Remote training and teleproctoring in gastrointestinal endoscopy for practicing surgeon in rural Uganda.

BACKGROUND: There is a significant, unmet need for endoscopy services in rural Uganda. With limited diagnostic and therapeutic interventions, patients in these communities often present with advanced disease. Practicing surgeons must continually adapt to new techniques to meet the needs of their patient populations. Here, we present a remotely proctored endoscopy training program for a surgeon practicing in an area devoid of endoscopic capabilities. METHODS: This was a retrospective case series conducted between February 2020 and December 2022 at Kyabirwa Surgical Center (KSC). After a 1-week in-person training camp, one surgeon performed endoscopy under guidance of a remote proctor. Patient data and outcomes were collected retrospectively. RESULTS: The previously endoscopic naïve practicing Ugandan surgeon was remotely proctored for 139 endoscopic cases and he subsequently independently performed 167 diagnostic colonoscopies and 425 upper endoscopies. Therapeutic endoscopy was conducted under remote guidance after proficiency in diagnostic endoscopy. A total of 43 therapeutic procedures were performed, including 29 esophageal stent placements, 5 variceal bandings, and 9 foreign body retrievals. All procedures were completed without complication. CONCLUSION: Our center developed a remotely proctored endoscopy program that allowed for training of practicing surgeons in an area lacking endoscopic services. Despite its limitations, remotely proctored endoscopy serves as a unique but highly valuable method of expanding access to endoscopy, particularly in areas that lack adequate training opportunities.

Commercial insurance delays direct-acting antiviral treatment for hepatitis C kidney transplantation into uninfected recipients.

INTRODUCTION: The advent of direct-acting antivirals (DAAs) has created an avenue for transplantation of hepatitis C virus (HCV)-infected donors into uninfected recipients (D+/R-). The donor transmission of HCV is then countered by DAA administration during the post-operative period. However, initiation of DAA treatment is ultimately dictated by insurance companies. METHODS: A retrospective chart review of 52 D+/R- kidney recipients who underwent DAA treatment post-transplant was performed. Patients were grouped according to their prescription coverage plans, managed by either commercial or government pharmacy benefit managers (PBMs). RESULTS: Thirty-nine patients had government PBMs and 13 had commercial PBMs. Demographics were similar between the two groups. All patients developed HCV viremia, but cleared the virus after treatment with DAA. Patients with government PBMs were treated earlier compared to those with commercial PBMs (11 days vs 26 days, P = .01). Longer time to DAA initiation resulted in higher peak viral loads (ß = 0.39, R2  = .15, P = .01) and longer time to HCV viral load clearance (ß = 0.41, R2  = .17, P = .01). CONCLUSIONS: D+/R- transplantation offers patients an alternative strategy to increase access. However, treatment can be profoundly delayed by a third-party payer authorization process that may be subjecting patients to unnecessary risks and worsened outcomes.

Transplantation of viral-positive hepatitis C-positive kidneys into uninfected recipients offers an opportunity to increase organ access.

The advent of direct-acting antivirals (DAAs) has provided the impetus to transplant kidneys from hepatitis C virus-positive donors into uninfected recipients (D+/R-). Thirty D+/R- patients received DAA treatment. Sustained virologic response (SVR12) was defined as an undetectable viral load in 12 weeks after treatment. An age-matched cohort of uninfected donor and recipient pairs (D-/R-) transplanted during same time period was used for comparison. The median day of viral detection was postoperative day (POD) 2. The detection of viremia in D+/R- patients was 100%. The initial median viral load was 531 copies/µL (range: 10-1 × 108 copies/µL) with a median peak viral load of 3.4 × 105 copies/µL (range: 804-1.0 × 108 copies/µL). DAAs were initiated on median POD 9 (range: 5-41 days). All 30 patients had confirmed SVR12. During a median follow-up of 10 months, patient and graft survival was 100%, and acute rejection was 6.6% with no major adverse events related to DAA treatment. Delayed graft function was significantly decreased in D+/R- patients as compared to the age-matched cohort (27% vs 60%; P = .01). D+/R- transplantation offers patients an alternative strategy to increase access.

Protective Efficacy of Broadly Neutralizing Antibodies with Incomplete Neutralization Activity against Simian-Human Immunodeficiency Virus in Rhesus Monkeys.

HIV broadly neutralizing antibodies (bnAbs) have been shown to occasionally display unusual virus neutralization profiles with nonsigmoidal slopes and plateaus at <100% neutralization against a variety of viruses. The significance of incomplete neutralization for the ability of bnAbs to mediate protective effects in vivo, however, is undetermined. In the current study, we selected two bnAbs, PGT121 and 3BNC117, as they incompletely neutralize the clade C simian-human immunodeficiency virus (SHIV) stock (SHIV-327c) at 85% and 70%, respectively, and performed a protection study in rhesus macaques. The animals were intravenously (i.v.) administered PGT121 or 3BNC117 at 10 and 2 mg/kg of body weight before being rectally challenged with a single high dose of SHIV-327c. PGT121 protected 6 out of 7 monkeys, while 6 out of 7 3BNC117-pretreated animals became infected, although with significantly delayed plasma viremia compared to the control animals. These data suggest that complete neutralization is not imperative for bnAbs to prevent infection but that with increasing levels of incomplete neutralization the sterilizing activity diminishes.IMPORTANCE Multiple antibodies have been identified that potently neutralize a broad range of circulating HIV strains. However, not every virus-antibody combination results in complete neutralization of the input virus, suggesting that a fraction of virus particles are resistant to antibody neutralization despite high antibody concentrations. This observation of "incomplete neutralization" is associated with nonsigmoidal neutralization curves plateauing below 100% neutralization, but the significance of the phenomenon for the ability of neutralizing antibodies to mediate protective effects in vivo is undetermined. In this study, we show that the broadly neutralizing antibody PGT121, which neutralized only up to 85% of the SHIV-327c challenge stock in vitro, protected 6 out of 7 rhesus macaques against infection while the antibody 3BNC117, which neutralized up to 70% of SHIV-327c in vitro, did not prevent, though it significantly delayed, establishment of infection, suggesting that with increasing levels of incomplete neutralization the ability of a bnAb to mediate sterilizing protection diminishes.

Improving pancreas graft utilization through importation.

BACKGROUND: We analyze our outcomes utilizing imported allografts as a strategy to shorten wait list time for pancreas transplantation. METHODS: This is an observational retrospective cohort of 26 recipients who received either a locally procured (n = 16) or an imported pancreas graft (n = 10) at our center between January 2014 and May 2017. Wait list times of this cohort were compared to UNOS Region 9 (New York State and Western Vermont). Hospital financial data were also reviewed to analyze the cost-effectiveness of this strategy. RESULTS: Imported pancreas grafts had significantly increased cold ischemia times (CIT) and peak lipase (PL) levels compared to locally procured grafts (CIT 827 vs 497 minutes; P = .001, PL 563 vs 157 u/L; P = .023, respectively). There were no differences in graft or patient survival. The median wait time was significantly lower for simultaneous kidney-pancreas transplants at our center (518 days, n = 21) compared to Region 9 (1001 days, n = 65) P = .038. Despite financial concerns, the cost of transport for imported grafts was offset by lower standard acquisition costs. CONCLUSIONS: Imported pancreas grafts may be a cost-effective strategy to increase organ utilization and shorten wait times in regions with longer waiting times.

A Decade of Liver Transplantation in the United States: Drivers of Discard and Underutilization.

Background: Organ shortage remains a major challenge for the field of transplantation. Maximizing utilization and minimizing discard of available organs is crucial to reduce waitlist times. Our aim was to investigate the landscape of liver recovery, discard over the past decade in the United States, and identify areas to reduce organ discard. Methods: This study used the Scientific Registry of Transplant Recipients United Network for Organ Sharing database to analyze the rates and associated reasons of discarded organs from 2010 to 2021. All deceased donors were evaluated, and data were analyzed by organ type, year, and region. Organ disposition was analyzed by year and region. Donor demographics and liver biopsy data were also analyzed. Results: The volume of liver transplantation increased steadily, with a 44% increase from 2010 to 2021. Donation after circulatory death transplantation increased by 239%, comprising 10.6% of transplants in 2021, yet discard rates remained high at 30% for this donor subset. For all donor types, the liver discard rate has remained stable around 10% despite a 74% increase in available donors. Seventy percent of liver discards were attributed to organ factors, with biopsy findings accounting for 40% of all discards. Of livers that were biopsied, 70% had macrosteatosis of <30%. Conclusions: Analysis of trends in transplantation and discard allow for identifying areas of underutilization. Donation after circulatory death livers have expanded the pool of transplanted livers but remain discarded at high rates. Significant differences remain in discard rates between geographic regions. We identify several areas to lower the discard rates. The expanding role of machine perfusion may allow for utilization of previously discarded organs.

Leaking Umbilical Hernias in Cirrhotic Patients, Repair or Observe?

BACKGROUND: Umbilical hernias (UHs) in cirrhotic patients are common, can be quite complicated and are associated with significant morbidity and mortality. Leakage of ascites is a challenging entity and poses significant risks. METHODS: This is a retrospective study of patients with cirrhosis and UHs with ascitic leakage. Patients were divided into two groups: patients managed operatively during index admission (Group 1) and those managed non-surgically during index admission (Group 2). Group 2 was further divided into those that subsequently underwent repair of UH and those managed medically. RESULTS: Of 47 cirrhotic patients with leaking UHs, 19 patients were managed surgically during index admission (Group 1). In Group 2, 15 patients were managed non-surgically and 13 subsequently underwent surgery. The groups had comparable demographics, MELD-Na and Child-Pugh class. Group 2 had a higher rate of emergency surgery (92% vs 58%, P = .04) and higher rate of recurrence (31 vs. 0%, P = .02). The non-surgical patients in Group 2 had higher 1-year mortality (67%) compared to Group 1 (21%) and surgical patients in Group 2 (31%, P = .007). Multi-variable logistic regression for 1-year mortality demonstrated MELD-Na as the most significant risk factor (OR = 1.2, P = .05) and undergoing UH repair as the most significant protective factor (OR = .16, P = .02). CONCLUSIONS: Cirrhotic patients with leaking UHs should undergo urgent repair. Non-operative management confers high risk of continued or increased ascitic leakage necessitating more emergent surgery. Despite high rate of post-operative complications related to cirrhosis, there is a clear mortality benefit to the repair of leaking UHs in cirrhotic patients.

Tracheal Bronchus With Delayed Pleural Fistula After Pneumonectomy Managed With Eloesser Flap.

Bronchopleural fistula (BPF) typically occurs in the weeks after lobectomy or pneumonectomy and rarely occurs years after a surgical procedure. Management of BPF can be challenging, especially when it manifests in a delayed fashion. The report presents a case of asymptomatic BPF and pleurocutaneous fistula in a patient with a remote history of right pneumonectomy and unusual anatomy.

High terminal creatinine donors should not preclude simultaneous kidney and pancreas transplantation.

BACKGROUND: Simultaneous pancreas and kidney transplantation (SPK) in the setting of end-stage renal disease offers unmatched outcomes in insulin dependent diabetic patients. Donor pool expansion through the transplantation of kidneys with acute kidney injury (AKI) is controversial. METHODS: 59 SPK transplants were classified by presence of donor AKI, defined as donor terminal creatinine ≥ 1.5x the initial creatinine or donor terminal creatinine > 4.0 mg/dL. Endpoints included graft and patient survival, delayed graft function (DGF), serum creatinine, glomerular filtration rate (GFR), Hemoglobin A1c (HbA1c) and acute rejection. RESULTS: The donor AKI group (n = 35) had significantly higher rates of DGF (38 v. 9%, p = 0.01). There was no difference in creatinine or GFR at 1, 3, 6 and 12 months. HbA1c was comparable at 3, 6 and 12 months. There was no significant difference in the percentage of patients that required anti-diabetic agents after transplant (14 v. 4%, p = 0.56). CONCLUSIONS: We observed increased rates of DGF in SPK recipients with donor AKI. However, equivalent outcomes of pancreas and kidney function in both groups were observed.

Ketorolac Use for Pain Management in Trauma Patients With Rib Fractures Does not Increase of Acute Kidney Injury or Incidence of Bleeding.

INTRODUCTION: Ketorolac is useful in acute pain management to avoid opiate-related complications; however, some surgeons fear associated acute kidney injury (AKI) and bleeding despite a paucity of literature on ketorolac use in trauma patients. We hypothesized that our institution's use of intravenous ketorolac for rib fracture pain management did not increase the incidence of bleeding or AKI. METHODS: Rib fracture patients aged 15 years and above admitted between January 2016-June 2018 were identified in our trauma registry along with frequency of bleeding events. AKI was defined as ≥ 1.5x increase in serum creatinine from baseline measured on the second day of admission (after 24 hours of resuscitation) or an increase of ≥ .3 mg/dL over a 48-hour period. Patients receiving ketorolac were compared to patients with no ketorolac use. RESULTS: Two cohorts of 199 control and 205 ketorolac patients were found to be similar in age, gender, admission systolic blood pressure (SBP), injury severity score, intravenous radiocontrast received, and transfusion requirements. Analysis revealed no difference in frequency of AKI using both definitions (8% vs. 7.3%, P = .79) and (19.6% vs. 15.1%, P = .24), respectively, or bleeding events (2.5% vs. 0%, P = .03). Logistic regression demonstrated that ketorolac use was not an independent predictor for AKI but age and admission SBP < 90 were. CONCLUSION: Use of ketorolac in this cohort of trauma patients with rib fractures did not increase the incidence of AKI or bleeding events.

The use of LCP-Tacrolimus (Envarsus XR) in simultaneous pancreas and kidney (SPK) transplant recipients.

BACKGROUND: Extended release LCP-tacrolimus (LCPT) allows once-daily dosing in transplant recipients. The improved bioavailability may be beneficial for simultaneous pancreas-kidney recipients (SPK). METHODS: This is a study of 39 SPK recipients on standard immediate-release tacrolimus (IR-TAC, n = 21) or LCPT (n = 18). Coefficient of variability (CV = 100∗standard deviation/mean) was calculated to assess drug levels. Hemoglobin A1c (HbA1c), tacrolimus and creatinine levels were measured postoperatively. RESULTS: There was no difference in tacrolimus CV in the IR-TAC and LCPT groups at 1 month or 3 months postoperatively; however, a greater difference was observed at 1 year (41.0 vs. 33.1%; p = 0.19). There were six episodes of acute rejection in the IR-TAC group compared to zero episodes in the LCPT group (p = 0.01). HbA1c was significantly higher in the IR-TAC group compared to LCPT at 3 (5.5 vs. 4.9%, p = 0.01), 6 (5.6 vs. 4.9%, p = 0.01) and 12 months (5.8 vs. 5.1%, p = 0.07). CONCLUSIONS: Significantly lower rates of rejection were observed in patients receiving LCPT. The once daily dosing may facilitate medication adherence and result in improved long-term outcomes.

Preoperative C-Peptide Predicts Weight Gain After Pancreas Transplantation.

BACKGROUND: Transplant recipients are susceptible to cardiovascular complications, obesity, and increased insulin resistance after transplant. Here we assess weight gain in diabetic recipients after pancreas transplantation. METHODS: This is a single-center study of 32 simultaneous pancreas and kidney and 5 pancreas after kidney transplant recipients from 2014 to 2018. Starting C-peptide levels ≤ 0.1 ng/mL were used to denote insulin nondetectability (n = 25) and C-peptide levels > 0.1 ng/mL as insulin detectability (n = 12). Hemoglobin A1c, body mass index (BMI), and weight following transplantation were assessed. RESULTS: Hemoglobin A1c at 1 year was 5.9% in the insulin nondetectable recipients and 5.6% in the insulin detectable group (P = .56). Average BMI after transplant was higher in the insulin detectable group 28.6 versus 24.4 kg/m2 (P = .03) despite no difference in starting BMIs (24.9 versus 24.0 kg/m2, P = .42). The insulin detectable group also had a larger percentage weight change from their starting weight 13.1% versus 0.9 % at 1 year (P = .02). Linear regression demonstrated that starting C-peptide was a significant predictor of weight gain posttransplant. CONCLUSIONS: Patients with elevated C-peptides at time of transplant are susceptible to rapid weight gain postoperatively. These patients may benefit from aggressive nutritional management.

Transplant surgery enters a new era: Increasing immunosuppressive medication adherence through mobile apps and smart watches.

The high rate of immunosuppressive medication non-adherence in transplant recipients demands the search for a solution that targets modifiable risk factors and incorporates mobile health technology to better engage and educate patients. Kidney transplant recipients (kidneys alone or multi-organ) were randomized to receive a mobile app known as Transplant Hero, both the app and a smart watch, or neither. The coefficient of variability (CV) of tacrolimus levels was measured at one and three months. No statistically significant differences in CV levels were observed between the three groups at either one or three months. Although mobile health apps are a promising strategy for increasing medication adherence, further research is required to determine how to best use this technology.

Young donors with severe acute kidney injury offer an opportunity to expand the donor pool.

BACKGROUND: This study assessed our experience transplanting kidneys from young donors with severe acute kidney injury. METHODS: We performed a single center retrospective analysis of 315 kidney transplants between 1/1/2014-12/31/2016. Donor kidneys were classified according to the Acute Kidney Injury Network (AKIN) criteria. A case-matched cohort was created using recipient age, history of diabetes, donor specific antibody, donor age and donor after cardiac death. Primary endpoints were graft function measured by eGFR at 90 days and at 1-year. RESULTS: Stage 3 AKIN recipients had significantly greater eGFR at one year (63.9 ml/min v. 51.2 ml/min, p < 0.001) compared to those with Stage 0 AKIN. This difference was abrogated when compared to a case matched cohort (eGFR at 90 days or 1 year; p > 0.05). Donor and recipient characteristics on eGFR at 1 year were analyzed using linear and logistic regression. Only donor age had a significant impact on recipient eGFR. CONCLUSIONS: Donor kidneys with severe acute injury can achieve optimal 1-year outcomes. Donor age is the most significant predictor of eGFR >45 ml/min after transplant.

Predicting the broadly neutralizing antibody susceptibility of the HIV reservoir.

Broadly neutralizing antibodies (bNAbs) against HIV-1 are under evaluation for both prevention and therapy. HIV-1 sequence diversity observed in most HIV-infected individuals and archived variations in critical bNAb epitopes present a major challenge for the clinical application of bNAbs, as preexistent resistant viral strains can emerge, resulting in bNAb failure to control HIV. In order to identify viral resistance in patients prior to antibody therapy and to guide the selection of effective bNAb combination regimens, we developed what we believe to be a novel Bayesian machine-learning model that uses HIV-1 envelope protein sequences and foremost approximated glycan occupancy information as variables to quantitatively predict the half-maximal inhibitory concentrations (IC50) of 126 neutralizing antibodies against a variety of cross clade viruses. We then applied this model to peripheral blood mononuclear cell-derived proviral Env sequences from 25 HIV-1-infected individuals mapping the landscape of neutralization resistance within each individual's reservoir and determined the predicted ideal bNAb combination to achieve 100% neutralization at IC50 values <1 µg/ml. Furthermore, predicted cellular viral reservoir neutralization signatures of individuals before an analytical antiretroviral treatment interruption were consistent with the measured neutralization susceptibilities of the respective plasma rebound viruses, validating our model as a potentially novel tool to facilitate the advancement of bNAbs into the clinic.

Aurora A Kinase Amplifies a Midzone Phosphorylation Gradient to Promote High-Fidelity Cytokinesis.

During cytokinesis, aurora B kinase (ABK) relocalizes from centromeres to the spindle midzone, where it is thought to provide a spatial cue for cytokinesis. While global ABK inhibition in Drosophila S2 cells results in macro- and multi-nucleated large cells, mislocalization of midzone ABK (mABK) by depletion of Subito (Drosophila MKLP2) does not cause notable cytokinesis defects. Subito depletion was, therefore, used to investigate the contribution of other molecules and redundant pathways to cytokinesis in the absence of mABK. Inhibiting potential polar relaxation pathways via removal of centrosomes (CNN RNAi) or a kinetochore-based phosphatase gradient (Sds22 RNAi) did not result in cytokinesis defects on their own or in combination with loss of mABK. Disruption of aurora A kinase (AAK) activity resulted in midzone assembly defects, but did not significantly affect contractile ring positioning or cytokinesis. Live-cell imaging of a Förster resonance energy transfer (FRET)-based aurora kinase phosphorylation sensor revealed that midzone substrates were less phosphorylated in AAK-inhibited cells, despite the fact that midzone levels of active phosphorylated ABK (pABK) were normal. Interestingly, in the absence of mABK, an increased number of binucleated cells were observed following AAK inhibition. The data suggest that equatorial stimulation rather than polar relaxation mechanisms is the major determinant of contractile ring positioning and high-fidelity cytokinesis in Drosophila S2 cells. Furthermore, we propose that equatorial stimulation is mediated primarily by the delivery of factors to the cortex by noncentrosomal microtubules (MTs), as well as a midzone-derived phosphorylation gradient that is amplified by the concerted activities of mABK and a soluble pool of AAK.