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The graph convolutional network (GCN) is a go-to solution for machine learning on graphs, but its training is notoriously difficult to scale both in terms of graph size and the number of model parameters. Although some work has explored training on large-scale graphs, we pioneer efficient training of large-scale GCN models with the proposal of a novel, distributed training framework, called GIST. GIST disjointly partitions the parameters of a GCN model into several, smaller sub-GCNs that are trained independently and in parallel. Compatible with all GCN architectures and existing sampling techniques, GIST (i) improves model performance, (ii) scales to training on arbitrarily large graphs, (iii) decreases wall-clock training time, and (iv) enables the training of markedly overparameterized GCN models. Remarkably, with GIST, we train an astonishgly-wide 32–768-dimensional GraphSAGE model, which exceeds the capacity of a single GPU by a factor of 8×, to SOTA performance on the Amazon2M dataset.

The transplantation of organs from donors with hepatitis C virus (HCV) infection into uninfected recipients has expanded the available organ donor pool. With the advancement of direct-acting antivirals (DAAs), high rates of cure among transplant recipients are possible. Although DAAs are highly effective, treatment failure can occur following an appropriate 12-week course of a pan-genotypic regimen. Here we describe 4 kidney transplant recipients of organs from donors with HCV infection (3 with genotype 3, 1 genotype 1a) in whom first-line DAA treatment with either glecaprevir-pibrentasvir or sofosbuvir-velpatasvir was unsuccessful, started 22-35 days after the day of transplantation. All ultimately achieved sustained virologic response with second- or third-line therapy. Post-treatment resistance-associated substitutions were tested and noted to be present in 2 cases. Additionally, antiviral levels were assessed in 2 cases and found to be therapeutic in each. This article explores possible reasons for treatment failure, including medication interactions, bariatric surgery, viral dynamics, and drug resistance.

Nontuberculous mycobacteria are emerging pathogens, yet data on the epidemiology and management of extrapulmonary nontuberculous mycobacteria infections in orthotopic heart transplantation (OHT) and ventricular assist device (VAD) recipients are scarce. We retrospectively reviewed records of OHT and VAD recipients who underwent cardiac surgery at our hospital and developed Mycobacterium abscessuscomplex (MABC) infection from 2013 to 2016 during a hospital outbreak of MABC linked to heater-cooler units. We analyzed patient characteristics, medical and surgical management, and long-term outcomes. Ten OHT patients and 7 patients with VAD developed extrapulmonary M. abscessussubspecies abscessusinfection. The median time from presumed inoculation during cardiac surgery to the first positive culture was 106 days in OHT and 29 days in VAD recipients. The most common sites of positive cultures were blood (n = 12), sternum/mediastinum (n = 8), and the VAD driveline exit site (n = 7). The 14 patients diagnosed when alive received combination antimicrobial therapy for a median of 21 weeks, developed 28 antibiotic-related adverse events, and underwent 27 surgeries. Only 8 (47%) patients survived longer than 12 weeks after diagnosis, including 2 patients with VAD who experienced long-term survival after an explantation of infected VADs and OHT. Despite aggressive medical and surgical management, OHT and VAD patients with MABC infection experienced substantial morbidity and mortality.

Baricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19.

Despite emerging data suggesting reduced antibody responses among solid organ transplant recipients following SARS‐CoV‐2 vaccine, critical unanswered questions remain. The clinical implications of the reduced humoral response need to be assessed through prospective studies. Studies are likewise needed to inform which vaccine dosing strategies result in improved immunity and if such approaches maximize protection against severe infection in the vulnerable transplant population. In this Viewpoint, the authors review the existing data on SARS‐CoV‐2 vaccine in transplant recipients and outline next steps in understanding how to optimize immunologic responses to the vaccine.

Despite emerging data suggesting reduced antibody responses among solid organ transplant recipients following SARS-CoV-2 vaccine, critical unanswered questions remain. The clinical implications of the reduced humoral response need to be assessed through prospective studies. Studies are likewise needed to inform which vaccine dosing strategies result in improved immunity and if such approaches maximize protection against severe infection in the vulnerable transplant population.

Patients pursuing solid organ transplantation are encouraged to receive many vaccines on an accelerated timeline. Vaccination prior to transplantation offers the best chance of developing immunity and may expand the pool of donor organs that candidates can accept without needing posttransplant therapy. Furthermore, transplant recipients are at greater risk for acquiring vaccine‐preventable illnesses or succumbing to severe sequelae of such illnesses. However, a rising rate of vaccine refusal has challenged transplant centers to address the phenomenon of vaccine hesitancy. Transplant centers may need to consider adopting a policy of denial of solid organ transplantation on the basis of vaccine refusal for non‐medical reasons (i.e., philosophical or religious objections or personal beliefs that vaccines are unnecessary or unsafe). Arguments supporting such a policy are motivated by utility, stewardship, and beneficence. Arguments opposing such a policy emphasize justice and respect for persons, and seek to avoid worsening inequities or medical coercion. This paper examines these arguments and situates them within the special cases of pediatric transplantation, emergent transplantation, and living donation. Ultimately, a uniform national policy addressing vaccine refusal among transplant candidates is needed to resolve this ethical dilemma and establish a consistent, fair, and standard approach to vaccine refusal in transplantation. The authors summarize ethical arguments both in favor of and against mandating compliance with routine vaccination for solid organ transplant candidates during the waitlisting process.

Patients pursuing solid organ transplantation are encouraged to receive many vaccines on an accelerated timeline. Vaccination prior to transplantation offers the best chance of developing immunity and may expand the pool of donor organs that candidates can accept without needing posttransplant therapy. Furthermore, transplant recipients are at greater risk for acquiring vaccine-preventable illnesses or succumbing to severe sequelae of such illnesses. However, a rising rate of vaccine refusal has challenged transplant centers to address the phenomenon of vaccine hesitancy. Transplant centers may need to consider adopting a policy of denial of solid organ transplantation on the basis of vaccine refusal for non-medical reasons (i.e., philosophical or religious objections or personal beliefs that vaccines are unnecessary or unsafe). Arguments supporting such a policy are motivated by utility, stewardship, and beneficence. Arguments opposing such a policy emphasize justice and respect for persons, and seek to avoid worsening inequities or medical coercion. This paper examines these arguments and situates them within the special cases of pediatric transplantation, emergent transplantation, and living donation. Ultimately, a uniform national policy addressing vaccine refusal among transplant candidates is needed to resolve this ethical dilemma and establish a consistent, fair, and standard approach to vaccine refusal in transplantation.

Cryptococcusspecies can cause serious life-threatening infection in solid organ transplant recipients by reactivation of prior infection, posttransplant de novoinfection, or donor transmission from the transplanted organ. Although previously reported in the literature, the extent of donor-derived cryptococcosis in the United States has not been documented. We analyzed potential donor-derived Cryptococcustransmission events reported to the Organ Procurement and Transplantation Network (OPTN) for investigation by the Ad Hoc Disease Transmission Advisory Committee (DTAC). All reports between 2009 and 2019 in which transmission to recipients was designated proven or probable, or determined to be averted due to implementation of prophylaxis (intervention without disease transmission—“IWDT”) were included. During 2009–2019, 58 reports of potential donor-derived cryptococcosis were submitted to DTAC. Among these reports, 12 donors were determined to have resulted in proven or probable transmission to 23/34 (67.6%) recipients. Most of these donors (10/12 [83%]) exhibited central nervous system-related symptoms prior to death and 5/23 (22%) infected recipients died. For 11 different donors, prophylaxis, most often with fluconazole, was administered to 23/35 (65.7%) recipients. Clinicians should maintain awareness of donor-derived cryptococcosis and consider prompt prophylaxis or treatment followed by reporting to OPTN for further investigation.

HIV‐positive donor to HIV‐positive recipient (HIV D+/R+) transplantation is permitted in the United States under the HIV Organ Policy Equity Act. To explore safety and the risk attributable to an HIV+ donor, we performed a prospective multicenter pilot study comparing HIV D+/R+ vs HIV‐negative donor to HIV+ recipient (HIV D−/R+) kidney transplantation (KT). From 3/2016 to 7/2019 at 14 centers, there were 75 HIV+ KTs: 25 D+ and 50 D− (22 recipients from D− with false positive HIV tests). Median follow‐up was 1.7 years. There were no deaths nor differences in 1‐year graft survival (91% D+ vs 92% D−, P= .9), 1‐year mean estimated glomerular filtration rate (63 mL/min D+ vs 57 mL/min D−, P= .31), HIV breakthrough (4% D+ vs 6% D−, P> .99), infectious hospitalizations (28% vs 26%, P= .85), or opportunistic infections (16% vs 12%, P= .72). One‐year rejection was higher for D+ recipients (50% vs 29%, HR: 1.83, 95% CI 0.84‐3.95, P= .13) but did not reach statistical significance; rejection was lower with lymphocyte‐depleting induction (21% vs 44%, HR: 0.33, 95% CI 0.21‐0.87, P= .03). In this multicenter pilot study directly comparing HIV D+/R+ with HIV D−/R+ KT, overall transplant and HIV outcomes were excellent; a trend toward higher rejection with D+ raises concerns that merit further investigation. In this multicenter HOPE Act study of 75 HIV‐positive kidney transplant recipients, patient survival, graft survival, and HIV‐related complications are similar between those receiving kidneys from HIV‐positive and HIV‐negative deceased donors, but a trend toward higher rejection with HIV‐positive donors merits surveillance and careful tailoring of immunosuppression. See the editorial from Montero et al on page 1683.

Cryptococcusspecies can cause serious life‐threatening infection in solid organ transplant recipients by reactivation of prior infection, posttransplant de novoinfection, or donor transmission from the transplanted organ. Although previously reported in the literature, the extent of donor‐derived cryptococcosis in the United States has not been documented. We analyzed potential donor‐derived Cryptococcustransmission events reported to the Organ Procurement and Transplantation Network (OPTN) for investigation by the Ad Hoc Disease Transmission Advisory Committee (DTAC). All reports between 2009 and 2019 in which transmission to recipients was designated proven or probable, or determined to be averted due to implementation of prophylaxis (intervention without disease transmission—“IWDT”) were included. During 2009–2019, 58 reports of potential donor‐derived cryptococcosis were submitted to DTAC. Among these reports, 12 donors were determined to have resulted in proven or probable transmission to 23/34 (67.6%) recipients. Most of these donors (10/12 [83%]) exhibited central nervous system‐related symptoms prior to death and 5/23 (22%) infected recipients died. For 11 different donors, prophylaxis, most often with fluconazole, was administered to 23/35 (65.7%) recipients. Clinicians should maintain awareness of donor‐derived cryptococcosis and consider prompt prophylaxis or treatment followed by reporting to OPTN for further investigation. When accepting organs from donors with neurologic symptoms or immunocompromising conditions, transplant centers should be aware of the risk posed of donor‐derived cryptococcus infection in transplant recipients, which has been rare but can be severe.

Despite clinical and laboratory screening of potential donors for transmissible disease, unexpected transmission of disease from donor to recipient remains an inherent risk of organ transplantation. The Disease Transmission Advisory Committee (DTAC) was created to review and classify reports of potential disease transmission and use this information to inform national policy and improve patient safety. From January 1, 2008 to December 31, 2017, the DTAC received 2185 reports; 335 (15%) were classified as a proven/probable donor transmission event. Infections were transmitted most commonly (67%), followed by malignancies (29%), and other disease processes (6%). Forty‐six percent of recipients receiving organs from a donor that transmitted disease to at least 1 recipient developed a donor‐derived disease (DDD). Sixty‐seven percent of recipients developed symptoms of DDD within 30 days of transplantation, and all bacterial infections were recognized within 45 days. Graft loss or death occurred in about one third of recipients with DDD, with higher rates associated with malignancy transmission and parasitic and fungal diseases. Unexpected DDD was rare, occurring in 0.18% of all transplant recipients. These findings will help focus future efforts to recognize and prevent DDD. A 10‐year review finds that unexpected donor‐derived disease, while uncommon, results in significant morbidity and mortality in affected recipients.

The acute morbidity and mortality of COVID-19 have been well described. Evidence is emerging that COVID-19 may also result in negative long-term medical and psychiatric outcomes. A broad response from the public health community in North Carolina that includes robust surveillance and catch-up care is needed to reduce the long-term sequelae of COVID-19.

A 61‐year‐old female with well‐controlled human immunodeficiency virus (HIV) and end‐stage renal disease was on the kidney transplant waitlist awaiting an organ offer, including from HIV‐positive donors through the HIV Organ Policy Equity (HOPE) Act. We present three different scenarios where HIV‐positive donor offers were evaluated for this one recipient, discuss the donor evaluation process, explain where the infectious diseases provider fits in this scheme, and describe the challenges encountered by organ procurement organizations. This is the first case under the HOPE Act at our center where discovery of an HIV‐specific issue led to a turndown of an organ offer. This case report demonstrates that transplantation of organs from HIV‐positive deceased donors raises unique issues that benefit from HIV expertise to ensure safe donor‐recipient matching.

The recent identification of an outbreak of 2019‐ novel Coronavirus is currently evolving, and the impact on transplantation is unknown. However, it is imperative that we anticipate the potential impact on the transplant community in order to avert severe consequences of this infection on both the transplant community and contacts of transplant patients. Given the current spread of a novel coronavirus, transplant infectious disease experts discuss the impact of emerging infections on the transplant community and suggest current management strategies.

Pretransplant mortality rates in the United States remain high and are connected to effective organ donation and utilization. Thus, there is a need to maximize the utilization of available donors. In some cases, this has been safely achieved using organs from donors with infectious complications. For example, several studies describe the use of organs from donors with bacterial meningitis due to pathogens such as Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenza, and Escherichia coli, with good outcomes. Listeriais an aerobic and facultatively anaerobic, non-spore-forming, Gram-positive rod that can affect the central nervous system, causing meningitis and meningoencephalitis. Due to its virulence, ability to cause intracellular infection, and lack of clinical data, people dying with listeria may not be evaluated for organ donation, may not have organs recovered, or may have their organs recovered but not transplanted. Herein, we describe the outcomes of seven solid organ transplant recipients who received organs from two donors with Listeria monocytogenesCNS infection.

Since the 1918 influenza pandemic, non-randomised studies and small clinical trials have suggested that convalescent plasma or anti-influenza hyperimmune intravenous immunoglobulin (hIVIG) might have clinical benefit for patients with influenza infection, but definitive data do not exist. We aimed to evaluate the safety and efficacy of hIVIG in a randomised controlled trial.

Living kidney donation is possible for people living with HIV (PLWH) in the United States within research studies under the HIV Organ Policy Equity (HOPE) Act. There are concerns that donor nephrectomy may have an increased risk of end-stage renal disease (ESRD) in PLWH due to HIV-associated kidney disease and antiretroviral therapy (ART) nephrotoxicity. Here we report the first 3 cases of living kidney donors with HIV under the HOPE Act in the United States.

Mollicute infections, caused by Mycoplasmaand Ureaplasmaspecies, are serious complications after lung transplantation; however, understanding of the epidemiology and outcomes of these infections remains limited. We conducted a single-center retrospective study of 1156 consecutive lung transplants performed from 2010-2019. We used log-binomial regression to identify risk factors for infection and analyzed clinical management and outcomes. In total, 27 (2.3%) recipients developed mollicute infection. Donor characteristics independently associated with recipient infection were age ≤40 years (prevalence rate ratio [PRR] 2.6, 95% CI 1.0-6.9), White race (PRR 3.1, 95% CI 1.1-8.8), and purulent secretions on donor bronchoscopy (PRR 2.3, 95% CI 1.1-5.0). Median time to diagnosis was 16 days posttransplant (IQR: 11-26 days). Mollicute-infected recipients were significantly more likely to require prolonged ventilatory support (66.7% vs 21.4%), undergo dialysis (44.4% vs 6.3%), and remain hospitalized ≥30 days (70.4% vs 27.4%) after transplant. One-year posttransplant mortality in mollicute-infected recipients was 12/27 (44%), compared to 148/1129 (13%) in those without infection (P<.0001). Hyperammonemia syndrome occurred in 5/27 (19%) mollicute-infected recipients, of whom 3 (60%) died within 10 weeks posttransplant. This study highlights the morbidity and mortality associated with mollicute infection after lung transplantation and the need for better screening and management protocols.

ABSTRACTAmikacin is a major drug used for the treatment of Mycobacterium aviumcomplex (MAC) disease, but standard laboratory guidelines for susceptibility testing are not available. This study presents in vitroamikacin MICs for 462 consecutive clinical isolates of the MAC using a broth microdilution assay. Approximately 50% of isolates had amikacin MICs of 8 µg/ml, and 86% had MICs of =16 µg/ml. Of the eight isolates (1.7%) with MICs of 64 µg/ml, five had an MIC of 32 µg/ml on repeat testing. Ten isolates (2.1%) had an initial amikacin MIC of >64 µg/ml, of which seven (1.5%) had MICs of >64 µg/ml on repeat testing. These seven isolates had a 16S rRNA gene A1408G mutation and included M. avium, Mycobacterium intracellulare, and Mycobacterium chimaera. Clinical data were available for five of these seven isolates, all of which had received prolonged (>6 months) prior therapy, with four that were known to be treated with amikacin. The 16S mutation was not detected in isolates with MICs of =64 µg/ml. We recommend primary testing of amikacin against isolates of the MAC and propose MIC guidelines for breakpoints that are identical to the CLSI guidelines for Mycobacterium abscessus: =16 µg/ml for susceptible, 32 µg/ml for intermediate, and =64 µg/ml for resistant. If considered and approved by the CLSI, this will be only the second drug recommended for primary susceptibility testing against the MAC and should facilitate its use for both intravenous and inhaled drug therapies.

ABSTRACTBotulism developed in a patient following surgical repair of an open radial fracture. Symptoms resolved after treatment with antitoxin and antibiotics, and hardware excision was deferred. Subsequent osteomyelitis necessitated hardware exchange, and wound cultures grew Clostridium argentinense. This case highlights the management of botulism associated with orthopedic hardware.

There is an urgent need for an effective, oral, direct-acting therapeutic to block transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and prevent progression to severe coronavirus disease 2019 (COVID-19). In a phase 2a double-blind, placebo-controlled, randomized, multicenter clinical trial, we evaluated the safety, tolerability, and antiviral efficacy of the nucleoside analog molnupiravir in 202 unvaccinated participants with confirmed SARS-CoV-2 infection and symptom duration <7 days. Participants were randomized 1:1 to receive molnupiravir (200 mg) or placebo and then 3:1 to receive molnupiravir (400 or 800 mg) or placebo, orally twice daily for 5 days. Antiviral activity was assessed by reverse transcriptase polymerase chain reaction (RT-PCR) for SARS-CoV-2 RNA in nasopharyngeal swabs. Infectious virus was assessed by inoculation of cultured Vero cells with samples from nasopharyngeal swabs and was detected by RT-PCR. Time to viral RNA clearance (primary endpoint) was decreased in the 800-mg molnupiravir group (median 14 days) compared to the placebo group (median 15 days) (log rank Pvalue = 0.013). Of participants receiving 800 mg of molnupiravir, 92.5% achieved viral RNA clearance compared with 80.3% of placebo recipients by study end (4 weeks). Infectious virus (secondary endpoint) was detected in swabs from 1.9% of the 800-mg molnupiravir group compared with 16.7% of the placebo group at day 3 of treatment (P= 0.016). At day 5 of treatment, infectious virus was not isolated from any participants receiving 400 or 800 mg of molnupiravir compared with 11.1% of placebo recipients (P= 0.034 and 0.027, respectively). Molnupiravir was well tolerated across all doses.

Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19.

Historical influenza A epidemics have carried elevated rates of cardiovascular disease, including transient cardiac dysfunction. Whether such an association holds for the novel influenza A strain, pandemic 2009 influenza A(H1N1) [A(H1N1)], remains unknown. We report an index case of transient cardiac dysfunction associated with A(H1N1) infection. Next, we reviewed 123 sequential cases of patients hospitalized with pandemic A(H1N1) at a single academic medical center in the United States from April 1, 2009, through October 31, 2009. We identified that 4.9% (6/123) of patients had either new or worsened left ventricular dysfunction. These cases ranged in age from 23 to 51 years, and all had preexisting medical conditions. ICU level care was required in 83% (5/6) of the cases. Sixty-seven percent (4/6) of the cases had follow-up echocardiograms, and left ventricular function improved in all four. We conclude that potentially reversible cardiac dysfunction is a relatively common complication associated with hospitalized pandemic A(H1N1) influenza.

In this editorial, the authors highlight recent work from de Vera et al (page 2451) regarding the transplantation of kidneys from HCV antibody–positive donors to HCV-negative recipients that should increase provider confidence in the safety of using these organs.

In this editorial, the authors highlight recent work from de Vera et al (page 2451) regarding the transplantation of kidneys from HCV antibody–positive donors to HCV‐negative recipients that should increase provider confidence in the safety of using these organs.

Treatment options for drug-resistant cytomegalovirus (CMV) are limited. Letermovir is a novel antiviral recently approved for CMV prophylaxis following hematopoietic cell transplantation, but its efficacy in other settings is unknown.