Corrigendum: Real-World Treatment Patterns of Antiviral Prophylaxis for Cytomegalovirus Among Adult Kidney Transplant Recipients: A Linked USRDS-Medicare Database Study.

[This corrects the article DOI: 10.3389/ti.2022.10528.][This corrects the article DOI: 10.3389/ti.2023.12367.].

Real-World Outcomes Associated With Letermovir Use for Cytomegalovirus Primary Prophylaxis in Allogeneic Hematopoietic Cell Transplant Recipients: A Systematic Review and Meta-analysis of Observational Studies.

Background: A systematic review and meta-analysis of real-world observational studies was conducted to summarize the impact of letermovir cytomegalovirus (CMV) primary prophylaxis (PP) among adult allogeneic hematopoietic cell transplant (allo-HCT) recipients. Methods: Systematic searches in Medline/PubMed, Embase, and conferences (from database inception to October 2021) were conducted to identify studies for inclusion. Random-effects models were used to derive pooled estimates on the relative effectiveness of letermovir PP compared to controls. Results: Forty-eight unique studies (N = 7104 patients) were included, most of which were comparative, single-center, and conducted in the United States. Letermovir PP was associated with statistically significant reduction in odds of CMV reactivation (pooled odds ratio [pOR], 0.13 and 0.24; P < .05), clinically significant CMV infection (pOR, 0.09 and 0.19; P < .05), and CMV disease (pOR, 0.31 and 0.35; P < .05) by day +100 and day +200 after allo-HCT, respectively. Letermovir PP was associated with significantly lower odds of all-cause (pOR, 0.73; P < .01) and nonrelapse mortality (pOR, 0.65; P = .01) beyond day 200 after allo-HCT. Conclusions: Letermovir for CMV PP was effective in reducing the risk of CMV-related complications overall and mortality beyond day 200 among adult allo-HCT recipients.

Burden of neutropenia and leukopenia among adult kidney transplant recipients: A systematic literature review of observational studies.

BACKGROUND: Leukopenia and neutropenia (L/N) may affect treatment decisions, potentially resulting in poor clinical and economic outcomes among kidney transplant recipients (KTRs). The burden of L/N is poorly quantified systematically. This systematic literature review aimed to summarize the incidence of, risk factors for, and clinical and economic outcomes associated with L/N post-KT. METHODS: We systematically searched MEDLINE, Embase, and the Cochrane Library (from database inception-June 14, 2021) and conferences (past 3 years) to identify observational studies examining epidemiology, risk factors, or outcomes associated with L/N among adult KTRs. RESULTS: Of 2081 records, 82 studies met inclusion criteria. Seventy-three studies reported the epidemiology of L/N post-KT. Pooled incidence of neutropenia, defined as absolute neutrophil counts (ANC) <1000/µl, ranged from 13% to 48% within 1-year post-transplant; ANC <500/µl ranged from 15% to 20%. Leukopenia, defined as white blood cell counts <3500/µl, was 19% to 83%. Eleven studies reported independent risk factors associated with L/N post-KT. D+/R- cytomegalovirus status, mycophenolic acid (MPA), and tacrolimus use were the most consistent risk factors across studies. Fourteen studies reported L/N-associated clinical outcomes. We noted a trend toward a positive association between neutropenia and acute rejection/opportunistic infections. Mixed findings were noted on the association between L/N and graft failure or mortality. Dosage modifications of valganciclovir, MPA, cotrimoxazole, and anti-thymoglobulin and the need for granulocyte colony-stimulating factor (G-CSF) use were common with L/N. CONCLUSION: Findings suggest post-transplant L/N were common and associated with frequent modifications of immunosuppressive agents, requiring G-CSF use, and rejection or opportunistic infections. Findings highlight the need for interventions to reduce risk of L/N post-KT.

Real-World Treatment Patterns of Antiviral Prophylaxis for Cytomegalovirus Among Adult Kidney Transplant Recipients: A Linked USRDS-Medicare Database Study.

Limited data exist on cytomegalovirus (CMV) antiviral treatment patterns among kidney transplant recipients (KTRs). Using United States Renal Database System registry data and Medicare claims (1 January 2011-31 December 2017), we examined CMV antiviral use in 22,878 KTRs who received their first KT from 2011 to 2016. Three-quarters of KTRs started CMV prophylaxis (85.8% of high-, 82.4% of intermediate-, and 32.1% of low-risk KTRs). Median time to prophylaxis discontinuation was 98, 65, and 61 days for high-, intermediate-, and low-risk KTRs, respectively. Factors associated with receiving CMV prophylaxis were high-risk status, diabetes, receipt of a well-functioning kidney graft, greater time on dialysis before KT, panel reactive antibodies ≥80%, and use of antithymocyte globulin, alemtuzumab, and tacrolimus. KTRs were more likely to discontinue CMV prophylaxis if they developed leukopenia/neutropenia, had cardiovascular disease, or received their kidney from a deceased donor. These findings suggest that adherence to the recommended duration of CMV-prophylaxis for high and intermediate-risk patients is suboptimal, and CMV prophylaxis is overused in low-risk patients.

The changing impact of cytomegalovirus among hematopoietic cell transplant recipients during the past decade: A single institutional cohort study.

BACKGROUND: With advancements in allogeneic hematopoietic cell transplantation (alloHCT), the need for cytomegalovirus (CMV) surveillance persists. METHODS: We present a retrospective analysis on the impact of CMV with preemptive therapy in 1065 alloHCT patients with donor and/or recipient CMV seropositivity from 2009 to 2019. RESULTS: Fifty-one percent developed clinically significant CMV infection (CMV-CSI); 6.5% had CMV disease. In multivariate analysis stratified by serostatus and preparative regimen, the use of anti-thymocyte globulin (hazard ratios 2.97, 95% confidence interval 2.00-4.42, p < .001) was associated with development of CMV-CSI. Median length of stay for index hospitalization was longer in patients with CMV-CSI (27 vs. 25 days, respectively; p = .002), as were rates (32.9% vs. 17.7%; p < .001) and duration (9 d vs. 6 d; p < .001) of rehospitalization, and median total inpatient days (28 d vs. 26 d; p < .001). Patients with CMV-CSI had higher rates of neutropenia (47% vs. 20%; p < .001) and transfusion support (packed red blood cell, median 5 vs. 3; p < .001; platelets, median 3 vs. 3; p < .001). CONCLUSION: Preemptive therapy does not negate the impact of CMV-CSI on peri-engraftment toxicity and healthcare utilization. This cohort represents a large single center study on the impact of CMV in the preletermovir era and serves as a real-world comparator for assessing the impact of future prophylaxis.

Outcomes among CMV-mismatched and highly sensitized kidney transplants recipients who develop neutropenia.

Limited data exist on the incidence and clinical outcomes of neutropenia among kidney transplant recipients. Our study included 572 adults who received a kidney transplant at the University of California, San Francisco Medical Center between 2012 and 2018, and were CMV-mismatched or had a PRA ≥ 80%. Recipients with HIV, Hepatitis B and C, and primary non-function were excluded. Participants were followed for at least 1 year after transplantation. Neutropenia was defined as absolute neutrophil count < 1000 cells/µl. Cox proportional hazards regression models using neutropenia as a time-varying predictor were used to determine the risk of mycophenolic acid and valganciclovir changes, rejection, hospitalizations and use of granulocyte colony stimulating factor. Models were adjusted for demographics and transplant characteristics. Mean follow-up was 3.7 (SD, 1.8) years. The mean age of the cohort was 50.4 (13.1) years, and 57.5% were female. A total of 208 (36.3%) participants had neutropenia. Neutropenia was associated with an increased risk of valganciclovir or MPA dose reductions or discontinuations [adjusted hazard ratio, aHR: 7.78, 95% CI: 4.73-12.81], rejection [aHR 2.00, 95% CI: 1.10-3.64] and hospitalizations [aHR 3.32, 95% CI: 2.12-5.19]. Neutropenia occurs frequently after kidney transplantation and leads to more medication changes and adverse clinical outcomes.

Ameliorative potential of phloridzin in type 2 diabetes-induced memory deficits in rats.

Diabetes associated oxidative stress and impaired cholinergic neurotransmission causes cognitive deficits. Although phloridzin shows antioxidant- and insulin sensitizing-activities, its ameliorative potential in diabetes-induced memory dysfunction remains unexplored. In the present study, type 2 diabetes (T2D) was induced by streptozotocin (35 mg/kg, intraperitoneal) in rats on ad libitum high-fat diet. Diabetic animals were treated orally with phloridzin (10 and 20 mg/kg) for four weeks. Memory functions were evaluated by passive avoidance test (PAT) and novel object recognition (NOR) test. Brains of rats were subjected to biochemical analysis of glutathione (GSH), brain-derived neurotrophic factor (BDNF), malonaldehyde (MDA) and acetylcholinesterase (AChE). Role of cholinergic system in the effects of phloridzin was evaluated by scopolamine pre-treatment in behavioral studies. While diabetic rats showed a significant decrease in step through latency in PAT, and exploration time and discrimination index in NOR test; a substantial increase in all parameters was observed following phloridzin treatment. Phloridzin reversed abnormal levels of GSH, BDNF, MDA and AChE in the brain of diabetic animals. Moreover, in silico molecular docking study revealed that phloridzin acts as a potent agonist at M1 receptor as compared to acetylcholine. Viewed collectively, reversal of T2D-induced memory impairment by phloridzin might be attributed to upregulation of neurotrophic factors, reduced oxidative stress and increased cholinergic signaling in the brain. Therefore, phloridzin may be a promising molecule in the management of cognitive impairment comorbid with T2D.

Effect of apple peel extract on diabetes-induced peripheral neuropathy and wound injury.

PURPOSE: Diabetic peripheral neuropathy (DPN) affects up to 50 % diabetic patients. Moreover, uncontrolled diabetes associated with impaired wound healing. The present study was aimed at exploring the effect of apple peel extract (APE) on type 2 diabetes (T2D)-induced DPN and delayed wound healing. METHODS: In adult male Sprague-Dawley rats on high-fat diet, a single low dose streptozotocin (STZ, 35 mg/kg) was administered via intraperitoneal route to induce T2D. Plantar test using Hargreaves apparatus was used to evaluate the DPN. Six different groups of rats were treated orally with saline (naïve control and DPN control), APE (100, 200 and 400 mg/kg) and gabapentin (30 mg/kg) daily for 7 consecutive days and thermal paw withdrawal latency (PWL) was measured. To elucidate the underlying antioxidant effect of APE, the catalase (CAT), glutathione (GSH) and malonaldehyde (MDA) levels were measured. To evaluate the wound healing potential of APE, excision ischemic open wound model was used. Six different groups of rats were applied with 2 % gum acacia (naïve control and diabetic control), 1 % silver sulfadiazine (SSD) cream and APE cream (5, 10 and 20 %) twice daily for 28 days. Dry connective tissue parameters like hydroxyproline and hexosamine were also measured to further confirm the wound healing activity. RESULTS: Diabetes produced thermal hyperalgesia in rats with a significant decrease in PWL as compared to naive controls indicating induction of DPN. APE and gabapentin significantly improved PWL in diabetic animals. Biochemical analysis revealed a significant improvement in oxidative stress parameters such as catalase, GSH and MDA. Wound closure was significantly more after day 15 of topical application of APE and SSD as compared to control group. APE significantly increased hydroxyproline and hexosamine levels as compared to standard cream. Moreover, histopathology revealed that, topical application of APE cream showed an enhanced healing process. CONCLUSIONS: On the basis of the findings, we conclude that APE has a potential to be used as a therapeutic intervention for the management of DPN and delayed wound healing in the diabetic condition.

Phloridzin ameliorates type 2 diabetes-induced depression in mice by mitigating oxidative stress and modulating brain-derived neurotrophic factor.

PURPOSE: Type 2 diabetes (T2D) is linked with depression due to insulin resistance, oxidative stress and disruption of neurotrophic factors. We evaluated potential benefits of phloridzin in ameliorating depressive symptoms in T2D. METHODS: Adult male Swiss-albino mice (25-30 g) on high-fat-diet (HFD) for 2 weeks were administered with streptozotocin (STZ; 35 mg/kg, intraperitoneal) to induce T2D. Seven days after STZ administration, diabetic mice on HFD were distributed into different groups. Animals were subjected daily to oral treatment of saline (0.25 ml), fluoxetine (10-20 mg/kg) or phloridzin (10-20 mg/kg) for a period of 4 weeks. One hour after last dose, the immobility time of animals was evaluated in forced swim test (FST) and tail suspension test (TST). To further confirm the mechanisms involved in antidepressant effect of phloridzin, biochemical parameters like brain derived neurotropic factor (BDNF), glutathione (GSH), extracellular signal-regulated kinase (ERK), tyrosine receptor kinase B (TrkB) and cAMP-response element binding protein (CREB) were estimated in the brain. RESULTS: Animals with T2D showed a significant increase in immobility as compared to control in FST and TST. However, 4 weeks administration of fluoxetine or phloridzin attenuated this effect. A significant decline in GSH, BDNF, TrkB, CREB and ERK levels were noticed in the brain of mice with T2D. These changes were also attenuated by administration of phloridzin. CONCLUSIONS: Phloridzin may ameliorates T2D-induced depression by mitigating the oxidative stress, and up-regulation of neurotrophins in the brain. Therefore, phloridzin can be used as a therapeutic intervention for the management of depression co-morbid with T2D.

Phloridzin attenuates lipopolysaccharide-induced cognitive impairment via antioxidant, anti-inflammatory and neuromodulatory activities.

BACKGROUND: Lipopolysaccharide (LPS) is known to produce neuroinflammation and memory impairment. Although phloridzin (a phenolic phytoconstituent) shows antioxidant- and anti-inflammatory activities, its ameliorative potential in LPS-mediated neuroinflammation and memory dysfunction remains unexplored. OBJECTIVES: To investigate the protective effect of phloridzin against LPS-mediated memory impairment and neuroinflammation in mice. METHODS: Different groups of mice were treated with LPS (250 µg/kg) via intraperitoneal (ip) route to induce cognitive impairments. The animals were administered with phloridzin (10-20 mg/kg, oral) or donepezil (1 mg/kg, intraperitoneal), and memory functions were evaluated by Morris water maze (MWM) and Y-maze. At the end of the behavioral experiments, the animals were sacrificed and different biochemical parameters like acetylcholinesterase (AChE), brain derived neurotropic factor (BDNF), tumor necrosis factor (TNF-α), interleukin-6 (IL-6), superoxide dismutase (SOD) and glutathione (GSH) concentration in the hippocampus and the cerebral cortex were estimated. RESULTS: While LPS administered animals showed significantly decreased memory retention in both MWM and Y maze, a significant reversal in all the parameters were observed following treatment with phloridzin. LPS-treated animals showed significantly decreased level of antioxidants (SOD and GSH), neurotropic factor (BDNF) and cholinergic transmission (increased AChE) and increased levels of inflammatory/oxidative markers (TNF-α, IL-6 and MDA) in hippocampus and cortex. These changes were alleviated after the treatment with phloridzin. CONCLUSIONS: Phloridzin may have neuroprotective role against LPS-induced neuroinflammation and memory impairment by virtue of its antioxidant, anti-inflammatory, and enhanced cholinergic signalling activity in the hippocampus and cerebral cortex.

Antiviral treatment approaches for cytomegalovirus prevention in kidney transplant recipients: A systematic review of randomized controlled trials.

Various CMV anti-viral (AV) preventive strategies have been utilized in KTRs. We examined efficacy, safety and costs of CMV-AV prevention strategies in KTRs using a systematic literature review (SLR) of randomized controlled trials (RCTs) publications indexed in MEDLINE and Embase (from inception to November 2018). Thirty RCTs met inclusion criteria with 22 unique AV preventive strategies. Prophylaxis was associated with significantly lower rates of CMV infection/disease (CMVi/d) compared to no prophylaxis (pooled odds ratio, pOR with 95% confidence interval (CI): CMVi: 0.33; 0.19, 0.57; CMVd: 0.27; 0.19; 0.39). Preemptive therapy (PET) had lower rates of CMVd (0.29; 0.11, 0.77), and medical costs compared to no PET. Prophylaxis had significantly lower rates of early CMVi/d, and higher rates of late CMVi and hematological adverse events (leukopenia, 2.93; 1.22, 7.04), and similar overall medical costs compared to PET. Studies involving head-to-head comparison of different prophylaxis approaches showed mixed findings with respect to optimum dose, duration and route of administration on CMV outcomes. Although there was heterogeneity across populations and interventions, both prophylaxis and PET strategies reduced CMVi/d compared to no prophylaxis/PET and had differential safety profile in terms of hematological adverse events. For comprehensiveness we did not limit study inclusion based on date; the wide time-period may have contributed to the heterogeneity in prevention approaches which subsequently made pooling studies a challenge. Despite demonstrated efficacy of prophylaxis/PET, our findings highlight the potential need of a novel intervention with a better safety profile and perhaps improved outcomes.

Epidemiology, risk factors, and outcomes associated with cytomegalovirus in adult kidney transplant recipients: A systematic literature review of real-world evidence.

Kidney transplant recipients (KTRs) have increased risk for cytomegalovirus (CMV) infection/disease given the necessity of drug-induced immunosuppression. A comprehensive review of published literature reporting real-world data on prevention strategies utilized and associated CMV burden outcomes is limited. Such data could help inform future clinical practice and identify unmet needs in CMV management. We conducted a systematic review of observational studies published in Medline or EMBASE from January 2008 to November 2018 to identify current real-world CMV management approaches, CMV infection/disease risk factors, and outcomes associated with CMV infection. Descriptive statistics and pooled quantitative analyses were conducted. From 1608 records screened, 86 citations, including 69 803 adult KTR, were included. Prophylaxis and preemptive therapy (PET) were predominant approaches among D+/R- and R + CMV serostatus transplants, respectively. Valganciclovir and ganciclovir were frequently utilized across CMV risk strata. Despite prevention approaches, approximately one-fourth of KTR developed CMV infection. Age and D+/R- CMV serostatus were consistent risk factors for CMV infection/disease. CMV infection/disease was associated with increased mortality and graft loss. CMV was similarly associated with acute rejection (AR) risk, but with high heterogeneity among studies. Limited data were available on CMV and opportunistic infections (OIs) risk. CMV remains a significant issue. New strategies may be needed to optimize CMV management.

Healthcare Costs of Diabetes and Microvascular and Macrovascular Disease in Individuals with Incident Type 2 Diabetes Mellitus: A Ten-Year Longitudinal Study.

OBJECTIVE: The objective of this study was to estimate the incremental long-term costs associated with T2DM attributable to vascular diseases. RESEARCH DESIGN AND METHODS: This retrospective cohort study identified newly diagnosed (incident) T2DM patients in 2007 (baseline to 01/01/2006) using the HealthCore Integrated Research Database, a repository of nationally representative claims data. Incident T2DM patients were 1:1 exact matched on age, gender and other factors of interest to non-DM patients, and followed until the earlier of 8 follow-up years or death. Patients with documented vascular disease diagnosis were identified during the study period. All-cause and T2DM/vascular disease-related annual healthcare costs were examined for each follow-up year. RESULTS: The study included 13,883 individuals with T2DM and matched non-DM controls. Among individuals with T2DM, 11,792 (85%) had vascular disease versus 9251 (66.6%) non-T2DM between 01/01/2006 and 12/31/2015. Among T2DM patients, mean all-cause annual costs were greater than in non-T2DM patients ($13,806 vs $7,243, baseline, $21,745 vs $8,524, post-index year 1, $12,756-$14,793 vs $8,349-$9,940 years 2-8, p< 0.001), respectively. A similar trend was observed for T2DM/vascular disease-related costs (p< 0. 001). T2DM/vascular disease-related costs were largest during post-index year 1, accounting for the majority of all-cause cost difference between T2DM patients and matched non-DM controls. Incident T2DM individuals without vascular disease at any time had significantly lower costs compared to non-DM controls (p< 0. 001) between years 2-8 of follow-up. CONCLUSION: Vascular disease increased the cost burden for individuals with T2DM. The cost impact of diabetes and vascular disease was highest in the year after diagnosis, and persisted for at least seven additional years, while the cost of T2DM patients without vascular disease trended lower than for matched non-DM patients. These data highlight potential costs that could be offset by earlier and more effective detection and management of T2DM aimed at reducing vascular disease burden.

Impact of Preemptive Therapy for Cytomegalovirus on Hospitalizations and Cost after Hematopoietic Stem Cell Transplantation.

Cytomegalovirus (CMV) viremia occurs in 40% to 80% of CMV-seropositive (R+) recipients of allogeneic hematopoietic cell transplantation (HCT). The preemptive therapy (PET) strategy has reduced the risk of CMV end-organ disease (EOD) and associated mortality but may lead to substantial healthcare resource utilization (HCRU) and costs. Real-world data on the economic impact of PET is relevant for the evaluation of alternative strategies for CMV management. We examined the impact of clinically significant CMV treated with PET on inpatient length of stay (LOS), number of readmissions, and associated costs from day 0 through day 180 post-HCT. This was a retrospective study of R+ adults who underwent peripheral blood or marrow allogeneic HCT at Memorial Sloan Kettering Cancer Center between March 2013 and December 2017. Patients were routinely screened for CMV by qPCR and received PET according to institutional standards of care. Data were extracted from electronic medical records and hospital databases. Itemized cost data per patient were obtained from the Vizient database, adjusted to 2017 dollars using inflation indices. Study outcomes included HCRU evaluated by inpatient LOS and inpatient cost in patients who received PET for clinically significant CMV (PET group) compared with those who did not receive PET (no PET group) and the frequency and cost of CMV-related readmissions compared with non CMV-related readmissions. We used generalized linear models to examine the incremental HCRU and costs associated with PET controlling for other potential factors. Of 357 patients, PET was initiated in 208 (58.3%), at a median of 35 days after HCT. By day 180, 23 patients (6.4%) had developed CMV EOD and 3 (.8%) had died of CMV. Compared with the no PET group, the PET group had a longer LOS for HCT admission (P = .0276), longer total LOS by day 180 (P = .0001), a higher number of readmissions (P = .0001), a higher mean inpatient cost for HCT admission ($189,389 versus $151,646; P = .0133), and a higher total inpatient cost ($297,563 versus $205,815; P < .0001). Among PET recipients, CMV-related readmissions were associated with higher mean cost per episode compared with non CMV-related readmissions ($165,455 versus $89,419; P = .005). CMV-related readmissions comprised 40.6% of total all-cause readmissions and incurred 55.9% of total all-cause readmission costs in PET recipients. Our data show that patients treated with currently available PET had greater inpatient HCRU and cost, by day 180 compared with patients who did not receive PET. The cost of CMV-related readmissions accounted for 56% of total readmission cost among PET recipients. Future studies are needed to examine the cost-effectiveness of alternative strategies for CMV management.

Epidemiology and outcomes of residual neuromuscular blockade: A systematic review of observational studies.

OBJECTIVES: Complete reversal of neuromuscular blockade (NMB) is important for patient safety and prognosis following surgical procedures involving NMB agents (NMBAs). Published evidence on the epidemiology and consequences of residual neuromuscular blockade (rNMB; incomplete neuromuscular recovery) in real-world clinical settings is lacking with advances in NMB management. Therefore, we aimed to examine the burden of rNMB and its associated clinical, economic and humanistic outcomes using a systematic review framework. REVIEW METHODS: Electronic and conference database searches were performed to include observational studies examining rNMB or related outcomes in adults undergoing surgery and receiving NMBAs with or without NMBA antagonists. RESULTS: Of 1438 screened abstracts, 58 studies with 25,277 total patients were included. Inconsistent definitions of rNMB were reported across studies with 44 (76%) and 29 (50%) studies utilizing quantitative and qualitative measures to detect rNMB, respectively. The most common definition of rNMB was train-of-four ratio (TOFR) <0.9 (29 studies) and TOFR <0.7 (16 studies) measured at post-anesthesia care unit (PACU) entry. For TOFR <0.9 at PACU entry, rNMB incidence ranged from 0% to 90.5% (median 30%) overall; 0% to 16.0% in the sugammadex (SUG) group; 3.5% to 90.5% in the neostigmine (NEO) group; and 15% to 89% in the spontaneous recovery (SR) group. Twenty-one studies reported clinical outcomes (reintubation, mild hypoxemia, or a respiratory event) or resource utilization outcomes (hospital/PACU length of stay [LOS]) by presence/absence of rNMB. Patients with rNMB had higher rates of acute respiratory events compared to those without rNMB. CONCLUSIONS: Real-world observational studies show a significant burden of rNMB and associated health sequelae, though rNMB measures were not reported consistently across studies. Appropriate quantitative measurement is needed to accurately identify rNMB, and interventions are needed to reduce its burden and associated adverse outcomes.

Impact of Preemptive Therapy for Cytomegalovirus on Toxicities after Allogeneic Hematopoietic Cell Transplantation in Clinical Practice: A Retrospective Single-Center Cohort Study.

(Val)ganciclovir (vGCV) or foscarnet (FCN) as preemptive therapy (PET) for cytomegalovirus (CMV) after allogeneic hematopoietic cell transplantation (HCT) is associated with myelosuppression and nephrotoxicity, respectively. We analyzed a cohort of CMV-seropositive (R+) HCT recipients managed preemptively at a single center. The objectives of our study were to (1) quantify the frequencies of neutropenia and acute kidney injury (AKI) through day +100 (D100) post-HCT and at PET discontinuation and (2) assess the impact of PET on neutropenia and AKI in multivariate models. This was a retrospective cohort study of adult CMV R+ recipients who underwent allo-HCT at Memorial Sloan Kettering Cancer Center from March 18, 2013, through December 31, 2017, and were managed with PET. Patients were grouped by receipt of PET (PET and no PET). Neutropenia and AKI were defined by Common Terminology Criteria for Adverse Events version 4. Frequencies of toxicities by D100 were compared between relevant groups. The impact of PET on toxicities was examined in univariate and multivariate Poisson/negative binomial regression models. Of 368 CMV R+ HCT recipients, 208 (56.5%) received PET. Neutropenia by D100 occurred in 41.8% and 28.6% patients in PET and no PET, respectively (P = .0009). PET increased the risk of neutropenia (adjusted relative risk = 1.81; 95% confidence interval [CI], 1.48 to 2.21; P < .0001) in multivariate analyses. AKI by D100 occurred in 12.0% and 7.8% patients in PET and no PET, respectively (P = .19). PET increased the risk of AKI by 2.75-fold (95% CI, 1.71 to 4.42; P < .0001). When PET recipients were grouped by first antiviral, neutropenia by D100 occurred in 34.8% and 48.9% of vGCV and FCN recipients, respectively, (P = .08), and AKI occurred in 13.0% and 34.0% of vGCV and FCN recipients, respectively (P = .001). At discontinuation of vGCV or FCN, neutropenia was present in 11.2% versus 2.1% patients, respectively (P = .08), and AKI was present in 1.9% of versus 12.8% patients respectively (P = .005). Preemptive therapy for CMV increased the risk of neutropenia and AKI in the first 100 days post-HCT by 1.8-fold and 2.8-fold, respectively. Our results underscore the need for safer antivirals for CMV management in HCT recipients.

Incidence of residual neuromuscular blockade and use of neuromuscular blocking agents with or without antagonists: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: Neuromuscular blocking agents (NMBAs) have revolutionized the field of anesthesiology as they facilitate airway management and ensure optimal surgical conditions. Despite their beneficial and ubiquitous use during surgery, delayed or partial recovery from NMBAs, referred to as residual neuromuscular block (rNMB), is a common clinical problem. While it is well accepted that the antagonist sugammadex, compared to neostigmine, can more rapidly reverse rocuronium-induced NMB regardless of depth of block, the occurrence of rNMB for routinely used combinations of NMBAs with sugammadex or neostigmine has not yet been quantified or evaluated systematically. REVIEW METHODS: We conducted a systematic literature review and meta-analysis of randomized controlled trials (RCTs) to quantify and compare the incidence of rNMB [defined as train-of-four ratio (TOFR) <0.9] in patients with moderate and deep neuromuscular block. Methods recommended by Cochrane Collaboration and PRISMA group were followed. RESULTS: A total of 35 RCTs were identified, of which 20 contributed to the meta-analysis. For moderate block, rNMB incidence at 2 min after sugammadex administration was 19.2% (95% CI 0.0-57.8; 122 patients) and declined to 2.8% (95% CI 0.0-16.7; 93 patients) at 6 min post administration. For timepoints 10 to 60 min after administration, rNMB incidence ranged between 0.05% to 2.8%. In contrast, rNMB incidence at 2 min after neostigmine administration was 100% (95% CI 89.9-100; 182 patients) and was 82% (95% CI 71.4-91.2; 93 patients) at 6 min post administration. For timepoints 10 to 60 min after administration, rNMB incidence ranged between 14 and 32%. For deep block, rNMB incidence following sugammadex was essentially reduced to 1% at 15 min after administration. Residual NMB incidence following neostigmine remained at or above 95% for the first 60 min after administration. CONCLUSIONS: Overall, based on evidence from 20 RCTs, our results suggest that the combination of rocuronium or vecuronium plus sugammadex is more effective and more rapid in reversing NMB compared with combinations of rocuronium, vecuronium, cisatracurium, or pancuronium plus neostigmine.

The impact of intra-abdominal pressure on perioperative outcomes in laparoscopic cholecystectomy: a systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Laparoscopic cholecystectomy involves using intra-abdominal pressure (IAP) to facilitate adequate surgical conditions. However, there is no consensus on optimal IAP levels to improve surgical outcomes. Therefore, we conducted a systematic literature review (SLR) to examine outcomes of low, standard, and high IAP among adults undergoing laparoscopic cholecystectomy. METHODS: An electronic database search was performed to identify randomized controlled trials (RCTs) that compared outcomes of low, standard, and high IAP among adults undergoing laparoscopic cholecystectomy. A Bayesian network meta-analysis (NMA) was used to conduct pairwise meta-analyses and indirect treatment comparisons of the levels of IAP assessed across trials. RESULTS: The SLR and NMA included 22 studies. Compared with standard IAP, on a scale of 0 (no pain at all) to 10 (worst imaginable pain), low IAP was associated with significantly lower overall pain scores at 24 h (mean difference [MD]: - 0.70; 95% credible interval [CrI]: - 1.26, - 0.13) and reduced risk of shoulder pain 24 h (odds ratio [OR] 0.24; 95% CrI 0.12, 0.48) and 72 h post-surgery (OR 0.22; 95% CrI 0.07, 0.65). Hospital stay was shorter with low IAP (MD: - 0.14 days; 95% CrI - 0.30, - 0.01). High IAP was not associated with a significant difference for these outcomes when compared with standard or low IAP. No significant differences were found between the IAP levels regarding need for conversion to open surgery; post-operative acute bleeding, pain at 72 h, nausea, and vomiting; and duration of surgery. CONCLUSIONS: Our study of published trials indicates that using low, as opposed to standard, IAP during laparoscopic cholecystectomy may reduce patients' post-operative pain, including shoulder pain, and length of hospital stay. Heterogeneity in the pooled estimates and high risk of bias of the included trials suggest the need for high-quality, adequately powered RCTs to confirm these findings.

Does deep neuromuscular blockade during laparoscopy procedures change patient, surgical, and healthcare resource outcomes? A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Deep neuromuscular blockade may facilitate the use of reduced insufflation pressure without compromising the surgical field of vision. The current evidence, which suggests improved surgical conditions compared with other levels of block during laparoscopic surgery, features significant heterogeneity. We examined surgical patient- and healthcare resource use-related outcomes of deep neuromuscular blockade compared with moderate neuromuscular blockade in adults undergoing laparoscopic surgery. METHODS: We conducted a systematic literature review according to the quality standards recommended by the Cochrane Handbook for Systematic Reviews. Randomized controlled trials comparing outcomes of deep neuromuscular blockade and moderate neuromuscular blockade among adults undergoing laparoscopic surgeries were included. A random-effects model was used to conduct pair-wise meta-analyses. RESULTS: The systematic literature review included 15 studies-only 13 were analyzable in the meta-analysis and none were judged to be at high risk of bias. Compared with moderate neuromuscular blockade, deep neuromuscular blockade was associated with improved surgical field of vision and higher vision quality scores. Also, deep neuromuscular blockade was associated with a reduction in the post-operative pain scores in the post-anesthesia care unit compared with moderate neuromuscular blockade, and there was no need for an increase in intra-abdominal pressure during the surgical procedures. There were minor savings on resource utilization, but no differences were seen in recovery in the post-anesthesia care unit or overall length of hospital stay with deep neuromuscular blockade. CONCLUSIONS: Deep neuromuscular blockade may aid the patient and physician surgical experience by improving certain patient outcomes, such as post-operative pain and improved surgical ratings, compared with moderate neuromuscular blockade. Heterogeneity in the pooled estimates suggests the need for better designed randomized controlled trials.

Occurrence and Characteristics of Hospitalizations During First-Line Chemotherapy Among Individuals with Metastatic Colorectal Cancer.

OBJECTIVE: Choosing chemotherapy for metastatic colorectal cancer (mCRC) requires balancing clinical effectiveness and risk of complications. This study characterized real-world inpatient/emergency department (ED) hospitalizations during first-line chemotherapy among individuals with mCRC. METHODS: This retrospective cohort study used data from medical and pharmacy claims. All patients had mCRC with ≥1 claim for ≥1 of the 5 most frequently utilized first-line chemotherapy agents (fluorouracil, oxaliplatin, bevacizumab, irinotecan, capecitabine). The main outcome was all-cause hospitalizations (inpatient or ED setting) identified from claims via ICD-9/10-CM coding from index date until 30 days after the end of first-line chemotherapy or last available data. RESULTS: A total of 717 individuals (mean age 55 years; 58% male; ECOG 0/1/2+/missing in 44%/39%/6%/11%; median follow-up 116 days) met study criteria. Thirty-four distinct chemotherapy regimens were used. Overall, 40% of patients had ≥1 hospitalization (n=285; total 415 hospitalizations); 12% (n=85) had ≥2 hospitalizations. The median time to first hospitalization was 52 days; median inpatient length of stay was 4 days; infections/neutropenia (21%) and bowel-related complications (17%) were the most common issues associated with inpatient hospitalizations. In univariate analyses, insurance plan type, geographical location, ECOG, and renal disease were associated with hospitalization. In multivariable analyses, ECOG ≥1 was associated with a 67% increase (p<0.01) in the odds of hospitalization vs ECOG= 0. CONCLUSION: Approximately 40% of patients with mCRC were hospitalized during the study period. Hospital stays were typically short. Further research is needed to determine how many of these hospitalizations may be avoidable. We also observed a large amount of variation in regimens used in the first-line setting.