Manifestation of Nonuremic Calciphylaxis in the Extremities: Case Report and Review.

Nonuremic calciphylaxis is a rare condition presenting with peripheral ischemic ulcerations. Calciphylaxis is the deposition of calcium and phosphate into arteriolar walls caused by exceeding their solubility range in the blood. It is most commonly seen in patients with end-stage renal disease; however, nonuremic calciphylaxis occurs in patients with normal or mildly impaired renal function. Risk factors for nonuremic calciphylaxis include Coumadin therapy, obesity, and diabetes mellitus. Histopathologic examination of deep skin biopsy containing subcutaneous adipose tissue reveals medial calcification of dermal and subcutaneous arterioles. This diagnosis must be managed locally with wound care and systemically by control of blood calcium solubility. Avoidance of infection is critical to survival. Here we report a case of calciphylaxis in a patient with normal renal function and serum levels of calcium and phosphorus who presented with gangrene of the extremities. Increased awareness of this debilitating disease will lead to earlier diagnosis, proper treatment and improved patient outcomes.

The demise of islet allotransplantation in the United States: A call for an urgent regulatory update.

Islet allotransplantation in the United States (US) is facing an imminent demise. Despite nearly three decades of progress in the field, an archaic regulatory framework has stymied US clinical practice. Current regulations do not reflect the state-of-the-art in clinical or technical practices. In the US, islets are considered biologic drugs and "more than minimally manipulated" human cell and tissue products (HCT/Ps). In contrast, across the world, human islets are appropriately defined as "minimally manipulated tissue" and not regulated as a drug, which has led to islet allotransplantation (allo-ITx) becoming a standard-of-care procedure for selected patients with type 1 diabetes mellitus. This regulatory distinction impedes patient access to islets for transplantation in the US. As a result only 11 patients underwent allo-ITx in the US between 2016 and 2019, and all as investigational procedures in the settings of a clinical trials. Herein, we describe the current regulations pertaining to islet transplantation in the United States. We explore the progress which has been made in the field and demonstrate why the regulatory framework must be updated to both better reflect our current clinical practice and to deal with upcoming challenges. We propose specific updates to current regulations which are required for the renaissance of ethical, safe, effective, and affordable allo-ITx in the United States.

The clinical significance of receiving a kidney allograft from deceased donor with chronic histologic changes.

Allograft survival of deceased donor kidneys with suboptimal histology (DRTx/suboptimal histology: >10% glomerulosclerosis, >10% tubulointerstitial scarring, or >mild vascular sclerosis) is inferior to both DRTx with optimal histology (DRTx/optimal histology) and living donor kidneys irrespective of histologic changes (LRTx). In this report, we explored the reasons behind this guarded outcome with a special focus on the role of alloimmunity. We initially assessed gene expression in 39 time-zero allograft biopsies using the Nanostring 770 genes PanCancer Immune Profiling Panel. Subsequently, we studied 696 consecutive adult kidney allograft recipients that were grouped according to allograft type and histology at time-zero biopsy [DRTx/suboptimal histology (n = 194), DRTx/optimal histology (n = 166), and LRTx (n = 336)]. Part-1: Several immune pathways were upregulated in time-zero biopsies from DRTx/suboptimal histology (n = 11) compared to LRTx (n = 17) but not to DRTx/optimal histology (n = 11). Part-2: Amongst the three groups of recipients, DRTx/suboptimal histology had the highest incidence of acute rejection episodes, most of which occurred during the first year after transplantation (early rejection). This increase was mainly attributed to T cell mediated rejection, while the incidence of antibody-mediated rejection was similar amongst the three groups. Importantly, early acute T cell mediated rejection was a strong independent predictor for allograft failure in DRTx/suboptimal histology (adjusted HR: 2.13, P = 0.005) but not in DRTx/optimal histology nor in LRTx. Our data highlight an increased baseline immunogenicity in DRTx/suboptimal histology compared to LRTx but not to DRTx/optimal histology. However, our results suggest that donor chronic histologic changes in DRTx may help transfer such increased baseline immunogenicity into clinically relevant acute rejection episodes that have detrimental effects on allograft survival. These findings may provide a rationale for enhanced immunosuppression in recipients of DRTx with baseline chronic histologic changes to minimize subsequent acute rejection and to prolong allograft survival.

Analysis of dendritic cells and ischemia-reperfusion changes in postimplantation renal allograft biopsies may serve as predictors of subsequent rejection episodes.

Ischemia-reperfusion injury increases allograft immunogenicity and enhances myeloid dendritic cell maturation and trafficking to recipient's secondary lymphoid tissue. Here, we used postreperfusion biopsies from patients who received kidney allografts from deceased donors between 2006 and 2009 to assess the impact of ischemia-reperfusion damage and myeloid dendritic cell density on subsequent allograft rejection episodes. Histologic changes of severe ischemia-reperfusion damage in postreperfusion biopsies were found to be associated with subsequent rejection episodes and suboptimal allograft survival. Using BDCA-1 as a marker of myeloid dendritic cells, postreperfusion biopsies from deceased donors had lower dendritic cell density compared to postreperfusion biopsies from living donors or normal controls. This suggests a rapid emigration of donor dendritic cells out of the allograft. In our cohort, low dendritic cell density was associated with a subsequent increase in rejection episodes. However, it appears that the donor's cause of death also influenced dendritic cell density. Therefore, we assessed the additive impact of severe ischemia-reperfusion changes and low dendritic cell density on subsequent rejection. The aforementioned combination was a powerful and independent predictor of allograft rejection. Thus, our data highlight the prognostic value of histopathologic changes associated with ischemia-reperfusion in postreperfusion biopsies and suggest a rapid posttransplant emigration of myeloid dendritic cells out of the allograft to enhance alloimmunity. These findings may provide a rationale for minimizing ischemia-reperfusion injury and therapeutic targeting of donor-derived dendritic cells to promote rejection-free allograft survival.

The Use of Pediatric Flexible Intramedullary Nails for Minimally Invasive Fibular Fracture Fixation.

Fibular fractures in the setting of an unstable ankle joint require surgical fixation; however, several factors contradict open surgical correction. Severe soft tissue compromise can delay adequate fracture reduction and preclude the standard incisional approach. The soft tissue envelope in the setting of obesity, diabetes, and/or peripheral vascular disease further complicates definitive treatment. Poorly timed open fixation can lead to delayed healing of the incision site, with wound breakdown and the potential for hardware failure. Proximal fibular fractures are also at unique risk of neurovascular compromise with open reduction and internal fixation. Surgical fixation has now focused on minimizing the soft tissue insult using percutaneous techniques in the comorbid patient. We present a case that highlights a minimally invasive technique that provides dynamic stable internal fixation of fibular fractures with the use of flexible pediatric intramedullary nails, typically used in long bone fractures of children.

Charcot Pathogenesis: A Study of In Vivo Gene Expression.

Charcot neuroarthropathy is a rare but often difficult to manage disease in the neuropathic patient. Early signs such as unremarkable edema, marginal trauma, or minor infection can activate a cascade of bony destruction and lead to gross prominence or deformity, with dire consequences. The exact molecular mechanism is poorly understood. Current theory states that an inflammatory reaction leads to the activation of osteoclasts mediated by specific cytokines. Our study sought to test the genetic expression of certain biomarkers in diabetic patients with and without Charcot neuroarthropathy compared with patients with and without diabetes or neuropathy. A total of 30 patients participated in the study, 17 (57%) males and 13 (43%) females. Peripheral blood samples were drawn, and gene expression was measured using real-time polymerase chain reaction. The expression levels of receptor activator of nuclear factor kappa-B ligand and osteoprotegerin showed no significant increase in the Charcot neuroarthropathy group compared with the healthy control group. We determined that the levels of receptor activator of nuclear factor kappa-B ligand and osteoprotegerin were not significantly increased in Charcot neuroarthropathy patients compared with healthy control patients. These results demonstrate a need for further investigation into alternative molecular pathways to determine the exact mechanism of the disease process.

Direct oral anticoagulant considerations in solid organ transplantation: A review.

For more than 60 years, warfarin was the only oral anticoagulation agent available for use in the United States. In many recent clinical trials, several direct oral anticoagulants (DOACs) demonstrated similar efficacy with an equal or superior safety profile, with some other notable benefits. The DOACs have lower inter- and intrapatient variability, much shorter half-lives, and less known drug-drug and drug-food interactions as compared to warfarin. Despite these demonstrated benefits, the use of DOACs has not gained uniform acceptance because of lack of supportive data in special patient populations, including recipients of solid organ transplants maintained on immunosuppression. This review describes the properties of several novel DOACs including their pharmacology and mechanisms of action as they relate to use among solid organ transplant recipients. We have particularly focused on (i) dosing in patients with impaired renal and hepatic function; (ii) considerations for drug-drug interactions with immunosuppressive medications; and (iii) management of the anticoagulated patients at the time of unplanned surgery. The risks and benefits of the use of DOACs in solid organ transplant recipients should be carefully evaluated prior to the introduction of these agents in this highly distinct patient population.

Imaging- and physiology-guided percutaneous coronary intervention without contrast administration in advanced renal failure: a feasibility, safety, and outcome study.

AIMS: The feasibility, safety, and clinical utility of percutaneous coronary intervention (PCI) without radio-contrast medium in patients with advanced chronic kidney disease (CKD) are unknown. In this series, we investigated a specific strategy for 'zero contrast' PCI with the aims of preserving renal function and preventing the need for renal replacement therapy (RRT) in patients with advanced CKD. METHODS AND RESULTS: A total of 31 patients with advanced CKD [creatinine = 4.2 mg/dL, inter-quartile range (IQR) 3.1-4.8, estimated glomerular filtration rate = 16 ± 8 mL/min/1.73 m2] who had clinical indication for PCI based on a prior minimal contrast coronary angiogram were included. Zero contrast PCI was performed at least 1 week after diagnostic angiography using real-time intravascular ultrasound (IVUS) guidance, with pre- and post-PCI measurements of fractional flow reserve and coronary flow reserve to confirm physiological improvement. This approach resulted in successful PCI, no major adverse cardiovascular events and preservation of renal function without the need for RRT within a follow-up time of 79 days (IQR 33-207) in all patients. CONCLUSION: In patients with advanced CKD who require revascularization, PCI may safely be performed without contrast using IVUS and physiological guidance with high procedural success and without complications.

Irreducible Ankle Fracture Dislocation Due to Tibialis Posterior Tendon Interposition: A Case Report.

Traumatic ankle fractures and dislocations that fail closed reduction present a challenging set of circumstances that can potentially lead to unnecessary complications and require surgical intervention. Interposition of adjacent tendons occurs rarely and can obstruct the anatomic realignment. Because of the potential for neurovascular compromise and possible skin tension necrosis, an irreducible fracture dislocation must be addressed with open reduction and internal fixation. The present case details an unusual, low-energy, external rotation ankle fracture and dislocation that was incapable of skeletal traction relocation. The present report also details the intraoperative finding of a complex injury pattern.

Recommendations for including surgery on the public health agenda.

BACKGROUND: Surgical care has made limited inroads on the public health and global health agendas despite increasing data showing the enormous need. The objective of this study was to survey interested members of a global surgery community to identify patterns of thought regarding barriers to political priority. MATERIALS AND METHODS: All active members of the nongovernmental organization Surgeons OverSeas were surveyed and asked why surgical care is not receiving recognition and support on the public health and global health agenda. Responses were categorized using the Shiffman framework on determinants of political priority for global initiatives by two independent investigators, and the number of responses for each of the 11 factors was calculated. RESULTS: Seventy-five Surgeons OverSeas members replied (75 of 176; 42.6% response rate). A total of 248 individual reasons were collected. The most common responses were related to external frame, defined as public portrayals of the issue (60 of 248; 24.2%), and lack of effective interventions (48 of 248; 19.4%). Least cited reasons related to global governance structure (4 of 248; 2.4%) and policy window (4 of 248; 1.6%). CONCLUSIONS: This survey of a global surgery community identified a number of barriers to the recognition of surgical care on the global health agenda. Recommendations include improving the public portrayal of the problem; developing effective interventions and seeking strong and charismatic leadership.

Use of a flexible implant and bioabsorbable anchor for deltoid rupture repair in bimalleolar equivalent Weber B ankle fractures.

Supination external rotation ankle fractures are the most common ankle fracture subtype. Deltoid ligament injuries have often been associated with this type of injury pattern. A missed injury can lead to post-traumatic arthritis and persistent pain. The current data do not support acute deltoid rupture repair. This has been based primarily on level III and IV studies in which less than satisfactory results were reported. We believe that acute deltoid rupture repair could be indicated in select cases. We have outlined a new deltoid repair technique for use with bimalleolar, equivalent supination external rotation ankle fractures using a flexible implant and bioabsorbable anchor.

Managing renal transplant ischemia reperfusion injury: novel therapies in the pipeline.

Ischemia reperfusion injury (IRI) is an early, non-specific inflammatory response that follows perfusion of warm blood into a cold asanguinous organ following transplantation. The occurrence of IRI may have a pivotal impact on acute and long-term renal allograft function. Initially, IRI contributes to delayed graft function (DGF), a term typically defined as the need for dialysis within one wk after renal transplantation. DGF frequently leads to prolonged hospital stay, increased healthcare costs, and potentially worse prognosis. Strategies to prevent IRI have so far been fairly limited, poorly defined, inadequately studied, and mostly anecdotal. The purpose of this review is to summarize the existing and novel therapies, which may mitigate IRI in renal transplantation. Agents currently in the pipeline include: Diannexin, which reduces endothelial cell injury by shielding phosphatidylserine; YSPSL, which mimics the binding portion of P-selectin glycoprotein ligand-1 to competitively inhibit translocation of P-selectin and recruitment of polymorphonuclear leukocytes to the surface of endothelial cells; and I5NP, a synthetic small interfering ribonucleic acid that results in the inhibition of p53 expression. These agents represent an exciting frontier in transplant pharmacotherapy; they are in various phases of investigation and may have broader benefits in reducing complications of DGF.

Health profession students' outlooks on the medical profession during the COVID-19 pandemic: a global perspective.

BACKGROUND: This article summarizes a global study of the effect of the COVID-19 pandemic on junior health professions students' outlook on medicine. The pandemic has significantly affected health professions education. There is limited understanding of how students' pandemic experiences will affect them, and what impact these events may have on their career paths or the future of the professions. This information is important as it impacts the future of medicine. METHODS: In the Fall 2020 semester, 219 health professions students at 14 medical universities worldwide responded to the question: 'Has this experience (with COVID-19) changed your outlook on medicine as a profession?'. Short essay responses were semantically coded and organized into themes and subthemes using an inductive approach to thematic analysis. RESULTS: 145 responses were submitted. Themes were identified: (1) students reflected on the interaction between politics and healthcare; (2) reported becoming more aware of the societal expectations placed on healthcare professionals, including undertaking high risks and the sacrifices that healthcare professionals must make; (3) found reassurance from the recognized importance of healthcare professionals and expressed pride to be entering the profession; and (4) reflected on the current state of healthcare, including its limitations and future. CONCLUSION: Most students, independent of the extent of the pandemic in their respective countries, noted a change in their outlook regarding medicine. An overall positive outlook was noted in most junior students. Educators need to work on nurturing these sentiments and attitudes to help young students maintain a healthy relationship towards their chosen profession.

An overview of renal replacement therapy and health care personnel deficiencies in sub-Saharan Africa.

Chronic kidney disease (CKD) is a public health problem in sub-Saharan Africa (SSA) but there is limited data to guide programs or plan interventions. To help set priorities and understand the needs for renal replacement therapy a baseline assessment is required. World Health Organization (WHO) databases and Medline were searched to determine the number of physicians, nephrologists, and dialysis centers and patients in SSA. Data on renal transplant (RTx) programs were collected from the WHO Global Observatory on Donation & Transplantation database for deceased-donor and living-donor RTx. Of the 47 countries in SSA only 15 had recent data with most rates of physicians per 10,000 population under 2.0. Nigeria and South Africa had the greatest absolute numbers of physicians and nephrologists but Mauritius had the greatest proportion to population. South Africa had the most dialysis patients. Kenya, Nigeria and South Africa were the only countries with RTx programs and reported rates per million population of 0.60, 0.23 and 5.12, respectively. Treatment for patients with CKD in SSA is limited by a lack of physicians, nephrologists, and dialysis centers. Few countries are performing RTx. Resources are needed to increase the health workforce and increase RTx programs in SSA.

Arguments against the Requirement of a Biological License Application for Human Pancreatic Islets: The Position Statement of the Islets for US Collaborative Presented during the FDA Advisory Committee Meeting.

The Food and Drug Administration (FDA) has been regulating human islets for allotransplantation as a biologic drug in the US. Consequently, the requirement of a biological license application (BLA) approval before clinical use of islet transplantation as a standard of care procedure has stalled the development of the field for the last 20 years. Herein, we provide our commentary to the multiple FDA's position papers and guidance for industry arguing that BLA requirement has been inappropriately applied to allogeneic islets, which was delivered to the FDA Cellular, Tissue and Gene Therapies Advisory Committee on 15 April 2021. We provided evidence that BLA requirement and drug related regulations are inadequate in reassuring islet product quality and potency as well as patient safety and clinical outcomes. As leaders in the field of transplantation and endocrinology under the "Islets for US Collaborative" designation, we examined the current regulatory status of islet transplantation in the US and identified several anticipated negative consequences of the BLA approval. In our commentary we also offer an alternative pathway for islet transplantation under the regulatory framework for organ transplantation, which would address deficiencies of in current system.

John Jones, M.D.: pioneer, patriot, and founder of American surgery.

John Jones was a pioneer of American Surgery. Born in Long Island, New York in 1729, he received his medical degree in France from the University of Rheims. He returned to the colonies and helped to establish the medical school that would later become Columbia University's College of Physicians and Surgeons where he was appointed the first Professor of Surgery in the New World. He used his position to assert that surgeons trained in America should be familiar with all facets of medicine and not be mere technicians. Before the outbreak of the American Revolution, he wrote a surgical field manual, which was the first medical text published in America. A believer in the principles of the American Revolution, he would go on to count Benjamin Franklin and George Washington as his patients. Despite achieving many firsts in American medicine, his influence on surgical training is his most enduring legacy.

Intrinsic Fixation of the Tibial Sesamoid in First Metatarsophalangeal Joint Arthrodesis: A Cadaveric Study.

Nonunion rate of first metatarsophalangeal joint (MTP) joint arthrodesis is reportedly less than 6%, regardless of fixation type. Robust modern plating constructs aim to decrease incidence of nonunion while also allowing early postoperative weight-bearing. Quicker transition to weight-bearing postoperatively increases patient adherence, decreases adjacent joint stiffness, and reduces risk of deep vein thrombosis in the postoperative period. The purpose of this study was to investigate the effect tibial sesamoid fixation has on first MTP joint arthrodesis.

Acute Deltoid Ligament Repair in Ankle Fractures: Five-year Follow-up.

Direct repair of deep deltoid ruptures after traumatic ankle fracture is not commonly performed. Previous studies overlook the contributions of the medial deltoid to overall ankle stability and long-term patient satisfaction. Historically, deep deltoid injuries have been addressed indirectly through syndesmotic ligament repair. This technique fails to restore, however, the anatomic function of the primary medial stabilizing structure. The oversight of direct deltoid repair may be one contributing factor to the less than optimal outcomes after ankle fractures with syndesmotic injuries. This article reports a positive response with direct deep deltoid repair, at average 5-year follow-up, with 93% positive return to normal function.

Negative impact of neutrophil-lymphocyte ratio on outcome after liver transplantation for hepatocellular carcinoma.

BACKGROUND: The Milan criteria have been adopted by United Network for Organ Sharing (UNOS) to preoperatively assess outcome in patients with hepatocellular carcinoma (HCC) who receive orthotopic liver transplantation (OLT). These criteria rely solely on radiographic appearances of the tumor, providing no measure of tumor biology. Recurrence rates, therefore, remain around 20% for patients within the criteria. The neutrophil-lymphocyte ratio (NLR) is an indicator of inflammatory status previously established as a prognostic indicator in colorectal liver metastases. We aimed to determine whether NLR predicts outcome in patients undergoing OLT for HCC. DESIGN: Analysis of patients undergoing OLT for HCC between 2001 and 2007 at our institution. A NLR > or =5 was considered to be elevated. RESULTS: : A total of 150 patients were identified, with 13 patients having an elevated NLR. Of these, 62% developed recurrence compared with 14% with normal NLR (P < 0.0001). The disease-free survival for patients with high NLR was significantly worse than that for patients with normal NLR (1-, 3-, and 5-year survivals of 38%, 25%, and 25% vs. 92%, 85%, and 75%, P < 0.0001). Patients with high NLR also had poorer overall survival (5-year survival, 28% vs. 64%, P = 0.001). Patients within Milan with an elevated NLR had significantly poorer disease-free survival than those with normal NLR within Milan (5-year survival, 30% vs. 81%, P < 0.0001). On univariate analysis, 9 factors including an NLR > or =5 were significant predictors of poor disease-free survival. However, only a raised NLR remained significant on multivariate analysis (P = 0.005, HR: 19.98). CONCLUSION: Elevated NLR significantly increases the risk for tumor recurrence and recipient death. Preoperative NLR measurement may provide a simple method of identifying patients with poorer prognosis and act as an adjunct to Milan in determining, which patients benefit most from OLT.