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.

COVID-19 in hospitalized liver transplant recipients: An early systematic review and meta-analysis.

Adverse clinical outcomes related to SARS-CoV-2 infection among liver transplant (LTx) recipients remain undefined. We performed a meta-analysis to determine the pooled prevalence of outcomes among hospitalized LTx recipients with COVID-19. A database search of literature published between December 1, 2019, and November 20, 2020, was performed per PRISMA guidelines. Twelve studies comprising 517 hospitalized LTx recipients with COVID-19 were analyzed. Common presenting symptoms were fever (71%), cough (62%), dyspnea (48%), and diarrhea (28%). Approximately 77% (95% CI, 61%-93%) of LTx recipients had a history of liver cirrhosis. The most prevalent comorbidities were hypertension (55%), diabetes (45%), and cardiac disease (21%). In-hospital mortality was 20% (95% CI, 13%-28%) and rose to 41% (95% CI, 19%-63%) (P < 0.00) with ICU admission. Additional subgroup analysis demonstrated a higher mortality risk in the elderly (>60-65 years) (OR 4.26; 95% CI, 2.14-8.49). There was no correlation in respect to sex or time since transplant. In summary, LTx recipients with COVID-19 had a high prevalence of dyspnea and gastrointestinal symptoms. In-hospital mortality was comparable to non-transplant populations with similar comorbidities but appeared to be less than what is reported elsewhere for cirrhotic patients (26%-40%). Importantly, the observed high case fatality in the elderly could be due to age-associated comorbidities.

Pain resolution and glucose control in pediatric patients with chronic pancreatitis after total pancreatectomy with islet auto-transplantation.

BACKGROUND: Chronic pancreatitis (CP) and acute recurrent pancreatitis (ARP) in pediatric patients are strongly associated with genetic mutations and lead to pan-parenchymal disease refractory to medical and endoscopic treatment. Our aim was to assess pain resolution and glucose control in patients with CP and ARP following total pancreatectomy with islet auto-transplantation (TPIAT). METHODS: We retrospectively analyzed prospectively collected clinical data of 12 children who developed CP and ARP and underwent TPIAT when 21 years old or younger at the University of Chicago between December 2009 and June 2020. Patients with recurrent or persistent abdominal pain attributed to acute or chronic pancreatic inflammation and a history of medical interventions attempted for the relief of pancreatic pain were selected by a multi-disciplinary team for TPIAT. We followed patients post-operatively and reported data for pre-TPIAT, post-operative day 75, and yearly post-TPIAT. RESULTS: All 12 patients experienced complete resolution of pancreatic pain. The overall insulin-independence rate after 1 year was 66% (8/12) and 50% (3/6) at 4 years. Shorter duration of CP/ARP pre-TPIAT, higher mass of islets infused, and lower BMI, BMI percentile, and BSA were associated with insulin-independence post-TPIAT. CONCLUSIONS: TPIAT is a viable treatment option for pediatric patients with CP and ARP. Pediatric patients undergoing TPIAT for CP achieved resolution of pancreatic-type pain and reduced opioid requirements. The majority were able to achieve insulin-independence which was associated with lower pre-TPIAT BMI and higher islet mass transplanted (i.e., over 2000 IEQ/kg), the latter of which can be achieved by earlier TPIAT. LEVEL OF EVIDENCE: Treatment study, Level IV.

Out-of-pocket expenses incurred by patients obtaining free breast cancer care in Haiti.

BACKGROUND: Women with breast cancer in low-income and middle-income countries (LMICs) account for 51% of cases globally and often present with advanced disease. Fear of costs contributes to delay in seeking care, as health expenditures are financially catastrophic for families worldwide. Despite efforts to improve affordability of health care in LMICs, the financial burden of indirect costs (eg, transportation and lost wages) is often overlooked. We aimed to identify and quantify the expenditures of patients seeking breast cancer care in a LMIC. METHODS: Patients receiving breast cancer care free of charge at Hôpital Universitaire de Mirebalais (HUM) in Haiti were interviewed to quantify their costs and assess the effect of these costs on patients and families. These costs included expenses for food, lodging, transportation, childcare, medical costs at other institutions, and lost wages. 61 patients were interviewed during diagnostic, chemotherapy, and surgical visits between March 1, and May 12, 2014. Institutional review board exemption was granted from Boston Children's Hospital and Partners in Health/Zanmi Lasante. FINDINGS: The median non-medical out-of-pockent expenses incurred by breast cancer patients at HUM were US$233 (95% CI 170-304) for diagnostic visits, US$259 (95% CI 200-533) for chemotherapy, and US$38 (95% CI 23-140) for surgery. The median total out-of-pockent expense (including medical costs) was US$717 (95% CI 619-1171). These costs forced 52% of participants into debt and 20% to sell possessions. The median percentage of potential individual income spent on out-of-pocket costs was 60%. The median sum of out-of-pocket costs and lost wages was US$2996 (95% CI 1676-5179). INTERPRETATION: In Haiti, 74% of people earn less than US$2 per day. Even when breast cancer treatment is provided for free, out-of-pocket expenses could account for more than 91% of annual earnings at this income level. This financial burden is an overwhelming obstacle for Haiti's poorest citizens, and probably for many patients in LMICs. High-powered, multisite studies are needed to further characterise this burden worldwide. Funders and health-care providers should reduce indirect costs to achieve equitable access to oncology care. FUNDING: Boston Children's Hospital and Partners in Health.

The struggle for equity: an examination of surgical services at two NGO hospitals in rural Haiti.

BACKGROUND: Health systems must deliver care equitably to serve the poor. Both L'Hôpital Albert Schweitzer (HAS) and L'Hôpital Bon Sauveur (HBS) have longstanding commitments to provide equitable surgical care in rural Haiti. HAS charges fees that reflect a preference for the rural population near the hospital, with free care available for the poorest. HBS does not charge fees. The two hospitals are otherwise similar in surgical capacity and rural location. Using geography as a proxy for poverty, we analysed the equity achieved under the financial system at both hospitals. METHODS: We retrospectively reviewed operative case-logs for general surgery and orthopaedic cases at both hospitals from June 1, to Aug 31, 2012. The records were compared by total number of operations, geographic distribution of patients, and number of elective operations. The service areas were defined as the governmental administrative units closest to both hospitals. For HAS, we analysed the number of operations performed on patients from the most poor and least poor regions within the service area; similarly detailed geographic information was not available from HBS. Rates were compared with χ(2) tests. The Ethics Committees at both hospitals and the Institutional Review Board at Partners Healthcare approved the study. FINDINGS: Patients from the rural service area received 306 operations (86·2%) at HAS compared with 149 (38·1%) at HBS (p<0·0001). Only 16 operations (4·5%) at HAS were performed on patients from outside the service area for elective conditions compared with 179 (47·0%) at HBS (p<0·0001). Within its rural service area, HAS performed fewer operations on patients from the most destitute areas compared with other locations (4·0 operations per 10 000 population vs 10·1 operations per 10 000 population; p<0·0001). INTERPRETATION: Use of fees as part of an equity strategy will likely disadvantage the poorest patients, while providing care without fees might encourage patients to travel from urban areas that contain other hospitals. Health systems striving to serve the poor should continually evaluate and seek to improve equity, even within systems that provide free care. FUNDING: None.

Optimizing availability of obstetric surgical care in India: A cost-effectiveness analysis examining rates and access to Cesarean sections.

The objective of this study is to assess the cost-effectiveness of three different strategies with different availabilities of cesarean sections (CS). The setting was rural and urban areas of India with varying rates of CS and access to comprehensive emergency obstetric care (CEmOC) for women of reproductive age in India. Three strategies with different access to CEmOC and CS rates were evaluated: (A) India's national average (50.2% access, 17.2% CS rate), (B) rural areas (47.2% access, 12.8% CS rate) and(C) urban areas (55.7% access, 28.2% CS rate). We performed a first-order Monte Carlo simulation using a 1-year cycle time and 34-year time horizon. All inputs were derived from literature. A societal perspective was utilized with a willingness-to-pay threshold of $1,940. The outcome measures were costs and quality-adjusted life years were used to calculate the incremental cost-effectiveness ratio (ICER). Maternal and neonatal outcomes were calculated. Strategy C with the highest access to CEmOC despite the highest CS rate was cost-effective, with an ICER of 354.90. Two-way sensitivity analysis demonstrated this was driven by increased access to CEmOC. The highest CS rate strategy had the highest number of previa, accreta and ICU admissions. The strategy with the lowest access to CEmOC had the highest number of fistulae, uterine rupture, and stillbirths. In conclusion, morbidity and mortality result from lack of access to CEmOC and overuse of CS. While interventions are needed to address both, increasing access to surgical obstetric care drives cost-effectiveness and is paramount to optimize outcomes.

Evaluating the Prognostic Value of Islet Autoantibody Monitoring in Islet Transplant Recipients with Long-Standing Type 1 Diabetes Mellitus.

(1) Background: The correlation between titers of islet autoantibodies (IAbs) and the loss of transplanted islets remains controversial. We sought to evaluate the prognostic utility of monitoring IAbs in diabetic patients after islet transplantation (ITx); (2) Methods: Twelve patients with Type 1 diabetes mellitus and severe hypoglycemia underwent ITx. Serum concentration of glutamic acid decarboxylase (GAD), insulinoma antigen 2 (IA-2), and zinc transport 8 (ZnT8) autoantibodies was assessed before ITx and 0, 7, and 75 days and every 3 months post-operatively; (3) Results: IA-2A (IA-2 antibody) and ZnT8A (ZnT8 antibody) levels were not detectable before or after ITx in all patients (median follow-up of 53 months (range 24-61)). Prior to ITx, GAD antibody (GADA) was undetectable in 67% (8/12) of patients. Of those, 75% (6/8) converted to GADA+ after ITx. In 67% (4/6) of patients with GADA+ seroconversion, GADA level peaked within 3 months after ITx and subsequently declined. All patients with GADA+ seroconversion maintained long-term partial or complete islet function (insulin independence) after 1 or 2 ITx. There was no correlation between the presence of IAb-associated HLA haplotypes and the presence of IAbs before or after ITx; (4) Conclusions: There is no association between serum GADA trends and ITx outcomes. IA-2A and ZnT8A were not detectable in any of our patients before or after ITx.

The Impact of COVID-19 on Kidney Transplant Recipients in Pre-Vaccination and Delta Strain Era: A Systematic Review and Meta-Analysis.

Herein, we performed a meta-analysis of published clinical outcomes of corona virus disease 2019 (COVID-19) in hospitalized kidney transplant recipients. A systematic database search was conducted between December 1, 2019 and April 20, 2020. We analyzed 48 studies comprising 3137 kidney transplant recipients with COVID-19. Fever (77%), cough (65%), dyspnea (48%), and gastrointestinal symptoms (28%) were predominant on hospital admission. The most common comorbidities were hypertension (83%), diabetes mellitus (34%), and cardiac disease (23%). The pooled prevalence of acute respiratory distress syndrome and acute kidney injury were 58% and 48%, respectively. Invasive ventilation and dialysis were required in 24% and 22% patients, respectively. In-hospital mortality rate was as high as 21%, and increased to over 50% for patients in intensive care unit (ICU) or requiring invasive ventilation. Risk of mortality in patients with acute respiratory distress syndrome (ARDS), on mechanical ventilation, and ICU admission was increased: OR = 19.59, OR = 3.80, and OR = 13.39, respectively. Mortality risk in the elderly was OR = 3.90; however, no such association was observed in terms of time since transplantation and gender. Fever, cough, dyspnea, and gastrointestinal symptoms were common on admission for COVID-19 in kidney transplant patients. Mortality was as high as 20% and increased to over 50% in patients in ICU and required invasive ventilation.

Post-Hoc Analysis of a Randomized, Double Blind, Prospective Study at the University of Chicago: Additional Standardizations of Trial Protocol are Needed to Evaluate the Effect of a CXCR1/2 Inhibitor in Islet Allotransplantation.

A recent randomized, multicenter trial did not show benefit of a CXCR1/2 receptor inhibitor (Reparixin) when analysis included marginal islet mass (>3,000 IEQ/kg) for allotransplantation and when immunosuppression regimens were not standardized among participating centers. We present a post-hoc analysis of trial patients from our center at the University of Chicago who received an islet mass of over 5,000 IEQ/kg and a standardized immunosuppression regimen of anti-thymocyte globulin (ATG) for induction. Twelve islet allotransplantation (ITx) recipients were randomized (2:1) to receive Reparixin (N = 8) or placebo (N = 4) in accordance with the multicenter trial protocol. Pancreas and donor characteristics did not differ between Reparixin and placebo groups. Five (62.5%) patients who received Reparixin, compared to none in the placebo group, achieved insulin independence after only one islet infusion and remained insulin-free for over 2 years (P = 0.08). Following the first ITx with ATG induction, distinct cytokine, chemokine, and miR-375 release profiles were observed for both the Reparixin and placebo groups. After excluding procedures with complications, islet engraftment on post-operative day 75 after a single transplant was higher in the Reparixin group (n = 7) than in the placebo (n = 3) group (P = 0.03) when islet graft function was measured by the ratio of the area under the curve (AUC) for c-peptide to glucose in mixed meal tolerance test (MMTT). Additionally, the rate of engraftment was higher when determined via BETA-2 score instead of MMTT (P = 0.01). Our analysis suggests that Reparixin may have improved outcomes compared to placebo when sufficient islet mass is transplanted and when standardized immunosuppression with ATG is used for induction. However, further studies are warranted. Investigation of Reparixin and other novel agents under more standardized and optimized conditions would help exclude confounding factors and allow for a more definitive evaluation of their role in improving outcomes in islet transplantation. Clinical trial reg. no. NCT01817959, clinicaltrials.gov.

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.

En bloc liver and pancreas transplantation after total pancreatectomy with autologous islet transplantation.

We present a patient with intractable and debilitating pain secondary to chronic pancreatitis who was effectively treated with total pancreatectomy with islet autotransplantation (TPIAT). Islets engrafted into his liver significantly contributed to improved blood glucose control and quality of life. Subsequently, the patient developed alcohol related acute liver failure and en bloc liver and pancreas transplantation was performed to replace the failing liver with engrafted islets. Pancreas transplantation was required to resolve his life-threatening severe hypoglycemic episodes. Herein, we detail an innovative and multidisciplinary management of this complex medical problem.

The Bill & Melinda Gates Foundation: An opportunity to lead innovation in global surgery.

BACKGROUND: The Bill and Melinda Gates Foundation has made unparalleled contributions to global health and human development by bringing together generous funding, strategic partnerships, and innovative leadership. For the last twenty years, the Gates Foundation has supported the expansion of programs that directly address the fundamental barriers to the advancement of marginalized communities around the globe, with a transformative focus on innovations to combat communicable diseases and to ensure maternal and child health. Despite the wide spectrum of programs, the Gates Foundation has not, as of yet, explicitly supported the development of surgical care. METHODS: This article explores the pivotal role that the Gates Foundation could play in advancing the emerging global surgery agenda. First, we demonstrate the importance of the Gates Foundation's contributions by reviewing its history, growth, and evolution as a pioneering supporter of global health and human development. Recognizing the Foundation's use of metrics and data in strategic planning and action, we align the priorities of the Foundation with the growing recognition of surgical care as a critical component of efforts to ensure universal health care. RESULTS: To promote healthy lives and well-being for all, development of quality and affordable capacity for surgery, obstetrics and anesthesia is more important than ever. We present the unique opportunity for the Gates Foundation to bring its transformative vision and programing to the effort to ensure equitable, timely, and quality surgical care around the world.

The World Bank Group: Innovative financing for health and opportunities for global surgery.

The World Bank Group is the largest global development organization working to end poverty and promote shared prosperity. Its 5 institutions play an essential role in the advancement of global health through innovative health financing, data collection and management, policy reform, and advocacy. Previously, the World Bank Group has supported global surgery through data collection and advocacy. As it grows, it must continue to focus on the importance of surgical care in promoting health and avoiding poverty in low- and middle-income countries. The house of surgery and its community should play an active role in advocating for the many ways in which the World Bank Group could facilitate the strengthening of surgical systems to improve access to surgical care worldwide.

The Current State of Neurosurgery in Haiti.

BACKGROUND: Even though surgical conditions account for as much as 32% of the global burden of disease, 5 billion people worldwide do not have access to timely, affordable surgical and anesthetic care. Access to surgical care is separated along socioeconomic divides, and these disparities are most pronounced in low-and middle-income countries, such as the Caribbean nation of Haiti, where the availability of specialty surgical services like neurosurgery are scant, or completely absent. METHODS: This paper provides a narrative account of current neurosurgery-related activity in Haiti, a nation whose social, political, and economic context is unique in the Americas. RESULTS: After some background information and a bibliometric analysis of recent research efforts, we provide brief biographical sketches of Haiti's local neurosurgical leaders and an overview of recent initiatives in Haitian neurosurgical capacity building. CONCLUSIONS: The paper concludes with recommendations to guide the international neurosurgery community in future contributions.

Towards resilient health systems: opportunities to align surgical and disaster planning.

Natural disasters significantly contribute to human death and suffering. Moreover, they exacerbate pre-existing health inequalities by imposing an additional burden on the most vulnerable populations. Robust local health systems can greatly mitigate this burden by absorbing the extraordinary patient volume and case complexity immediately after a disaster. This resilience is largely determined by the predisaster local surgical capacity, with trauma, neurosurgical, obstetrical and anaesthesia care of particular importance. Nevertheless, the disaster management and global surgery communities have not coordinated the development of surgical systems in low/middle-income countries (LMIC) with disaster resilience in mind. Herein, we argue that an appropriate peridisaster response requires coordinated surgical and disaster policy, as only local surgical systems can provide adequate disaster care in LMICs. We highlight three opportunities to help guide this policy collaboration. First, the Lancet Commission on Global Surgery and the Sendai Framework for Disaster Risk Reduction set forth independent roadmaps for global surgical care and disaster risk reduction; however, ultimately both advocate for health system strengthening in LMICs. Second, the integration of surgical and disaster planning is necessary. Disaster risk reduction plans could recognise the role of surgical systems in disaster preparedness more explicitly and pre-emptively identify deficiencies in surgical systems. Based on these insights, National Surgical, Obstetric, and Anesthesia Plans, in turn, can better address deficiencies in systems and ensure increased disaster resilience. Lastly, the recent momentum for national surgical planning in LMICs represents a political window for the integration of surgical policy and disaster risk reduction strategies.

Out-of-pocket expenses incurred by patients obtaining free breast cancer care in Haiti: A pilot study.

BACKGROUND: Women in low- and middle-income countries account for 51% of breast cancer cases globally. These patients often delay seeking care and, therefore, present with advanced disease, partly because of fear of catastrophic health care expenses. Although there have been efforts to make health care affordable in low- and middle-income countries, the financial burden of out-of-pocket (OOP) expenses for nonmedical costs, such as transportation and lost wages, often is overlooked. METHODS: An institutional review board exemption was granted from Boston Children's Hospital and Partners in Health/Zanmi Lasante for this cross-sectional study. In total, 61 patients receiving breast cancer care free of charge at Hôpital Universitaire de Mirebalais (HUM) in Haiti were selected via convenience sampling. They were interviewed between March and May 2014 to quantify the expenses they incurred during the course of diagnosis and treatment. These expenses included medical costs at outside facilities, as well as nonmedical costs (eg, transportation, meals, etc). RESULTS: The median, nonmedical OOP expenses incurred by breast cancer patients at HUM were $233 (95% confidence interval [95% CI] $170-304) for diagnostic visits, $259 (95% CI $200-533) for chemotherapy visits, and $38 (95% CI $23-140) for surgery visits. The median total OOP expense (including medical costs) was $717 (95% CI $619-1,171). To pay for these expenses, 52% of participants stated that they went into debt; however, the amount of debt was not quantified. The median income of these patients was $1,333 (95% CI $778-2,640), and the median sum of OOP expenses and lost wages was $2,996 (95% CI $1,676-5,179). CONCLUSION: Despite receiving free care: at HUM, more than two-thirds of participants met conservative criteria for catastrophic medical expenses (defined as spending more than 40% of their potential household income on OOP payments). Further studies are needed to understand the magnitude of OOP health care expenses for the poor worldwide, how to aid them during their treatment program, and its impact on their health outcomes.