Therapeutic potential of Takeda‐G‐protein‐receptor‐5 (TGR5) agonists. Hope or hype?

The gastrointestinal tract regulates glucose and energy metabolism, and there is increasing recognition that bile acids function as key signalling molecules in these processes. For example, bile acid changes that occur after bariatric surgery have been implicated in the effects on satiety, lipid and cholesterol regulation, glucose and energy metabolism, and the gut microbiome. In recent years, Takeda‐G‐protein‐receptor‐5 (TGR5), a bile acid receptor found in widely dispersed tissues, has been the target of significant drug discovery efforts in the hope of identifying effective treatments for metabolic diseases including type 2 diabetes, obesity, atherosclerosis, fatty liver disease and cancer. Although the benefits of targeting the TGR5 receptor are potentially great, drug development work to date has identified risks that include histopathological changes, tumorigenesis, gender differences, and questions about the translation of animal data to humans. The present article reviews the noteworthy challenges that must be addressed along the path of development of a safe and effective TGR5 agonist therapy.     

Why have meta‐analyses of randomized controlled trials of the association between non‐white‐blood‐cell‐reduced allogeneic blood transfusion and postoperative infection produced discordant results?

Intention-to-treat analyses of randomized controlled trials (RCTs) of the association between non-white-blood-cell (WBC)-reduced allogeneic blood transfusion (ABT) and postoperative infection were reported as the reason why meta-analyses of RCTs of this association have produced discordant results. We examined three possible reasons for disagreements between meta-analyses: (i) sources of medical heterogeneity and integration of RCTs despite extreme heterogeneity; (ii) reliance on as-treated (vs. intention-to-treat) comparisons; and (iii) inclusion (or not) of the three most recent RCTs. When nine RCTs reported up to 2002 were combined despite extreme heterogeneity, both intention-to-treat and as-treated comparisons found an association between non-WBC-reduced ABT and postoperative infection [summary odds ratio (OR) = 1.38, 95% confidence interval (CI) 1.03-1.85, P < 0.05; and summary OR = 1.56, 95% CI 1.06-2.31, P < 0.05, respectively]. When 12 RCTs reported up to 2005 were integrated despite extreme heterogeneity, both intention-to-treat and as-treated comparisons found no association of non-WBC-reduced ABT with postoperative infection (summary OR = 1.24, 95% CI 0.98-1.56, P > 0.05; and summary OR = 1.31, 95% CI 0.98-1.75, P > 0.05, respectively). In both analyses, the separate integration of four RCTs transfusing red blood cells (RBCs) or whole blood filtered after storage showed an association between non-WBC-reduced ABT and postoperative infection, whereas the separate integration of six (or nine) RCTs, reported through 2002 or 2005, and transfusing prestorage-filtered RBCs showed no association, whether intention-to-treat or as-treated comparisons were used. Thus, the published meta-analyses have produced discordant results because they did (or did not) investigate medical sources of heterogeneity and did (or did not) include the most recent RCTs. Intention-to-treat and as-treated comparisons produced concordant results.     

Does Nonresponse Bias the Results of Retrospective Surveys of End‐of‐Life Care?

OBJECTIVES: To evaluate the effect of nonresponse bias on reports of the quality of end‐of‐life care that older adults receive. DESIGN: Nationwide retrospective survey of end‐of‐life care. SETTING: Sixty‐two Veterans Affairs Medical Centers. PARTICIPANTS: Patients were eligible if they died in a participating facility. One family member per patient was selected from medical records and invited to participate. MEASUREMENTS: The telephone survey included 14 items describing important aspects of the patient's care in the last month of life. Scores (0–100) reflect the percentage of items for which the family member reported that the patient received the best possible care, and a global item defined the proportion of families who said the patient received “excellent” care. To examine the effect of nonresponse bias, a model was created to predict the likelihood of response based on patient and family characteristics; then this model was used to apply weights that were equivalent to the inverse of the probability of response for that individual. RESULTS: Interviews were completed with family members of 3,897 of 7,110 patients (55%). Once results were weighted to account for nonresponse bias, the change in mean individual scores was 2% of families reporting “excellent” care. Of the 62 facilities in the sample, the scores of only 19 facilities (31%) changed more than 1% in either direction, and only 10 (16%) changed more than 2%. CONCLUSION: Although nonresponse bias is a theoretical concern, it does not appear to have a significant effect on the facility‐level results of this retrospective family survey.     

Non‐specific effects of diphtheria‐tetanus‐pertussis and measles vaccinations? An analysis of surveillance data from Navrongo,Ghana

Objectives Studies from low‐income countries have suggested that routine vaccinations may have non‐specific effects on child mortality; measles vaccine (MV) is associated with lower mortality and diphtheria‐tetanus‐pertussis (DTP) with relatively higher mortality. We used data from Navrongo, Ghana, to examine the impact of vaccinations on child mortality. Methods Vaccination status was assessed at the initiation of a trial of vitamin A supplementation and after 12 and 24 months of follow‐up. Within the placebo group, we compared the mortality over the first 4 months and the full 2 years of follow‐up for different vaccination status groups with different likelihoods of additional vaccinations during follow‐up. The frequency of additional vaccinations was assessed among children whose vaccination card was seen at 12 and 24 months of follow‐up. Results Among children with a vaccination card, more than 75% received missing DTP or MV during the first 12 months of follow‐up, whereas only 25% received these vaccines among children with no vaccination card at enrolment. Children without a card at enrolment had a significant threefold higher mortality over the 2‐year follow‐up period than those fully vaccinated. The small group of children with DTP3‐4 but no MV at enrolment had lower mortality than children without a card and had the same mortality as fully vaccinated children. In contrast, children with 1–2 DTP doses but no MV had a higher mortality during the first 4 months than children without a card [MRR = 1.65 (0.95, 2.87)]; compared with the fully vaccinated children, they had significantly higher mortality after 4 months [MRR = 2.38 (1.07, 5.30)] and after 2 years [MRR = 2.41 (1.41, 4.15)]. Children with 0–2 DTP doses at enrolment had higher mortality after 4 months (MRR = 1.67 (0.82, 3.43) and after 2 years [MRR = 1.85 (1.16, 2.95)] than children who had all three doses of DTP at enrolment. Conclusions As hypothesised, DTP vaccination was associated with higher child mortality than measles vaccination. To optimise vaccination policies, routine vaccinations need to be evaluated in randomised trials measuring the impact on survival.     

The “Short‐Coupled” Variant of Right Ventricular Outflow Ventricular Tachycardia: A Not‐So‐Benign Form of Benign Ventricular Tachycardia?

Idiopathic ventricular tachycardia (VT) originating from the right ventricular outflow tract (RVOT-VT) and idiopathic RVOT-extrasystoles are generally considered benign arrhythmias. We described three cases who originally presented with typical "benign looking" RVOT-extrasystoles or RVOT-VT but developed malignant polymorphic VT during follow-up. The unusual aspect of their RVOT-extrasystoles was their coupling interval, which appears to be intermediate between the ultra-short coupling interval of idiopathic VF and the long coupling interval seen in the truly benign RVOT-VT.     

Bad nights or bad bars? Multi‐level analysis of environmental predictors of aggression in late‐night large‐capacity bars and clubs

AIMS: To clarify environmental predictors of bar-room aggression by differentiating relationships due to nightly variations versus across bar variations, frequency versus severity of aggression and patron versus staff aggression. DESIGN, SETTING AND PARTICIPANTS: Male-female pairs of researcher-observers conducted 1334 observations in 118 large capacity (> 300) bars and clubs in Toronto, Canada. MEASUREMENTS: Observers independently rated aspects of the environment (e.g. crowding) at every visit and wrote detailed narratives of each incident of aggression that occurred. Measures of severity of aggression for the visit were calculated by aggregating ratings for each person in aggressive incidents. FINDINGS: Although bivariate analyses confirmed the significance of most environmental predictors of aggression identified in previous research, multivariate analyses identified the following key visit-level predictors (controlling for bar-level relationships): rowdiness/permissive environment and people hanging around after closing predicted both frequency and severity of aggression; sexual activity, contact and competition and people with two or more drinks at closing predicted frequency but not severity of aggression; lack of staff monitoring predicted more severe patron aggression, while having more and better coordinated staff predicted more severe staff aggression. Intoxication of patrons was significantly associated with more frequent and severe patron aggression at the bar level (but not at the visit level) in the multivariate analyses and negatively associated with severity of staff aggression at the visit level. CONCLUSIONS: The results demonstrate clearly the importance of the immediate environment (not just the type of bar or characteristics of usual patrons) and the importance of specific environmental factors, including staff behaviour, in predicting both frequency and severity of aggression.     

Horses for courses? Assessing the potential value of a surrogate,point‐of‐care test for SARS‐CoV‐2 epidemic control

Point‐of‐care tests (POCTs) offer considerable potential for improving clinical and public health management of COVID‐19 by providing timely information to guide decision‐making, but data on real‐world performance are in short supply. Besides SARS‐CoV‐2‐specific tests, there is growing interest in the role of surrogate (non‐specific) tests such as FebriDx, a biochemical POCT which can be used to distinguish viral from bacterial infection in patients with influenza‐like illnesses. This short report assesses what is currently known about FebriDx performance across settings and populations by comparison with some of the more intensively evaluated SARS‐CoV‐2‐specific POCTs. While FebriDx shows some potential in supporting triage for early‐stage infection in acute care settings, this is dependent on SARS‐CoV‐2 being the most likely cause for influenza‐like illnesses, with reduction in discriminatory power when COVID‐19 case numbers are low, and when co‐circulating viral respiratory infections become more prevalent during the autumn and winter. Too little is currently known about its performance in primary care and the community to support use in these contexts, and further evaluation is needed. Reliable SARS CoV2‐specific POCTs—when they become available—are likely to rapidly overtake surrogates as the preferred option given the greater specificity they provide.     

Should patients be informed about the risk of heparin‐induced thrombocytopenia before prolonged low‐molecular‐weight heparin thromboprophylaxis post‐trauma/orthopedic surgery?

OBJECTIVES: Heparin-induced thrombocytopenia (HIT) is an immune-mediated prothrombotic adverse drug effect that occurs less frequently with low-molecular-weight heparin (LMWH) than with unfractionated heparin (UFH) in post-trauma/orthopedic surgery patients. The life-threatening nature of HIT raises the question whether informed consent for this treatment-induced adverse effect should be obtained, particularly as LMWH is often continued during the outpatient period when clinical and platelet count monitoring become problematic. Paradoxically, refusal of thromboprophylaxis as a result of seeking informed consent could increase risk for thrombosis. METHODS: We evaluated in patients undergoing routine LMWH thromboprophylaxis post-trauma/orthopedic surgery the feasibility of obtaining informed consent, using a standardized questionnaire to determine patient preferences. We also identified the proportion of HIT patients in our laboratory comprised of trauma/orthopedic surgery patients from 1995-1997 and 2002-2004 (time periods characterized, respectively, by UFH and LMWH thromboprophylaxis for this patient population). RESULTS: None of 460 patients in whom informed consent was administered rejected LMWH thromboprophylaxis. The patients' perception of the informed consent process and the written information provided about the risk of HIT and its risk due to clinical consequences were highly favorable. From 1995-1997 to 2002-2004, the proportion of HIT identified among trauma/orthopedic surgery patients declined from 30.3% to 1.2% (P < 0.0001). CONCLUSIONS: Obtaining informed consent about HIT is feasible in written form and does not cause refusal of LMWH thromboprophylaxis. Despite the uncommon occurrence of HIT during LMWH thromboprophylaxis, informed consent increases patient's awareness of this potentially life-threatening adverse drug effect, an outcome that could increase outpatient recognition of the diagnosis.     

Does on‐ versus off‐hours presentation impact in‐hospital outcomes of ST‐segment elevation myocardial infarction patients transferred to a tertiary care center?

Objectives : To determine whether in‐hospital outcome differs for transferred patients with ST‐segment elevation myocardial infarction (STEMI) presenting during business (ON) hours vs. after (OFF) hours. Background : Door‐to‐device (DTD) time is a prognostic factor in patients with STEMI and is longer during OFF hours. However, the in‐hospital mortality is controversial. Methods : This registry study included 786 consecutive patients with STEMI referred for primary percutaneous coronary intervention to a tertiary care center with an on‐site cardiac catheterization team 24 hrs a day/7 days (24/7) a week. ON hours were defined as weekdays 8 a.m. to 5 p.m., while OFF hours were defined as all other times, including holidays. The primary outcomes were in‐hospital death, reinfarction, and length of stay (LOS). Results : ON hours (29.5%, n = 232) and OFF hours (70.5%, n = 554) groups had similar demographic and baseline characteristics. A significantly higher proportion of patients presenting ON hours had a DTD time ≤120 min compared to OFF hours patients (32.6% vs. 22.1%, P = 0.007). The rates of in‐hospital death (8.2% vs. 6%), reinfarction (0% vs. 1.1%), and mean LOS (5.7 ± 6 vs. 5.7 ± 5) were not significantly different in the ON vs. OFF hours groups, all P = nonsignificant. Conclusion : In a tertiary care center with an on‐site cardiac catheterization team 24/7, there are no differences in in‐hospital outcomes of transferred patients with STEMI during ON vs. OFF hours. © 2010 Wiley‐Liss, Inc.     

Can C‐peptide mediated anti‐inflammatory effects retard the development of microvascular complications of type 1 diabetes?

Hyperglycemia is considered to be the major cause of microvascular complications of diabetes. Growing evidence highlights the importance of hyperglycemia‐mediated inflammation in the initiation and progression of microvascular complications in type 1 diabetes. We hypothesize that lack of proinsulin C‐peptide and lack of its anti‐inflammatory properties contribute to the development of microvascular complications. Evidence gathered over the past 20 years shows that C‐peptide is a biologically active peptide in its own right. It has been shown to reduce formation of reactive oxygen species and nuclear factor‐κB activation induced by hyperglycemia, resulting in inhibition of cytokine, chemokine and cell adhesion molecule formation as well as reduced apoptotic activity. In addition, C‐peptide stimulates and induces the expression of both Na⁺, K⁺‐ATPase and endothelial nitric oxide synthase. Animal studies and small‐scale clinical trials in type 1 diabetes patients suggest that C‐peptide replacement combined with regular insulin therapy exerts beneficial effects on kidney and nerve dysfunction. Further clinical trials in patients with microvascular complications including measurements of inflammatory markers are warranted to explore the clinical significance of the aforementioned, previously unrecognized, C‐peptide effects. Copyright © 2013 John Wiley & Sons, Ltd.     

Over‐expansion of balloon‐expandable transcatheter heart valves. Is there a limit?

• Transcatheter aortic valve implantation can be successful in selected patients with annuli beyond the current recommended limits for available transcatheter valves.
• Over‐expansion of balloon‐expandable valves beyond current guidelines may play a role.
• The limits of over‐expansion of balloon‐expandable valves are not well understood.