information will be obtained from the hospital EMR. In addition, health service utilization information will be verified by patient participants through self-reports via a questionnaire.Baseline and follow-up questionnaires containing the validated survey tools listed in t tests and Wilcoxon signed rank tests comparing baseline and 6-month values for all patient-level outcomes. For patients enrolled in the Medly Program on hospital discharge, the 30-day readmission rate will be compared with the readmission rate before the launch of the Medly Program, as determined using hospital administrative data. Secondary analyses aimed at determining the longitudinal impact of the Medly Program , and the correlation of independent variables  with outcomes will be analyzed using general linear mixed model procedures. In addition, descriptive statistics will be produced for all variables collected, which may inform necessary subgroup analyses. All statistical analyses will be performed using the statistical software application SPSS  [The primary analyses will be paired Student on, USA) .d=0.3) in the number of hospitalizations because of HF within the first 6 months of enrollment with 80% power and an alpha of .05 (two-sided) [We will aim to recruit at least 108 patients into the Medly Program at the HF clinic before analyses of patient-level outcomes are undertaken. This number is based on being able to detect a small effect size (Cohen o-sided) . This nuThe mixed-methods implementation evaluation will be guided by the framework by Proctor et al, which describes outcomes that can serve as indicators of implementation success , and theImplementation outcomes are defined by Proctor et al as “the effects of deliberate and purposive actions to implement new treatments, practice, and services” . A totalSeparate semistructured interview guides based on the constructs in the CFIR will be formulated for each category of program staff previously outlined. Interviews will be conducted at baseline, 4 months, and 12 months to align with the different phases of Stetler et al’s typology of formative evaluations . The intDescriptive statistics will be produced for the indicators of the implementation outcome to provide an objective measure of implementation success.Furthermore, 2 independent researchers will analyze interview transcripts and documents using the Framework Method of qualitative analysis . An initQuantitative and qualitative data will be triangulated such that the interview data will help explain success or failure of the implementation.A sequential explanatory mixed-methods approach  will be Adherence will be assessed by analyzing patient usage rates of the Medly system—specifically, the proportion of days for which the patient took a complete reading  over the previous 30 days. Usage data will be obtained and exported on a regular basis through Google Analytics .A sample of patients enrolled in the Medly Program will participate in semistructured interviews aimed at understanding reasons for adherence or nonadherence and their general experiences with the Medly Program. Interview guides will be formulated based on the constructs of the Unified Theory of Acceptance and Use of Technology 2 . For exaMonthly adherence rates will be examined using descriptive statistics to identify any patterns in the increase or decrease of patient adherence to Medly over time. In addition, general linear mixed model procedures will be performed to determine if any baseline patient characteristics  or time since program enrollment predicts patient adherence to the Medly system. Semistructured interviews will be analyzed using the Framework Method , as prevThe costs associated with implementing the Medly Program will be determined from the perspectives of the public payer, hospital, and patient. In reporting these results, costs will be interpreted in relation to the patient-level impacts determined in objective 1.Costs will be calculated using a 6-month time frame. Specifically, we will compare costs before the implementation of the Medly Program (assessed at baseline) versus the costs after enrollment of patients into the program (measured at 6 months). This time frame was chosen because it represents the time horizon over which most of the health effects and costs of using the Medly Program are expected. Most of the cost variables will be self-reported by patients and triangulated using administrative data whenever possible . Therefore, questions related to the cost will be added to the patient outcome questionnaires (objective 1) and will be administered at baseline and 6 months.Costs to the public payer will be determined by looking at health care utilization of patients enrolled in the Medly Program before versus after their enrollment. These will include hospitalizations, ED visits, HF clinic visits, family physician visits, and use of home care services. In addition, costs for inpatient medications will be considered.Costs from the hospital perspective will be valued based on time spent by human resources involved in the Medly Program. This time will be converted to costs based on those individuals’ respective salaries. This will include time the clinicians spent reviewing and responding to Medly alerts as well as time the clinicians spend in training sessions, learning to use the system, and seeking technical support. In addition, costs for the hospital perspective will include equipment costs  and the salary for employing a telehealth analyst responsible for recruiting, training, onboarding, managing inventory support, and providing training.Costs for patients will primarily be determined by the time they spend accessing care for HF. This will involve determining their employment status and annual income as well as time they spend traveling to and from appointments, time spent at appointments, and how much work time was missed because of their HF condition (vacation or unpaid). In addition, this will include the time patients spent learning to use the Medly system, time spent using the system, and time getting technical support. Additional costs considered include travel, parking, and all other out-of-pocket costs related to accessing care or using the intervention. Moreover, time of informal caregivers  will be valued as part of the patient perspective. Costs for informal caregivers will be based on the average hourly rate of personal support workers.The Medly Program was launched in August 2016. As of April 4, 2018, 166 patients have been enrolled. The primary impact analysis is expected to be conducted by January 2019.This study aims to evaluate the implementation and impact of a smartphone-based TM program being implemented as part of the standard of care in a specialty care setting in a large Canadian city.Unlike TM systems evaluated in the context of academic research, the lack of strict patient inclusion and exclusion criteria for the Medly Program has the potential to lead to heterogeneity among evaluation participants, which will make it difficult to generalize the results to other health care settings. Another important limitation is that the nature of this evaluation and the availability of data do not allow for a distinct comparator group. Without discounting these limitations, we believe that one of the strengths of this evaluation is its pragmatic nature and that these threats to internal and external validity will be mitigated through a detailed description of the context and participants when results are reported. The interpretation of the Medly Program evaluation results will include comparisons with previous TM RCTs conducted within the HF clinic  and otheUnlike other TM studies that focus primarily on quantitative outcomes, this evaluation will also examine the context and mechanisms that lead to them. Therefore, this pragmatic mixed-methods study will allow for an interpretation of results using realist evaluation principles . The inf


The Open Science Prize was established with the following objectives: first, to encourage the crowdsourcing of open data to make breakthroughs that are of biomedical significance; second, to illustrate that funders can indeed work together when scientific interests are aligned; and finally, to encourage international collaboration between investigators with the intent of achieving important innovations that would not be possible otherwise. The process for running the competition and the successes and challenges that arose are presented. Open data and open science can confer benefits to researchers, including increases in citation, media attention, and potential collaborations . While oTo encourage international partnerships in leveraging open research data, the National Institutes of Health (NIH), Wellcome Trust (WT), and Howard Hughes Medical Institute (HHMI) partnered on funding the Open Science Prize (OSP). The importance of open data and open science for the NIH is reflected in its strategic plan , which shttps://www.federalregister.gov/documents/2015/10/20/2015-26392/announcement-of-requirements-and-registration-for-the-open-science-prize). The prize was open to any solution that exhibited the benefits of making research outputs open and usable and demonstrated new and innovative ways of enabling this. For NIH, the America Creating Opportunities to Meaningfully Promote Excellence in Technology, Education, and Science Reauthorization Act of 2010  provided United States funding agencies the authority to provide prizes and awards [The OSP utilized a prize competition as a funding mechanism .There are several aspects of the OSP that were notable. First, international collaborations among solvers were required, with at least 1 team member based in the US and 1 team member based outside of the US. Second, the prize competition was structured in 2 phases: Phase I sought the most innovative and promising ideas and proposed open science tools  and Phase II provided a grand prize award  for the best prototype of the Phase I finalists. Thus, not only could a diverse set of ideas come forth, but initial feedback could be given to the most promising ideas in the prototype phase. Third, an innovative funding model was incorporated for the OSP. NIH provided funds to the US member(s) of the teams selected for the awards per requirements in the America Competes Act, and WT and HHMI provided funds to the non-US member(s). Fourth, in an effort to invite broad input on the innovations, a group of advisors (see acknowledgments) with expertise in open science, health information technology, and/or biomedical research methods were selected to provide comments on the submitted applications and prototypes. In addition, the public was invited during a 5-week period to vote and comment on their favorite prototypes of the 6 finalists during Phase II of the competition. Public comments are posted on the OSP website. Fifth, to the extent practical with the resources available, all aspects of the competition were made open. For example, the executive summaries of all submissions were made public on the OSP Open Data Science Symposium organized by NIH. The teams were asked to develop written narratives summarizing progress to date and addressing key factors such as innovation, utility, feasibility and technical merit, and development and sustainability plan for their prototypes. These summaries, along with videos that many of the teams created, were publicly displayed on the OSP website, and the public was invited to cast their votes and provide input. During Phase II, 3,730 votes were received from voters representing 76 countries. The judging criteria for Phase II was similar to the criteria utilized for Phase I, but in Phase II, the emphasis was on the prototype developed as opposed to an anticipatory idea.The OSP received 96 submissions for Phase I of the competition, with entries coming from 45 countries spanning 6 continents . Phase Ihttp://www.nextstrain.org) in which the outputs of statistical analyses of viral genome sequences can be used by public health officials for epidemiological insights within days of genome sequences having been obtained from viral pathogen samples taken from patients. Nextstrain.org expanded upon the submitters’ prior work on influenza tracking (nextflu.org) to include many other viral pathogens. Using OSP funds, the team developed detailed phylogeographic analyses of viral movement, created a platform for rapid  data sharing of pathogen genome data with open source code, and constructed a database and associated parsing scripts to quickly consolidate emerging data from multiple sources.Based on the review of all information provided, the funders selected “Real-Time Evolutionary Tracking for Pathogen Surveillance and Epidemiological Investigation” as the grand prize winner of the OSP. “Real-Time Evolutionary Tracking for Pathogen Surveillance and Epidemiological Investigation” was developed by a team from the Fred Hutchinson Cancer Research Center in Washington and the University of Basel, Switzerland. The project uses an online visualization platform  through the reuse of open data. In taking such ideas forward, however, the following lessons learned may be instructive and helpful:Partnerships are always more time-consuming than first imagined. Though the benefits of collaborative working are significant—shared expertise, better reach, ability to leverage additional funding, etc.—funders should enter into these partnerships mindful that meeting the differing requirements/rules/ambitions of a group of funders is not always straightforward, and an ability to compromise and work through issues is key. It is also critical for funding partners to develop a strong shared commitment and understanding of what they are trying to achieve, as it creates a foundation for working through the challenges that arise and forges good personal/working relationships.A 2-step funding model is an effective way to encourage innovation whilst minimizing the cost. The benefits are 2-fold: the short-listed applicants receive funds in order to make the best case for support of their prototype, and the funders, judges, and advisors benefit from seeing the progress made between the 2 stages, which can inform the further selection process. However, it could be argued that having Phase I applicants provide detailed specifications of the technology to be developed may not have encouraged more innovative, off-the-wall, or high-risk ideas that if successful could have more impact. How to adapt the funding and review processes to encourage more innovation, particularly from groups outside traditional health research sectors, requires further discussion and deliberation.Public participation is a good way to increase the reach of the competition and generate interest and enthusiasm for open data. The nature of this competition means that engagement with and wider use of the tools is critical to their impact. Holding a public vote was an effective way to raise awareness of open science. It allowed a number of tools to be highlighted, not just the overall winner. It is important to strike the right balance when deciding the contribution that public voting makes to the determination of the eventual winner.Proposals at differing stages of development were received. Define clearly whether applications have to focus on a completely new concept (or tool) or whether an existing tool/service—which wishes to add additional new functionality—is also eligible. If both are eligible, it is important to consider how to tension the 2 types of applications against one another in the fairest and most transparent way.Setting a broad remit allowed a wide range of ideas to be proposed, but the 6 finalists naturally did not fully represent the breadth of ideas proposed. Consider establishing different categories—best new tool, best cross-cutting application, etc.—rather than having a single winner. Alternatively, consider refining the OSP funding model to create future global initiatives focused in particular areas .The international funding partnership increased both the global reach of the competition as well as the resources available. Expanding partnerships to include other international funding organizations with common interests in open data could further help to leverage resources and address intractable global health issues.Furthermore, it is recommended that funders consider ways to incentivize the sustainability of tools and technologies that leverage open biomedical data to improve biomedical research and public health. We encourage others to explicitly discuss international funding models and the sharing of resources to advance the use of biomedical open data.The OSP was useful to all 3 of the funding agencies in that it provided a range of exemplars that successfully demonstrated the benefits of open data for sparking innovation and generating new societal benefits. Prior developer challenges have emphasized the leveraging of open digital content to create innovative tools . The OSP took this concept 1 step further and encouraged international collaborations to solve global health issues by leveraging open digital content. OSP complements other funding initiatives focused on data-driven discovery  by focusing specifically on publicly available open data.#openscienceprize) views, the OSP garnered much interest from scientists and citizens around the world. The OSP has provided a pathway that agencies dealing with any type of open data can utilize to incentivize innovative, international team–based science.While market intelligence is typically a benefit of challenge competitions, the international aspects of this competition enriched each of the funding agencies’ understanding of new ideas emerging around the globe and of the mechanisms behind that. The 6 solutions that moved from Phase I to Phase II were exemplars of innovative and useful tools/platforms that leverage open data. Moreover, the other 90 entries provided insight into emerging areas of interest, such as community annotation and knowledge-extraction tools. The other way in which the competition was notable was in its ability to highlight the value of open health data to the broader scientific community. As evidenced by the submissions, press coverage, and Twitter (