Prokop, Larry J.

Abstract Context Interventions targeting hypoglycemia in people with diabetes are important for improving quality of life and reducing morbidity and mortality. Objective To support development of the Endocrine Society Clinical Practice Guideline for management of individuals with diabetes at high risk for hypoglycemia. Methods We searched several databases for studies addressing 10 questions provided by a guideline panel from the Endocrine Society. Meta-analysis was conducted when feasible. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess certainty of evidence. Results We included 149 studies reporting on 43 344 patients. Continuous glucose monitoring (CGM) reduced episodes of severe hypoglycemia in patients with type 1 diabetes (T1D) and reduced the proportion of patients with hypoglycemia (blood glucose [BG] levels <54 mg/dL). There were no data on use of real-time CGM with algorithm-driven insulin pumps vs multiple daily injections with BG testing in people with T1D. CGM in outpatients with type 2 diabetes taking insulin and/or sulfonylureas reduced time spent with BG levels under 70 mg/dL. Initiation of CGM in hospitalized patients at high risk for hypoglycemia reduced episodes of hypoglycemia with BG levels lower than 54 mg/dL and time spent under 54 mg/dL. The proportion of patients with hypoglycemia with BG levels lower than 70 mg/dL and lower than 54 mg/dL detected by CGM was significantly higher than point-of-care BG testing. We found no data evaluating continuation of personal CGM in the hospital. Use of an inpatient computerized glycemic management program utilizing electronic health record data was associated with fewer patients with and episodes of hypoglycemia with BG levels lower than 70 mg/dL and fewer patients with severe hypoglycemia compared with standard care. Long-acting basal insulin analogs were associated with less hypoglycemia. Rapid-acting insulin analogs were associated with reduced severe hypoglycemia, though there were more patients with mild to moderate hypoglycemia. Structured diabetes education programs reduced episodes of severe hypoglycemia and time below 54 mg/dL in outpatients taking insulin. Glucagon formulations not requiring reconstitution were associated with longer times to recovery from hypoglycemia, although the proportion of patients who recovered completely from hypoglycemia was not different between the 2 groups. Conclusion This systematic review summarized the best available evidence about several interventions addressing hypoglycemia in people with diabetes. This evidence base will facilitate development of clinical practice guidelines by the Endocrine Society.

Thyroid hormone (TH) augmentation, although commonly used for major depression, is sparingly used for bipolar disorder (BD) after the failure of mood-stabilizing agents. While the exact mechanisms of thyroid hormone action in BD remains unclear, central thyroid hormone deficit has been postulated as a mechanism for rapid cycling. This systematic review—conducted in accordance with the PRISMA guidelines—of eight studies synthesizes the evidence for TH augmentation in BD. A systematic search of the Ovid MEDLINE, Embase, PsycINFO, and Cochrane databases was conducted for randomized controlled trials (RCT), open-label trials, and observational studies of levothyroxine (LT4) and triiodothyronine (T3) for BD. Open-label studies of high dose LT4 augmentation for bipolar depression and rapid cycling showed improvement in depression outcomes and reduction in recurrence, respectively. However, an RCT of high-dose LT4 did not show benefit in contrast to placebo. An RCT comparing LT4, T3, and placebo showed benefit only in rapid-cycling bipolar women. A meta-analysis could not be completed due to significant differences in study designs, interventions, and outcomes. Our systematic review shows mixed evidence and a lack of high-quality studies. The initial promise of supratherapeutic LT4 augmentation from open-label trials has not been consistently replicated in RCTs. Limited data are available for T3. The studies did not report significant thyrotoxicosis, and TH augmentation were well tolerated. Therefore, TH augmentation, especially with supratherapeutic doses, should be reserved for highly treatment-resistant bipolar depression and rapid-cycling BD.

Peripheral nerve stimulation (PNS) has been utilized for over 50 years with accumulating evidence of efficacy in a variety of chronic pain conditions. The level and strength of evidence supporting the use of PNS for peripheral neuropathic pain remains unclear. The purpose of this review is to synthesize data from prospective studies on the efficacy of PNS for neuropathic pain as it pertains to pain intensity, neurological deficits/neuropathy (e.g., weakness, sensory deficits, gait/balance), and other secondary outcomes (quality of life, satisfaction, emotional functioning, and adverse events). In compliance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, this review identified articles from MEDLINE(R), EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus. Overall, per the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria, pooled results demonstrate very low quality or low quality of evidence supporting modest to substantial improvement in pain and neurological function after PNS implantation for treatment of peripheral neuropathic pain. PNS for phantom limb pain was the only indication that had moderate level evidence. Future prospective and well-powered studies are warranted to assess the efficacy of PNS for peripheral neuropathic pain.

Abstract Aims To evaluate the association of basic life support with survival after sports-related sudden cardiac arrest (SR-SCA). Methods and results In this systematic review and meta-analysis, a search of several databases from each database inception to 31 July 2021 without language restrictions was conducted. Studies were considered eligible if they evaluated one of three scenarios in patients with SR-SCA: (i) bystander presence, (ii) bystander cardiopulmonary resuscitation (CPR), or (iii) bystander automated external defibrillator (AED) use and provided information on survival. Risk of bias was evaluated using Risk of Bias in Non-randomized Studies of Interventions. The primary outcome was survival at the longest follow up. The meta-analysis was conducted using the random-effects model. The Grading of Recommendations Assessment, Development, and Evaluations (GRADE) approach was used to rate certainty in the evidence. In total, 28 non-randomized studies were included. The meta-analysis showed significant benefit on survival in all three groups: bystander presence [odds ratio (OR) 2.55, 95% confidence interval (CI) 1.48–4.37; I2 = 25%; 9 studies—988 patients], bystander CPR (OR 3.84, 95% CI 2.36–6.25; I2 = 54%; 23 studies—2523 patients), and bystander AED use (OR 5.25, 95% CI 3.58–7.70; I2 = 16%; 19 studies—1227 patients). The GRADE certainty of evidence was judged to be moderate. Conclusion In patients with SR-SCA, bystander presence, bystander CPR, and bystander AED use were significantly associated with survival. These results highlight the importance of witness intervention and encourage countries to develop their first aid training policy and AED installation in sport settings.

ImportanceApproval by the US Food and Drug Administration of immune checkpoint inhibition (ICI) for advanced gastroesophageal cancer (aGEC) irrespective of PD-L1 status has generated controversy. Exploratory analyses from individual trials indicate a lack of meaningful benefit from ICI in patients with absent or low PD-L1 expression; however, analysis of a single variable while ignoring others may not consider the instability inherent in exploratory analyses.ObjectiveTo systematically examine the predictive value of tissue-based PD-L1 status compared with that of other variables for ICI benefit in aGEC to assess its stability.Data SourcesMEDLINE, Embase, Scopus, Web of Science, Cochrane Central Register (2000-2022).Study Selection, Data Extraction, and SynthesisRandomized clinical trials (RCTs) were included of adults with aGEC (adenocarcinoma [AC] or squamous cell carcinoma [SCC]) randomized to anti−PD-1 or PD-L1−containing treatment vs standard of care (SOC). Study screening, data abstraction, and bias assessment were completed independently by 2 reviewers. Of 5752 records screened, 26 were assessed for eligibility; 17 trials were included in the analysis.Main Outcomes and MeasuresThe prespecified primary end point was overall survival. The mean hazard ratio (HR) for ICI vs SOC was calculated (random-effects model). Predictive values were quantified by calculating the ratio of mean HRs between 2 levels of each variable.ResultsIn all, 17 RCTs (9 first line, 8 after first line) at low risk of bias and 14 predictive variables were included, totaling 11 166 participants (5067 with SCC, 6099 with ACC; 77.6% were male and 22.4% were female; 59.5% of patients were younger than 65 years, 40.5% were 65 years or older). Among patients with SCCs, PD-L1 tumor proportion score (TPS) was the strongest predictor of ICI benefit (HR, 0.60 [95% CI, 0.53-0.68] for high TPS; and HR, 0.84 [95% CI, 0.75-0.95] for low TPS), yielding a predictive value of 41.0% favoring high TPS (vs ≤16.0% for other variables). Among patients with AC, PD-L1 combined positive score (CPS) was the strongest predictor (after microsatellite instability high status) of ICI benefit (HR, 0.73 [95% CI, 0.66-0.81] for high CPS; and HR, 0.95 [95% CI, 0.84-1.07] for low CPS), yielding a predictive value of 29.4% favoring CPS-high (vs ≤12.9% for other variables). Head-to-head analyses of trials containing both levels of a variable and/or having similar design generally yielded consistent results.Conclusions and RelevanceTissue-based PD-L1 expression, more than any variable other than microsatellite instability-high, identified varying degrees of benefit from ICI-containing therapy vs SOC among patients with aGEC in 17 RCTs.

The introduction of robotics in living donor liver transplantation has been revolutionary. We aimed to examine the safety of robotic living donor right hepatectomy (RLDRH) compared to open (ODRH) and laparoscopic (LADRH) approaches. A systematic review was carried out in Medline and six additional databases following PRISMA guidelines. Data on morbidity, postoperative liver function, and pain in donors and recipients were extracted from studies comparing RLDRH, ODRH, and LADRH published up to September 2020; PROSPERO (CRD42020214313). Dichotomous variables were pooled as risk ratios and continuous variables as weighted mean differences. Four studies with a total of 517 patients were included. In living donors, the postoperative total bilirubin level (MD: −0.7 95%CI −1.0, −0.4), length of hospital stay (MD: −0.8 95%CI −1.4, −0.3), Clavien–Dindo complications I–II (RR: 0.5 95%CI 0.2, 0.9), and pain score at day > 3 (MD: −0.6 95%CI −1.6, 0.4) were lower following RLDRH compared to ODRH. Furthermore, the pain score at day > 3 (MD: −0.4 95%CI −0.8, −0.09) was lower after RLDRH when compared to LADRH. In recipients, the postoperative AST level was lower (MD: −0.5 95%CI −0.9, −0.1) following RLDRH compared to ODRH. Moreover, the length of stay (MD: −6.4 95%CI −11.3, −1.5) was lower after RLDRH when compared to LADRH. In summary, we identified low- to unclear-quality evidence that RLDRH seems to be safe and feasible for adult living donor liver transplantation compared to the conventional approaches. No postoperative deaths were reported.

Background: Dermatofibromas are common skin tumors that typically occur on the extremities and trunk and demonstrate benign behavior, frequent recurrences, and very rare metastasis. Facial dermatofibromas are rare and not well studied. We analyzed clinicopathologic features of facial dermatofibromas. Design: Considering the rarity of the condition, we conducted a cohort study and a systematic review. We queried medical records of a single tertiary care center for dermatofibromas from January 1, 2000, to July 1, 2021. A systematic review of multiple databases was conducted through October 27, 2021, to include studies reporting facial dermatofibromas. Random-effects meta-analysis was used to estimate pooled odds ratio and proportions with associated 95% confidence interval (CI). Results: The cohort study identified 2858 cases of dermatofibromas, of which, 23 cases from 18 patients were on the face (1%). The mean age was 52.7 ± 17.8 years. Fifty-six percent of the cases were women. The most common location was the forehead (6 cases). The mean follow-up was 54 months. Forty-four percent of the cases had subcutaneous involvement, and 39% were the cellular type. Margins were positive in 89% of the cases, recurrence rate was 22%, and no metastases were observed. The systematic review included 10 studies (119 patients). Meta-analyses showed that facial dermatofibromas were 2% of all dermatofibromas (95% CI: 1%–3%). The local recurrence rate was 14% (95% CI: 6%–26%). Facial dermatofibromas with subcutaneous involvement were more likely to recur [odds ratio 4.53 (95% CI: 1.12–18.24)]. Before histopathologic examination, clinical differential diagnosis included dermatofibromas in only 9% of the cases (95% CI: 2%–19%). Conclusion: Facial dermatofibromas are rare and are difficult to fully excise. Cellular type and subcutaneous or muscular involvement are common in these cases and tend to have higher local recurrence rate than other nonfacial dermatofibromas. Wider excisions might be necessary for complete excision.

Introduction: Current proposed Dietary Guidelines for Americans, 2015 suggested replacing refined grains (e.g., white rice) with whole grains (e.g., brown rice) for improved health outcomes; however, the association between white rice consumption and risk of cardiovascular disease (CVD) was not fully investigated. The purpose of this study was to explore the associations between rice consumption, metabolic syndrome and cardiovascular disease. Methods: We conducted a comprehensive search of MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Scopus, and the Cochrane Central Register of Controlled Trials from database inception through May 2015. Observational studies were included if the studies reported hazard ratios (HRs) or odd ratios (ORs) of the associations between rice consumption, metabolic syndrome and cardiovascular disease. Data were extracted by one reviewer and then reviewed by two independent reviewers. Conflicts were resolved through consensus. Using the DerSimonian and Laird random effects models, we calculated pooled HRs and pooled ORs with 95% confidence intervals (95% CIs). Subgroup analyses were performed to explore potential sources of heterogeneity. The quality of the included studies and publication bias were assessed. Results: Out of 343 retrieved articles, we identified 6 cross-sectional and 9 prospective studies with a total of 575,852 individuals with 24,649 total CVD events and 4,409 metabolic syndrome cases. The highest category of white rice consumption (≥5 times/week) was associated with a 37% higher risk of metabolic syndrome (pooled OR, 1.37; 95% CI: 1.03-1.84; p<0.001; I 2 = 78.7%) but not a higher risk of cardiovascular disease (pooled HR, 1.01; 95% CI: 0.95-1.08; p=0.65; I 2 = 0%), compared to the lowest category (≤1 time/month). Conclusions: Higher white rice consumption has not been shown to increase the risk of cardiovascular diseases but may be associated with increased risk of metabolic syndrome.

Introduction: Obesity is a growing global health problem associated with substantial morbidity and mortality. The risk of obesity on incident new-onset heart failure is controversial. The aim of this systematic review and meta-analysis was to explore the association between overweight, obesity and incident new-onset heart failure. Methods: We systematically searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Scopus, and the Cochrane Central Register of Controlled Trials from database inception through April 2015. Prospective cohort studies were included if the studies reported hazard ratios (HRs) of the association between overweight or obesity and new-onset heart failure (HF) relative to individuals with normal weight. Data were extracted by one reviewer followed by independent screening and extraction of study characteristics and outcome data by two other reviewers. Conflicts were resolved through consensus. Random-effects meta-analyses were used to pool the hazard ratio from the included studies. Subgroup analyses were performed to explore the potential sources of heterogeneity. Results: Out of 1,865 retrieved articles, we identified 10 relevant studies. Median follow-up was 12 years with a total of 82,167 individuals and 4,570 total HF events. Compared to normal body weight (body mass index (BMI) <25 kg/m2), overweight (BMI 25-29.9 kg/m2) was associated with 27% higher risk of new-onset heart failure events (pooled HR, 1.27; 95% confidence intervals (95% CI): 1.15-1.41; p<0.001; I 2 = 0%) and obesity (BMI ≥30 kg/m2) was associated with a two-fold increased risk for new-onset heart failure events (pooled HR, 2.09; 95% CI, 1.68-2.60; p<0.001; I 2 = 67.8%). Conclusions: Compared with normal-weight individuals, both overweight and obesity were independently associated with significantly higher incidence of heart failure. These results highlight the need for better understanding of mechanisms of obesity and heart failure.