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Background: In randomized controlled trials (RCTs), the power is often ‘reverse engineered’ based on the number of participants that can realistically be achieved. An attractive alternative is planning a new trial conditional on the available evidence; a design of particular interest in RCTs that use a sham control arm (sham-RCTs). Methods: We explore the design of sham-RCTs, the role of sequential meta-analysis and conditional planning in a systematic review of renal sympathetic denervation for patients with arterial hypertension. The main efficacy endpoint was mean change in 24-hour systolic blood pressure. We performed sequential meta-analysis to identify the time point where the null hypothesis would be rejected in a prospective scenario. Evidence-based conditional sample size calculations were performed based on fixed-effect meta-analysis. Results: In total, six sham-RCTs (981 participants) were identified. The first RCT was considerably larger (535 participants) than those subsequently published (median sample size of 80). All trial sample sizes were calculated assuming an unrealistically large intervention effect which resulted in low power when each study is considered as a stand-alone experiment. Sequential meta-analysis provided firm evidence against the null hypothesis with the synthesis of the first four trials (755 patients, cumulative mean difference -2.75 (95%CI -4.93 to -0.58) favoring the active intervention)). Conditional planning resulted in much larger sample sizes compared to those in the original trials, due to overoptimistic expected effects made by the investigators in individual trials, and potentially a time-effect association. Conclusions: Sequential meta-analysis of sham-RCTs can reach conclusive findings earlier and hence avoid exposing patients to sham-related risks. Conditional planning of new sham-RCTs poses important challenges as many surgical/minimally invasive procedures improve over time, the intervention effect is expected to increase in new studies and this violates the underlying assumptions. Unless this is accounted for, conditional planning will not improve the design of sham-RCTs.

Objective To examine the comparative efficacy and complications of long-acting and intermediate-acting insulin for different patient characteristics for type 1 diabetes mellitus (T1DM).Design Systematic review and individual patient data (IPD) network meta-analysis (NMA).Data sources MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched through June 2015.Eligibility criteria Randomised controlled trials (RCTs) on adults with T1DM assessing glycosylated haemoglobin (A1c) and severe hypoglycaemia in long-acting and intermediate-acting insulin regimens.Data extraction and synthesis We requested IPD from authors and funders. When IPD were not available, we used aggregate data. We conducted a random-effects model, and specifically a one-stage IPD-NMA for those studies providing IPD and a two-stage IPD-NMA to incorporate those studies not providing IPD.Results We included 28 RCTs plus one companion report, after screening 6680 titles/abstracts and 205 full-text articles. Of the 28 RCTs, 27 studies provided data for the NMA with 7394 participants, of which 12 RCTs had IPD on 4943 participants. The IPD-NMA for A1c suggested that glargine once daily (mean difference [MD]=−0.31, 95% confidence interval [CI]: −0.48 to −0.14) and detemir once daily (MD=−0.25, 95% CI: –0.41 to −0.09) were superior to neutral protamine Hagedorn (NPH) once daily. NPH once/two times per day improved A1c compared with NPH once daily (MD=−0.30, 95% CI: –0.50 to −0.11). Results regarding complications in severe hypoglycaemia should be considered with great caution due to inconsistency in the evidence network. Accounting for missing data, there was no evidence of inconsistency and long-acting insulin regimens ranked higher regarding reducing severe hypoglycaemia compared with intermediate-acting insulin regimens (two-stage NMA: glargine two times per day SUCRA (Surface Under the Cumulative Ranking curve)=89%, detemir once daily SUCRA=77%; one-stage NMA: detemir once daily/two times per day SUCRA=85%). Using multiple imputations and IPD only, complications in severe hypoglycaemia increased with diabetes-related comorbidities (regression coefficient: 1.03, 95% CI: 1.02 to 1.03).Conclusions Long-acting insulin regimens reduced A1c compared with intermediate-acting insulin regimens and were associated with lower severe hypoglycaemia. Of the observed differences, only glargine once daily achieved a clinically significant reduction of 0.30%. Results should be interpreted with caution due to very low quality of evidence.PROSPERO registration number CRD42015023511.

Missing data result in less precise and possibly biased effect estimates in single studies. Bias arising from studies with incomplete outcome data is naturally propagated in a meta-analysis. Conventional analysis using only individuals with available data is adequate when the meta-analyst can be confident that the data are missing at random (MAR) in every study--that is, that the probability of missing data does not depend on unobserved variables, conditional on observed variables. Usually, such confidence is unjustified as participants may drop out due to lack of improvement or adverse effects. The MAR assumption cannot be tested, and a sensitivity analysis to assess how robust results are to reasonable deviations from the MAR assumption is important. Two methods may be used based on plausible alternative assumptions about the missing data. Firstly, the distribution of reasons for missing data may be used to impute the missing values. Secondly, the analyst may specify the magnitude and uncertainty of possible departures from the missing at random assumption, and these may be used to correct bias and reweight the studies. This is achieved by employing a pattern mixture model and describing how the outcome in the missing participants is related to the outcome in the completers. Ideally, this relationship is informed using expert opinion. The methods are illustrated in two examples with binary and continuous outcomes. We provide recommendations on what trial investigators and systematic reviewers should do to minimize the problem of missing outcome data in meta-analysis.

Abstract Processing of N-terminally elongated antigenic peptide precursors by Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) is a key step in antigen presentation and the adaptive immune response. Although ERAP1 can efficiently process long peptides in solution, it has been proposed that it can also process peptides bound onto Major Histocompatibility Complex I molecules (MHCI). In a previous study, we suggested that the occasionally observed “ontο MHCI” trimming by ERAP1 is likely due to fast peptide dissociation followed by solution trimming, rather than direct action of ERAP1 onto the MHCI complex. However, other groups have proposed that ERAP1 can trim peptides covalently bound onto MHCI, which would preclude peptide dissociation. To explore this interaction, we constructed disulfide-linked MHCI-peptide complexes using HLA-B*08 and a 12mer kinetically labile peptide, or a 16mer carrying a phosphinic transition-state analogue N-terminus with high-affinity for ERAP1. Kinetic and biochemical analyses suggested that while both peptides could access the ERAP1 active site when free in solution, they were unable to do so when tethered in the MHCI binding groove. Our results suggest that MHCI binding protects, rather than promotes, antigenic peptide precursor trimming by ERAP1 and thus solution trimming is the more likely model of antigenic peptide processing.

The current study examined the changes in muscle oxygenation values and swimming performance after six sessions of sprint interval training during a three-week period in untrained swimmers. Twelve swimmers of both genders (age: 23.5 ± 5.6yrs) executed the twice-weekly experimental training protocol (EXP, n = 12), consisting of a 4 × 50 m front-crawl swimming (repeated sprint training—RST) with maximal intensity, and 2 min of passive recovery in between, after a short in-water warm-up. The control group (CON, n = 9) performed a continuous swimming set (200 m) at 120 b pm−1, with the same weekly frequency. Performance times in two maximum swim trials (400 m: T400 and 50 m: T50), muscle oxygenation of the deltoid muscle (SmO2) immediately after T400 and T50, 1-min heart rate recovery (HRR1) after T400, T50, and swim strokes during both swim trials (S/T400, S/T50) were assessed. For the EXP group, T400 improved by 2.4 (p = 0.011). In contrast, T50 presented no significant improvement (1%, p > 0.05). SmO2 decreased at T400 (5.5%, p = 0.017) and increased at T50 (3.7%, p = 0.030). HRR1 improved after T400 (7.9%, p = 0.002), T50 (4.6%, p = 0.005) and RST (9.6%, p = 0.002). S/T400 and S/T50 remained relatively unchanged (p > 0.05). The CON group presented no significant changes in any of the variables examined. In conclusion, six sprint interval training sessions can improve aerobic capacity over a 3-week training period, as indicated by the enhanced T400 performance and the reduced HRR1 values, in previously trained swimmers. Finally, the sensitivity of the near-infrared spectroscopy method to detect short-term training-induced changes is highlighted. [ABSTRACT FROM AUTHOR]

Valentin Felixovich Voyno-Yasenetsky (VFVY; also known as Saint Luke of Simferopol) was a famous professor of anatomy and surgery of the previous century. He was a particularly skilled surgeon, proficient in various surgical subspecialties, with main interest in regional anesthesia and pyogenic infections. The primary aim of this article is to explore his scientific contributions to surgical operations of the nervous system. His contributions are in three primary fields, namely, neuroanatomy, neurosurgery, and regional anesthesia. His work is characterized by meticulous descriptions of various anatomical structures of the brain and skull and of the intraoperative findings of his neurosurgical procedures. He clarified neurosurgical terms and described neurosurgical techniques. He also provided advice regarding the safety of neurosurgical procedures. Furthermore, he pioneered in techniques for regional anesthesia of the sciatic and trigeminal nerves. His exceptional talent as a scientist and surgeon, as well as his contributions to the neurosciences, makes him an exemplary doctor for modern neurosurgeons. [ABSTRACT FROM AUTHOR]

Background: Extracranial internal carotid aneurysms consist a rare pathology with an overall incidence less than 1% in the general population, and warrant treatment due to their association with cerebrovascular events and neurological complications. The incidence is even lower in the pediatric population. Case Report: A 14-month infant presented in our clinic with neck swelling of unknown origin, with subsequent MR imaging revealing an extracranial internal carotid aneurysm. Due to the patient's age and risk of surgical complications, the decision to proceed with endovascular repair with stent placement and complete exclusion of the aneurysm from the circulation was made, after multidisciplinary consultation. Results: In the pediatric population, pediatric population, endovascular stent placement can be considered at least as a last resort treatment when surgical access harbors significant risks or is impossible. [ABSTRACT FROM AUTHOR]

Aim: To investigate the role of autonomic nervous system in subpopulations of children with enuresis. Methods: We included 35 children with enuresis, divided in children with (17) and without nocturnal polyuria (18) and 43 healthy controls. For all participants hormones and neurotransmitters were measured. Patients and controls wore a sleep tracker device and children with enuresis underwent a 24 h blood pressure monitoring, nocturnal urine output measurement and uroflowmetry. Results: Children with enuresis had lower than controls copeptin and aldosterone, with the latter being more prominent in patients without nocturnal polyuria. Dopamine was lower in patients without nocturnal polyuria compared with patients with nocturnal polyuria. Children without polyuria experienced episodes only during NREM sleep, whereas in children with polyuria episodes occurred in both REM and NREM sleep. Children with enuresis experienced a non‐dipping phenomenon during sleep which was more prominent in the group without polyuria. Conclusion: In patients with nocturnal polyuria, nocturnal enuresis is associated with sympathetic hyperactivity which results in pressure polyuria and significantly lower systolic dipping during sleep. On the contrary, in children without nocturnal polyuria, it is mostly associated with bladder overactivity due to parasympathetic overstimulation as demonstrated by the NREM‐related enuretic episodes and the lower aldosterone and dopamine levels. [ABSTRACT FROM AUTHOR]

This study aimed to monitor the oxygenation and blood supply in three quadriceps muscles [the vastus lateralis (VL), vastus medialis (VM), and rectus femoris (RF)] during squatting exercise to exhaustion. Eighteen young resistance-trained males performed five sets of 15 back squats in a Smith machine, with two warm-up sets [at 14% and 45% of the 15-repetition maximum (15RM)] and three main sets at 100% of the 15RM. Three near-infrared spectroscopy devices were attached to the VL, VM, and RF to record the muscle oxygen saturation (SmO2) and total hemoglobin (tHb, an index of muscle blood supply). The blood lactate concentration was measured after each set with a portable analyzer. The SmO2 and tHb data were analyzed by repeated-measures two-way ANOVA (muscle × set). Lactate data were analyzed by repeated-measures one-way ANOVA. The statistical significance was set at α = 0.05. The SmO2 dropped during each set (hitting zero in many instances) and was reinstated during recovery. The three main sets caused severe deoxygenation in the VL and VM, as opposed to moderate deoxygenation in the RF. From one set to the next, the initial value and the drop in the SmO2 increased, whereas the final SmO2 value decreased. The tHb increased in the VL, did not change considerably in the VM, and decreased in the RF during each set. The blood lactate concentration increased gradually from one set to the next, reaching about 10 mmol/L. These findings show pronounced differences in the physiological and metabolic responses of three quadriceps muscles to squatting exercise, thus highlighting the importance of studying such responses at multiple sites. [ABSTRACT FROM AUTHOR]

Many studies have shown that COVID-19 caused many problems in mental health. This paper presents the results of the Cyprus sample, part of the global initiative named "The Collaborative Outcomes Study on Health and Functioning during Infection Times" (COH-FIT). Methods: The study took place from April 2019 to January 2022, using the Greek version of the online standard COH-FIT questionnaire on 917 Cypriot adults. Weighted t-tests were applied to test the differences between pre-pandemic and intra-pandemic scores using the anesrake package. Results: Participant responses indicated a significant negative impact of the pandemic on measures of mental health (−7.55; 95% CI: −9.01 to −6.07), with worsening in the scores for anxiety (12.05; 95% CI: 9.33 to 14.77), well-being (−11.06; 95% CI: −12.69 to −9.45) and depression (4.60; 95% CI: 2.06 to 7.14). Similar negative effects were observed for feelings of anger (12.92; 95% CI: 10.54 to 15.29), helplessness (9.66; 95% CI: 7.25 to 12.07), fear (22.25; 95% CI: 19.25 to 25.26), and loneliness (12.52; 95% CI: 9.94 to15.11). Increased use of social media (0.89; 95% CI: 0.71 to 1.09), internet (0.86; 95% CI: 0.67 to 1.04), and substance consumption (0.06; 95% CI: 0.00 to 0.11) were reported, along with a significant decrease in physical health (−3.45; 95% CI: −4.59 to −2.32), self-care (−7.10; 95% CI: −9.00 to −5.20), and social function (−11.27; 95% CI: −13.19 to −9.35), including support (−0.72; 95% CI: −1.09 to −0.34) and family function (−7.97; 95% CI: −9.90 to −6.05). Conclusions: The COVID-19 pandemic significantly affected the daily life and emotional well-being of Cypriots. Identifying factors that influence vulnerability and resilience is essential to prioritize mental health support and address the long-term effects of the pandemic. [ABSTRACT FROM AUTHOR]

Sand flies infect more than 1 million people annually with Leishmania parasites and other bacterial and viral pathogens. Progress in understanding sand fly adaptations to xenobiotics has been hampered by the limited availability of genomic resources. To address this gap, we sequenced, assembled, and annotated the transcriptomes of 11 phlebotomine sand fly species. Subsequently, we leveraged these genomic resources to generate novel evolutionary insights pertaining to their adaptations to xenobiotics, including those contributing to insecticide resistance. Specifically, we annotated over 2,700 sand fly detoxification genes and conducted large-scale phylogenetic comparisons to uncover the evolutionary dynamics of the five major detoxification gene families: cytochrome P450s (CYPs), glutathione-S-transferases (GSTs), UDP-glycosyltransferases (UGTs), carboxyl/cholinesterases (CCEs), and ATP-binding cassette (ABC) transporters. Using this comparative approach, we show that sand flies have evolved diverse CYP and GST gene repertoires, with notable lineage-specific expansions in gene groups evolutionarily related to known xenobiotic metabolizers. Furthermore, we show that sand flies have conserved orthologs of (i) CYP4G genes involved in cuticular hydrocarbon biosynthesis, (ii) ABCB genes involved in xenobiotic toxicity, and (iii) two primary insecticide targets, acetylcholinesterase-1 (Ace1) and voltage gated sodium channel (VGSC). The biological insights and genomic resources produced in this study provide a foundation for generating and testing hypotheses regarding the molecular mechanisms underlying sand fly adaptations to xenobiotics. [ABSTRACT FROM AUTHOR]

Abstract Culex mosquitoes particularly Culex quinquefasciatus are important arboviral and filariasis vectors, however despite this important epidemiological role, there is still a paucity of data on their bionomics. The present study was undertaken to assess the insecticide resistance status of Cx. quinquefasciatus populations from four districts of Yaoundé (Cameroon). All Culex quinquefasciatus populations except one displayed high resistance to bendiocarb and malathion with mortalities ranging from 0 to 89% while high resistance intensity against both permethrin and deltamethrin was recorded. Molecular analyses revealed high frequencies of the ACE-1 G119S mutation (ranging from 0 to 33%) and kdr L1014F allele (ranging from 55 to 74%) in all Cx. quinquefasciatus populations. Significant overexpression was detected for cytochrome P450s genes CYP6AA7 and CYP6Z10, as well as for Esterase A and Esterase B genes. The total cuticular hydrocarbon content, a proxy of cuticular resistance, was significantly increased (compared to the S-lab strain) in one population. The study confirms strong insecticide resistance mediated by different mechanisms in Cx. quinquefasciatus populations from the city of Yaoundé. The expansion of insecticide resistance in Culex populations could affect the effectiveness of current vector control measures and stress the need for the implementation of integrated vector control strategies in urban settings.