Acute cerebrovascular events in severe and nonsevere COVID-19 patients: a systematic review and meta-analysis.

The degree to which COVID-19 severity influences the development of acute cerebrovascular events (ACVE) is unknown. Therefore, we aimed to describe the prevalence and risk of ACVE in patients with severe and nonsevere COVID-19. We systematically reviewed MEDLINE, EMBASE, Web of Science, and Scopus and identified observational and interventional studies of patients with COVID-19 allocated by respiratory severity that reported ACVE development. Case reports/series were excluded. The main outcome assessed was the pooled rate of ACVE in patients with severe and nonsevere COVID-19. To determine the risk of ACVE development by COVID-19 severity, a meta-analysis was performed. PROSPERO registration number: CRD42020178905. About 19 of 5758 identified studies were analyzed. From 11,886 COVID-19 patients analyzed, 421 had at least one ACVE [3.6%, 95% confidence interval (CI) 2.904-4.179]. Severe COVID-19 increased the risk of ACVE (odds ratio 1.96, 95% CI 1.22-3.15; P = 0.005; I 2 = 64%), specifically hemorrhagic stroke (4.12, 2.0-8.53; P = 0.001; I 2 = 0%). There was no difference in the risk of developing ischemic stroke between patients with severe and nonsevere COVID-19 (1.53, 0.87-2.7; P = 0.14; I 2 = 52%). From the patients who developed any ACVE, those with severe COVID-19 had a greater mortality risk than those with nonsevere COVID-19 (3.85, 1.08-13.70; P = 0.04; I 2 = 0%). The main limitations of our study were the heterogeneity found in the main meta-analysis studies and in their reported definition for COVID-19 severity. In conclusion, our findings provide evidence that COVID-19 respiratory severity could lead to ACVE development that increases mortality. The effect of COVID-19 management in ACVE needs to be evaluated.

Variation in hypoglycemia ascertainment and report in type 2 diabetes observational studies: a meta-epidemiological study.

INTRODUCTION: Observational studies constitute an important evidence base for hypoglycemia in diabetes management. This requires consistent and reliable ascertainment and reporting methodology, particularly in studies of type 2 diabetes where hypoglycemia risk is heterogeneous. Therefore, we aimed to examine the definitions of hypoglycemia used by observational studies of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We conducted a meta-epidemiological review of observational studies reporting on hypoglycemia or evaluating glucose-lowering medications in adults with type 2 diabetes. MEDLINE and Google Scholar were searched from January 1970 to May 2018. The definitions of non-severe, severe and nocturnal hypoglycemia were examined. RESULTS: We reviewed 243 studies: 47.7% reported on non-severe hypoglycemia, 77.8% on severe hypoglycemia and 16.9% on nocturnal hypoglycemia; 5.8% did not specify. Among 116 studies reporting non-severe hypoglycemia, 18.1% provided no definition, 23.3% used glucose values, 38.8% relied on patient-reported symptoms, 17.2% accepted either glucose values or patient-reported symptoms and 2.6% relied on International Classification of Disease (ICD) codes. Among 189 studies reporting severe hypoglycemia, 11.1% provided no definition, 53.4% required symptoms needing assistance, 3.7% relied on glucose values, 14.8% relied on ICD codes, 2.6% relied on ICD codes or glucose values and 15.9% required both symptoms needing assistance and glucose values. Overall, 38.2% of non-severe and 67.7% of severe hypoglycemia definitions were consistent with the International Hypoglycemia Study Group. CONCLUSIONS: The marked heterogeneity in how hypoglycemia is defined in observational studies may contribute to the inadequate understanding and correction of hypoglycemia risk factors among patients with type 2 diabetes.

Documentation of hypoglycemia assessment among adults with diabetes during clinical encounters in primary care and endocrinology practices.

PURPOSE: To examine the proportion of diabetes-focused clinical encounters in primary care and endocrinology practices where the evaluation for hypoglycemia is documented; and when it is, identify clinicians' stated actions in response to patient-reported events. METHODS: A total of 470 diabetes-focused encounters among 283 patients nonpregnant adults (≥18 years) with type 1 or type 2 diabetes mellitus in this retrospective cohort study. Participants were randomly identified in blocks of treatment strategy and care location (95 and 52 primary care encounters among hypoglycemia-prone medications (i.e. insulin, sulfonylurea) and others patients, respectively; 94 and 42 endocrinology encounters among hypo-treated and others, respectively). Documentation of hypoglycemia and subsequent management plan in the electronic health record were evaluated. RESULTS: Overall, 132 (46.6%) patients had documentation of hypoglycemia assessment, significantly more prevalent among hypo-treated patients seen in endocrinology than in primary care (72.3% vs. 47.4%; P = 0.001). Hypoglycemia was identified by patient in 38.2% of encounters. Odds of hypoglycemia assessment documentation was highest among the hypo-treated (OR 13.6; 95% CI 5.5-33.74, vs. others) and patients seen in endocrine clinic (OR 4.48; 95% CI 2.3-8.6, vs. primary care). After documentation of hypoglycemia, treatment was modified in 30% primary care and 46% endocrine clinic encounters; P = 0.31. Few patients were referred to diabetes self-management education and support (DSMES). CONCLUSIONS: Continued efforts to improve hypoglycemia evaluation, documentation, and management are needed, particularly in primary care. This includes not only screening at-risk patients for hypoglycemia, but also modifying their treatment regimens and/or leveraging DSMES.

Acanthosis Nigricans in the Knuckles of Infants: A Novel Clinical Marker of High Metabolic Risk.

INTRODUCTION: Acanthosis nigricans (AN) is an early clinical sign of insulin resistance (IR) primarily in adults. The prevalence and association of AN and IR in infants, however, remains uncertain. We aimed to describe the prevalence of AN and its association with IR in a group of Latin-American infants. METHODS: We studied a random sample of 227 healthy infants between 9 and 24 months of age. After a complete clinical history was obtained and a physical examination was performed, fasting plasma glucose and serum insulin were measured. Three blinded evaluators assessed AN in each patient. Infants with AN were categorized as cases. The HOMA-IR index cutoffs of ≥ 90th and ≥ 95th percentiles were considered IR. RESULTS: There were 49 infants with AN (21.6%) (cases) and 178 without AN (78.4%) (controls). Cases had a significantly higher mean serum insulin, fasting plasma glucose, and HOMA-IR levels of 3.67 ± 2.56 µU/ml vs. 2.42 ± 1.45 µU/ml, P = 0.005; 84.2 ± 12.6 mg/dL vs. 77 ± SD 9.9 mg/dL, P ≤ 0.001; HOMA-IR 0.77 ± 0.54 vs. 0.46 ± 0.28, P ≤ 0.001, respectively. More cases than controls presented HOMA-IR levels ≥ 95th percentile (cases 18.4%; controls 0.5%, P ≤ 0.001) and ≥ 90th percentile (cases 32.7%; controls 1.6%, P ≤ 0.001). AN in the knuckles had a high sensitivity and a negative predictive value (NPV) for detecting patients with HOMA-IR levels above the 95th percentile (sensitivity 90%; NPV 99.4%) and above the 90th percentile (sensitivity 84.2%; NPV 98.3%). CONCLUSION: AN in the knuckles is a prevalent, non-invasive, costless, and reliable screening clinical tool that can be used for early detection of infants with IR and a high metabolic risk.

Participants' awareness of ethical compliance, safety and protection during participation in pharmaceutical industry clinical trials: a controlled survey.

BACKGROUND: The rapid increase of industry-sponsored clinical research towards developing countries has led to potentially complex ethical issues to assess. There is scarce evidence about the perception of these participants about the ethical compliance, security, and protection. We sought to evaluate and contrast the awareness and perception of participants and non-participants of industry-sponsored research trials (ISRT) on ethical, safety, and protection topics. METHODS: A Cases-control survey conducted at twelve research sites in México. Previous and current participants of ISRT (cases) as well as non-participants (controls) with one of four chronic diseases, were asked to complete the survey which focused on ethical compliance and protection issues of ISRT, and the perception of participating in a trial. RESULTS: A total of 604 cases and 604 controls were surveyed. Cases significantly answered that ethics committees are aware of what is happening in studies (50.5% vs. 33.8%, P = ≤ 0.001), and that medical care of industry-sponsored research trials is better than their usual medical care (77.2% vs. 38.2%, P = < 0.001). The same proportion of cases and controls thought patients must receive economical reimbursement for participating in a research study (49.5% vs. 53.1%, P = 0.205). The informed consent of the pharmaceutical clinical trial was fully read by 90.4% of the cases. Most cases were satisfied or very satisfied with their overall study participation (35.6 and 62.3%, respectively). CONCLUSION: Previous and current participants of industry-sponsored research trials have a more positive attitude towards ethics committees, the quality of medical care of the research trials, and the main purpose of economical reimbursements, when compared to non-participants.

Acanthosis nigricans in the knuckles: An early, accessible, straightforward, and sensitive clinical tool to predict insulin resistance.

Any clinical/biochemical marker revealing obesity or diabetes before their appearance is valuable. Insulin resistance (IR) is present in both disorders many years before occurrence. Accordingly, we determined whether acanthosis nigricans (AN) in the knuckles is associated to higher insulin and homeostasis model assessment for estimated insulin resistance (HOMA-IR) index values, and assessed the influence of body-mass index (BMI) and the diagnostic performance of AN in the knuckles to detect IR. In this cross-sectional controlled study, we included men or women, 18 to 23 years old, with or without AN in the knuckles. In 149 cases with AN in the knuckles and 145 controls, fasting insulin was higher in cases (13.45 µU/mL ± 7.8 vs. 8.59 µU/mL ± 3.63, P < .001, respectively). Mean HOMA-IR index was also higher (2.86 ± 1.68 vs. 1.78 ± 0.77, P < .001). A significant increase in fasting insulin and HOMA-IR values between and within BMI groups from normal through obese category was identified in controls and cases. By multivariate regression analysis, cases with normal BMI were significantly associated to a HOMA-IR ≥2.5 (OR = 3.09, CI95% = 1.75-5.48, P = .001). A model of AN in the knuckles, normal BMI, and increased waist circumference allowed identifying 2 out of 3 cases with HOMA-IR index ≥2.5. AN in the knuckles could be addressed with two aims: as an easy, accessible, and costless diagnostic tool suggesting hyperinsulinemia secondary to IR, and, an early marker of IR even in the absence of overweight or obesity.

Systematic review and meta-analysis of the effect of SGLT-2 inhibitors on microvascular outcomes in patients with type 2 diabetes: a review protocol.

INTRODUCTION: Sodium glucose cotransporter 2 (SGLT-2) inhibitors are a relatively new drug-class of glucose-lowering medications. Several trials and systematic reviews have demonstrated their beneficial effect on some macrovascular outcomes. Their effect on microvascular outcomes has been reported as positive in several trials, however, their effect remains uncertain. Therefore, we report the protocol of a systematic review and meta-analysis aimed at determining the effect of SGLT-2 inhibitors regarding patient-important and surrogate microvascular outcomes in patients with type 2 diabetes. METHODS AND ANALYSIS: A comprehensive search will be conducted to find eligible articles from each database's earliest inception to November 2017. These databases will include Ovid, MEDLINE, EMBASE, Web of Science, and Scopus. We will search for randomized controlled trials (RCTs) that compare any of the SGLT-2 inhibitors with any other active treatment or placebo assessing microvascular outcomes in either their primary or secondary outcomes. Reviewers working independently and in duplicate will review all abstracts, and full-text manuscripts for eligibility, and will systematically extract the data and will assess the risk of bias in the included studies. Random-effects models will also be used. ETHICS AND DISSEMINATION: The results of the systematic review will be disseminated via publication in a peer-reviewed journal regardless of outcome and will be presented at relevant conferences. The data we will use do not include individual patient data, so ethical approval is not required PROSPERO REGISTRATION NUMBER: CRD42017076460.

Hypoglycemia Among Patients with Type 2 Diabetes: Epidemiology, Risk Factors, and Prevention Strategies.

PURPOSE OF REVIEW: Hypoglycemia is the most common and often treatment-limiting serious adverse effect of diabetes therapy. Despite being potentially preventable, hypoglycemia in type 2 diabetes incurs substantial personal and societal burden. We review the epidemiology of hypoglycemia in type 2 diabetes, discuss key risk factors, and introduce potential prevention strategies. RECENT FINDINGS: Reported rates of hypoglycemia in type 2 diabetes vary widely as there is marked heterogeneity in how hypoglycemia is defined, measured, and reported. In randomized controlled trials, rates of severe hypoglycemia ranged from 0.7 to 12 per 100 person-years. In observational studies, hospitalizations or emergency department visits for hypoglycemia were experienced by 0.2 (patients treated without insulin or sulfonylurea) to 2.0 (insulin or sulfonylurea users) per 100 person-years. Patient-reported hypoglycemia is much more common. Over the course of 6 months, 1-4% non-insulin users reported need for medical attention for hypoglycemia; 1-17%, need for any assistance; and 46-58%, any hypoglycemia symptoms. Similarly, over a 12-month period, 4-17% of insulin-treated patients reported needing assistance and 37-64% experienced any hypoglycemic symptoms. Hypoglycemia is most common among older patients with multiple or advanced comorbidities, patients with long diabetes duration, or patients with a prior history of hypoglycemia. Insulin and sulfonylurea use, food insecurity, and fasting also increase hypoglycemia risk. Clinical decision support tools may help identify at-risk patients. Prospective trials of efforts to reduce hypoglycemia risk are needed, and there is emerging evidence supporting multidisciplinary interventions including treatment de-intensification, use of diabetes technologies, diabetes self-management, and social support. Hypoglycemia among patients with type 2 diabetes is common. Patient-centered multidisciplinary care may help proactively identify at-risk patients and address the multiplicity of factors contributing to hypoglycemia occurrence.

Sheehan's Syndrome Revisited: Underlying Autoimmunity or Hypoperfusion?

Sheehan's syndrome remains a frequent obstetric complication with an uncertain pathophysiology. We aimed to assess the incidence of hypopituitarism (≥2 hormonal axis impairment) within the first six postchildbirth months and to determine the existence of anti-pituitary antibodies. From 2015 to 2017, adult pregnant women, who developed moderate to severe postpartum hemorrhage (PPH), were consecutively included in the study. Pituitary function was assessed 4 and 24 weeks after PPH. At the end of the study, anti-pituitary antibodies were assessed. Twenty women completed the study. Mean age was 26.35 (±5.83) years. The main etiology for severe PPH was uterine atony (65%) which resulted mostly in hypovolemic shock grades III-IV. Within the first four weeks after delivery, 95% of patients had at least one hormonal pituitary affected and 60% of the patients fulfilled diagnostic criteria for hypopituitarism. At the end of the study period, five patients (25%) were diagnosed with hypopituitarism (GH and cortisol axes affected). Anti-pituitary antibodies were negative in all patients. At 6 months follow-up, one in every four women with a history of moderate-to-severe PPH was found with asymptomatic nonautoimmune-mediated hypopituitarism. The role of autoimmunity in Sheehan's syndrome remains uncertain. Further studies are needed to improve the remaining knowledge gaps.

The efficacy and adverse events of testosterone replacement therapy in hypogonadal men: A systematic review and meta-analysis of randomized, placebo-controlled trials.

CONTEXT: The efficacy and safety of testosterone replacement therapy (TRT) in hypogonadal men remain incompletely understood. OBJECTIVE: To conduct a systematic review and meta-analysis of randomized clinical trials (RCT) to determine the effects of TRT on patient-important outcomes and adverse events in hypogonadal men. DATA SOURCES: We searched Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Database of Systematic Reviews, Ovid Cochrane Central Register of Controlled Trials, and Scopus from inception to March 2th, 2017. STUDY SELECTION: RCTs that assessed the efficacy and adverse events of TRT of at least 12 weeks compared with placebo in adult men with hypogonadism, defined by morning testosterone ≤300 ng/dL and at least one symptom or sign of hypogonadism. DATA EXTRACTION: Reviewers working independently and in duplicate assessed the quality of the trials and collected data on patient characteristics, interventions, and outcomes. DATA SYNTHESIS: We found 11 publications, reporting on 4 eligible trials (including 1,779 patients) at low risk of bias. Compared to placebo, TRT was associated with a small but significant increase in sexual desire or libido [standardized mean difference (SMD): 0.17, 95% CI 0.01, 0.34] (n=1383), erectile function [SMD: 0.16, 95% CI 0.06, 0.27] (n=1344), and sexual satisfaction [SMD: 0.16, 95% CI 0.01, 0.31] (n=676), but had no effect on energy or mood. TRT was associated with an increased risk of developing erythrocytosis [relative risk: 8.14, 95% CI: 1.87, 35.40] (n=1579) compared to placebo, but had no significant effect on lower urinary tract symptoms (LUTS). CONCLUSION: In hypogonadal men TRT improves sexual desire, erectile function, and sexual satisfaction, however it increases the risk of erythrocytosis.

Early Clinical Expressions of Insulin Resistance: The Real Enemy to Look For.

The type 2 diabetes mellitus epidemic threatens public healthcare systems worldwide. Efforts to prevent chronic complications of diabetes and reduce their associated mortality have been ineffective. Hence, early prevention of type 2 diabetes mellitus and cardiovascular disease needs to be prioritized. This strategy, however, must be centered not on an approach based on hyperglycemia but on early pathophysiologic mechanisms, such as insulin resistance. Non-alcoholic fatty liver disease, androgenic alopecia, acanthosis nigricans, and polycystic ovarian syndrome are all well-accepted early clinical manifestations of insulin resistance that represent, in themselves, a risk for further development of type 2 diabetes and that appear years before hyperglycemia. Therefore, focusing efforts on detecting and rigorously treating patients with early clinical expression of insulin resistance (insulin resistance clinical syndrome) is probably the course of action that needs to be taken to counterbalance the type 2 diabetes mellitus epidemic.

Riley-Day Syndrome in a Hispanic Infant of Non-Jewish Ashkenazi Descent.

Riley-Day syndrome is an autosomal recessive sensory and autonomic neuropathy. Patients present a lack of fungiform papilla, alacrima and usually feeding difficulties. It is present almost exclusively in Ashkenazi Jewish individuals and has a poor prognosis. We describe an unusual case of Riley-Day syndrome with pseudostrabismus in a non-Ashkenazi Jewish patient. A one-year-old female infant was referred for evaluation of strabismus, absence of fungiform papillae, feeding difficulty, gastroesophageal reflux and episodes of self-mutilation. Deep tendon reflexes were depressed, the blinking rate and corneal reflex were diminished as well and corneas were opaque due to corneal erosions. Reduced lacrimal production was confirmed by the Schirmer test. Eye drops were recommended every 2-3 hours for corneal erosion and the patient was referred to the genetics department for further diagnostic confirmation.

Metformin Use and Vitamin B12 Deficiency: Untangling the Association.

BACKGROUND: Current evidence linking vitamin B12 deficiency with metformin use is inconsistent. Hence, there is uncertainty regarding the diagnostic approach in this scenario. Furthermore, this possible association has not been studied in the complete spectrum of patients with diabetes. MATERIALS AND METHODS: We conducted a cross-sectional, controlled study with the objective of assessing differences in serum vitamin B12 levels among patients with and without diabetes with different metformin-treatment regimens. A total of 150 participants were recruited: patients with diabetes (group 1: metformin alone ≥850mg/day, group 2: patients with type 2 diabetes naive to treatment and group 3: metformin ≥850mg/day, in addition to any other oral glucose lowering agent or insulin, or both) and without diabetes (group 4: polycystic ovary syndrome or group 5: healthy individuals). Serum vitamin B12, folate levels and complete blood counts were obtained for the entire population. Methylmalonic acid and homocysteine were obtained for patients when vitamin B12 levels were found to be borderline or low. RESULTS: When patients with or without diabetes were compared, no significant difference was found in relation to their vitamin B12 levels (517.62 versus 433.83; P = 0.072). No difference in vitamin B12 levels was found among participants with metformin use and metformin naive participants (503.4 versus 462.3; P = 0.380). CONCLUSIONS: Irrespective of metformin use, no significant difference in the serum levels of vitamin B12 was observed, both in patients with and without diabetes. In the light of the body of evidence and the results of this study, a universal recommendation for vitamin B12 deficiency screening cannot be made.

Participants' perception of pharmaceutical clinical research: a cross-sectional controlled study.

BACKGROUND: There is scarce scientific information assessing participants' perception of pharmaceutical research in developed and developing countries concerning the risks, safety, and purpose of clinical trials. METHODS: To assess the perception that 604 trial participants (cases) and 604 nonparticipants (controls) of pharmaceutical clinical trials have about pharmaceutical clinical research, we surveyed participants with one of four chronic diseases from 12 research sites throughout Mexico. RESULTS: Participation in clinical trials positively influences the perception of pharmaceutical clinical research. More cases (65.4%) than controls (50.7%) perceived that the main purpose of pharmaceutical research is to cure more diseases and to do so more effectively. In addition, more cases considered that there are significant benefits when participating in a research study, such as excellent medical care and extra free services, with this being the most important motivation to participate for both groups (cases 52%, controls 54.5%). We also found a sense of trust in their physicians to deal with adverse events, and the perception that clinical research is a benefit to their health, rather than a risk. More controls believed that clinical trial participants' health is put at risk (57% vs 33.3%). More cases (99.2%) than controls (77.5%) would recommend participating in a clinical trial, and 90% of cases would enroll in a clinical trial again. CONCLUSION: Participation in clinical trials positively influences the perception that participants have about pharmaceutical clinical research when compared to nonparticipants. This information needs to be conveyed to clinicians, public health authorities, and general population to overcome misconceptions.

Secretion of biologically active human interleukin 22 (IL-22) by Lactococcus lactis.

Interleukin-22 (IL-22) participates in the modulation of innate immunity and inflammation. This cytokine has important therapeutic potential, such as with ulcerative colitis, liver and lung injury, and infection, in different animal models. We generated a Lactococcus lactis strain that secretes human IL-22 under the regulation of the nisin-inducible promoter. Identification and secretion of this cytokine was demonstrated using western blots of culture supernatants from IL-22-expressing bacteria. The recombinant IL-22 protein produced by L. lactis was biologically active as determined by its ability to induce IL-10 secretion when co-cultured with a colon epithelial cell line in vitro. We consider this novel strain a promising live vaccine for various therapeutic applications.