Glucagon-like peptide-1 secretion in people with versus without type 2 diabetes: a systematic review and meta-analysis of cross-sectional studies.

AIMS/HYPOTHESIS: The aim of this systematic review was to synthesise the study findings on whether GLP-1 secretion in response to a meal tolerance test is affected by the presence of type 2 diabetes (T2D). The influence of putative moderators such as age, sex, meal type, meal form, and assay type were also explored. METHODS: A literature search identified 32 relevant studies. The sample mean and SD for fasting GLP-1TOTAL and GLP-1TOTAL iAUC were extracted and used to calculate between-group standardised mean differences (SMD), which were meta-analysed using a random-effects model to derive pooled estimates of Hedges' g and 95 % prediction intervals (PI). RESULTS: Pooled across 18 studies, the overall SMD in GLP-1TOTAL iAUC between individuals with T2D (n = 270, 1047 ± 930 pmol·L-1·min) and individuals without T2D (n = 402, 1204 ± 937 pmol·L-1·min) was very small, not statistically significant and heterogenous across studies (g = -0.15, p = 0.43, PI: -1.53, 1.23). Subgroup analyses demonstrated an effect of assay type whereby Hedges' g for GLP-1 iAUC was greater in individuals with, versus those without T2D when using ELISA or Mesoscale (g = 0.67 [moderate], p = 0.009), but not when using RIA (g = -0.30 [small], p = 0.10). Pooled across 30 studies, the SMD in fasting GLP-1TOTAL between individuals with T2D (n = 580, 16.2 ± 6.9 pmol·L-1) versus individuals without T2D (n = 1363, 12.4 ± 5.7 pmol·L-1) was small and heterogenous between studies (g = 0.24, p = 0.21, PI: -1.55, 2.02). CONCLUSIONS: Differences in fasting GLP-1TOTAL and GLP-1TOTAL iAUC between individuals with, versus those without T2D were generally small and inconsistent between studies. Factors influencing study heterogeneity such as small sample sizes and poor matching of groups may help to explain the wide prediction intervals observed. Considerations to improve comparisons of GLP-1 secretion in T2D and potential mediating factors more important than T2D diagnosis per se are outlined. PROSPERO ID: CRD42020195612.

Structural Features of Microvascular Networks Trigger Blood Flow Oscillations.

We analyse mathematical models in order to understand how microstructural features of vascular networks may affect blood flow dynamics, and to identify particular characteristics that promote the onset of self-sustained oscillations. By focusing on a simple three-node motif, we predict that network "redundancy", in the form of a redundant vessel connecting two main flow-branches, together with differences in haemodynamic resistance in the branches, can promote the emergence of oscillatory dynamics. We use existing mathematical descriptions for blood rheology and haematocrit splitting at vessel branch-points to construct our flow model; we combine numerical simulations and stability analysis to study the dynamics of the three-node network and its relation to the system's multiple steady-state solutions. While, for the case of equal inlet-pressure conditions, a "trivial" equilibrium solution with no flow in the redundant vessel always exists, we find that it is not stable when other, stable, steady-state attractors exist. In turn, these "nontrivial" steady-state solutions may undergo a Hopf bifurcation into an oscillatory state. We use the branch diameter ratio, together with the inlet haematocrit rate, to construct a two-parameter stability diagram that delineates regimes in which such oscillatory dynamics exist. We show that flow oscillations in this network geometry are only possible when the branch diameters are sufficiently different to allow for a sufficiently large flow in the redundant vessel, which acts as the driving force of the oscillations. These microstructural properties, which were found to promote oscillatory dynamics, could be used to explore sources of flow instability in biological microvascular networks.

Hepatitis A Virus Infections Among Men Who Have Sex with Men - Eight U.S. States, 2017-2018.

During 1995-2011, the overall incidence of hepatitis A decreased by 95% in the United States from 12 cases per 100,000 population during 1995 to 0.4 cases per 100,000 population during 2011, and then plateaued during 2012─2015. The incidence increased by 294% during 2016-2018 compared with the incidence during 2013-2015, with most cases occurring among populations at high risk for hepatitis A infection, including persons who use illicit drugs (injection and noninjection), persons who experience homelessness, and men who have sex with men (MSM) (1-3). Previous outbreaks among persons who use illicit drugs and MSM led to recommendations issued in 1996 by the Advisory Committee on Immunization Practices (ACIP) for routine hepatitis A vaccination of persons in these populations (4). Despite these long-standing recommendations, vaccination coverage rates among MSM remain low (5). In 2017, the New York City Department of Health and Mental Hygiene contacted CDC after public health officials noted an increase in hepatitis A infections among MSM. Laboratory testing* of clinical specimens identified strains of the hepatitis A virus (HAV) that subsequently matched strains recovered from MSM in other states. During January 1, 2017-October 31, 2018, CDC received reports of 260 cases of hepatitis A among MSM from health departments in eight states, a substantial increase from the 16 cases reported from all 50 states during 2013-2015. Forty-eight percent (124 of 258) of MSM patients were hospitalized for a median of 3 days. No deaths were reported. In response to these cases, CDC supported state and local health departments with public health intervention efforts to decrease HAV transmission among MSM populations. These efforts included organizing multistate calls among health departments to share information, providing guidance on developing targeted outreach and managing supplies for vaccine campaigns, and conducting laboratory testing of clinical specimens. Targeted outreach for MSM to increase awareness about hepatitis A infection and improve access to vaccination services, such as providing convenient locations for vaccination, are needed to prevent outbreaks among MSM.

Test-retest reliability of the two-point discrimination test on the sole of the foot in people with multiple sclerosis.

BACKGROUND: Two-point discrimination (TPD) is an assessment of tactile acuity. People with multiple sclerosis (MS) can have reduced foot sole tactile acuity, which has been linked to impaired balance. OBJECTIVE: To quantify the test-retest reliability of TPD on the sole of the foot in people with MS. APPROACH: 41 participants (32 females), with mean (SD) age of 60 (9) years, and Expanded Disability Status Scale of <7.5, had their TPD measured at the head of the first metatarsal and the heel on two occasions, 2-14 d apart. Mean systematic change, within-subjects SD, limits of agreement (LOA), coefficient of variation and the intraclass correlation coefficient (ICC) were quantified as point estimates (95% CI). MAIN RESULTS: Systematic learning effects were evident. The within-subjects SD at the metatarsal and the heel was 6.7 mm (5.5-8.6) and 8.3 mm (6.7-10.8), and the LOAs were 18.6 mm (15.2-24.) and 23.7 mm (18.7-30.1), respectively. ICCs for metatarsal and heel was 0.87 (0.76-0.93) and 0.90 (0.80-0.95), respectively, but these were likely inflated by sample heterogeneity. SIGNIFICANCE: In people with MS, TPD on the sole of the foot has an adequate test-retest reliability for research purposes, but there is substantial measurement variability for individual patients.

Automated quality control for a molecular surveillance system.

BACKGROUND: Molecular surveillance and outbreak investigation are important for elimination of hepatitis C virus (HCV) infection in the United States. A web-based system, Global Hepatitis Outbreak and Surveillance Technology (GHOST), has been developed using Illumina MiSeq-based amplicon sequence data derived from the HCV E1/E2-junction genomic region to enable public health institutions to conduct cost-effective and accurate molecular surveillance, outbreak detection and strain characterization. However, as there are many factors that could impact input data quality to which the GHOST system is not completely immune, accuracy of epidemiological inferences generated by GHOST may be affected. Here, we analyze the data submitted to the GHOST system during its pilot phase to assess the nature of the data and to identify common quality concerns that can be detected and corrected automatically. RESULTS: The GHOST quality control filters were individually examined, and quality failure rates were measured for all samples, including negative controls. New filters were developed and introduced to detect primer dimers, loss of specimen-specific product, or short products. The genotyping tool was adjusted to improve the accuracy of subtype calls. The identification of "chordless" cycles in a transmission network from data generated with known laboratory-based quality concerns allowed for further improvement of transmission detection by GHOST in surveillance settings. Parameters derived to detect actionable common quality control anomalies were incorporated into the automatic quality control module that rejects data depending on the magnitude of a quality problem, and warns and guides users in performing correctional actions. The guiding responses generated by the system are tailored to the GHOST laboratory protocol. CONCLUSIONS: Several new quality control problems were identified in MiSeq data submitted to GHOST and used to improve protection of the system from erroneous data and users from erroneous inferences. The GHOST system was upgraded to include identification of causes of erroneous data and recommendation of corrective actions to laboratory users.

Weight loss interventions for adults with overweight/obesity and chronic musculoskeletal pain: a mixed methods systematic review.

Worldwide prevalence of adult overweight and obesity is a growing public health issue. Adults with overweight/obesity often have chronic musculoskeletal pain. Using a mixed-methods review, we aimed to quantify the effectiveness and explore the appropriateness of weight loss interventions for this population. Electronic databases were searched for studies published between 01/01/90 and 01/07/16. The review included 14 randomized controlled trials that reported weight and pain outcomes and three qualitative studies that explored perceptions of adults with co-existing overweight/obesity and chronic musculoskeletal pain. The random-effects pooled mean weight loss was 4.9 kg (95%CI:2.9,6.8) greater for intervention vs control. The pooled mean reduction in pain was 7.3/100 units (95%CI:4.1,10.5) greater for intervention vs control. Study heterogeneity was substantial for weight loss (I2  = 95%, tau = ±3.5 kg) and pain change (I2  = 67%, tau = ±4.1%). Meta-regression slopes for the predictors of study quality, mean age and baseline mean weight on mean study weight reduction were shallow and not statistically significant (P > 0.05). The meta-regression slope between mean pain reduction and mean weight lost was shallow, and not statistically significant, -0.09 kg per unit pain score change (95%CI:-0.21,0.40, P = 0.54). Meta-synthesis of qualitative findings resulted in two synthesized findings; the importance of healthcare professionals understanding the effects of pain on ability to control weight and developing management/education programmes that address comorbidity.

Inter-individual differences in weight change following exercise interventions: a systematic review and meta-analysis of randomized controlled trials.

Previous reports of substantial inter-individual differences in weight change following an exercise intervention are often based solely on the observed responses in the intervention group. Therefore, we aimed to quantify the magnitude of inter-individual differences in exercise-mediated weight change. We synthesized randomized controlled trials (RCTs) of structured, supervised exercise interventions. Fourteen electronic databases were searched for relevant studies published up to March 2017. Search terms focused on structured training, RCTs and body weight. We then sifted these results for those RCTs (n = 12, 1500 participants) that included relevant comparator group data. Standard deviations (SDs) of weight change were extracted, thereby allowing the SD for true inter-individual differences in weight loss to be calculated for each study. Using a random effects meta-analysis, the pooled SD (95% CI) for true individual responses was 0.8 (-0.9 to 1.4) kg. The 95% prediction interval (based on 2SDs) for true inter-individual responses was -2.8 to 3.6 kg. The probability (% chance) that the true individual response variability would be clinically meaningful (>2.5 kg) in a future study in similar settings was 23% ('unlikely'). Therefore, we conclude that evidence is limited for the notion that there are clinically important individual differences in exercise-mediated weight change.

Hydraulic fracturing volume is associated with induced earthquake productivity in the Duvernay play.

A sharp increase in the frequency of earthquakes near Fox Creek, Alberta, began in December 2013 in response to hydraulic fracturing. Using a hydraulic fracturing database, we explore relationships between injection parameters and seismicity response. We show that induced earthquakes are associated with completions that used larger injection volumes (104 to 105 cubic meters) and that seismic productivity scales linearly with injection volume. Injection pressure and rate have an insignificant association with seismic response. Further findings suggest that geological factors play a prominent role in seismic productivity, as evidenced by spatial correlations. Together, volume and geological factors account for ~96% of the variability in the induced earthquake rate near Fox Creek. This result is quantified by a seismogenic index-modified frequency-magnitude distribution, providing a framework to forecast induced seismicity.

GHOST: global hepatitis outbreak and surveillance technology.

BACKGROUND: Hepatitis C is a major public health problem in the United States and worldwide. Outbreaks of hepatitis C virus (HCV) infections associated with unsafe injection practices, drug diversion, and other exposures to blood are difficult to detect and investigate. Effective HCV outbreak investigation requires comprehensive surveillance and robust case investigation. We previously developed and validated a methodology for the rapid and cost-effective identification of HCV transmission clusters. Global Hepatitis Outbreak and Surveillance Technology (GHOST) is a cloud-based system enabling users, regardless of computational expertise, to analyze and visualize transmission clusters in an independent, accurate and reproducible way. RESULTS: We present and explore performance of several GHOST implemented algorithms using next-generation sequencing data experimentally obtained from hypervariable region 1 of genetically related and unrelated HCV strains. GHOST processes data from an entire MiSeq run in approximately 3 h. A panel of seven specimens was used for preparation of six repeats of MiSeq libraries. Testing sequence data from these libraries by GHOST showed a consistent transmission linkage detection, testifying to high reproducibility of the system. Lack of linkage among genetically unrelated HCV strains and constant detection of genetic linkage between HCV strains from known transmission pairs and from follow-up specimens at different levels of MiSeq-read sampling indicate high specificity and sensitivity of GHOST in accurate detection of HCV transmission. CONCLUSIONS: GHOST enables automatic extraction of timely and relevant public health information suitable for guiding effective intervention measures. It is designed as a virtual diagnostic system intended for use in molecular surveillance and outbreak investigations rather than in research. The system produces accurate and reproducible information on HCV transmission clusters for all users, irrespective of their level of bioinformatics expertise. Improvement in molecular detection capacity will contribute to increasing the rate of transmission detection, thus providing opportunity for rapid, accurate and effective response to outbreaks of hepatitis C. Although GHOST was originally developed for hepatitis C surveillance, its modular structure is readily applicable to other infectious diseases. Worldwide availability of GHOST for the detection of HCV transmissions will foster deeper involvement of public health researchers and practitioners in hepatitis C outbreak investigation.

The intra- and inter-observer reliability of a novel protocol for two-point discrimination in individuals with chronic low back pain.

Two-point discrimination is measured as an indicator of cortical reorganisation in musculoskeletal medicine. Nevertheless, data are lacking for the reliability of this measure in patients with non-specific chronic low back pain (NSCLBP). We aimed to quantify the intra- and inter-observer reliability of a novel protocol for measuring two-point discrimination in these patients. 35 participants (12 males, 23 females, mean age 52, SD 15 years) with NSCLBP were recruited. Three clinicians made 14 consecutive measurements of two-point discrimination with callipers. One of these clinicians repeated the assessment protocol within 7 d. During each measurement, the calliper width was widened in 5 mm increments until participants could consistently identify two points. Intra- and inter-observer agreement was quantified using mean difference, within-subject SD and limits of agreement (LOA). After using the first measurement for familiarisation, the mean of measurements 2-5 within an assessment resulted in the optimum compromise between clinic time constraints and acceptable intra-observer reliability; the within-subjects SD being 7.5 mm (LOA: 20.8 mm). Inter-observer reliability was generally poorer; requiring the mean of measurements 2-9 within an assessment for a similar within-subjects SD of 8.6 mm (LOA: 23.7 mm). It was estimated that these within-subjects SDs were small enough for a clinically-important change to be detected with a feasible sample size in future studies. The intra-observer reliability of our assessment protocol is acceptable for detecting a clinically relevant difference in two-point discrimination for future research purposes. Nevertheless, individual patient measurement variability is relatively high, especially between different clinicians.

Predicting future weight status from measurements made in early childhood: a novel longitudinal approach applied to Millennium Cohort Study data.

BACKGROUND/OBJECTIVE: There are reports that childhood obesity tracks into later life. Nevertheless, some tracking statistics such as correlations do not quantify individual agreement, whereas others such as diagnostic test statistics can be difficult to translate into practice. We aimed to employ a novel analytic approach, based on ordinal logistic regression, to predict weight status of 11-year-old children from measurements at age 5 years. SUBJECTS/METHODS: The UK 1990 growth references were used to generate clinical weight status categories of 12 076 children enrolled in the Millennium Cohort Study. Using ordinal regression, we derived the predicted probability (percent chances) of 11-year-old children becoming underweight, normal weight, overweight, obese and severely obese from their weight status category at age 5 years. RESULTS: The chances of becoming obese (including severely obese) at age 11 years were 5.7% (95% confidence interval: 5.2 to 6.2%) for a normal-weight 5-year-old child and 32.3% (29.8 to 34.8%) for an overweight 5-year-old child. An obese 5-year-old child had a 68.1% (63.8 to 72.5%) chance of remaining obese at 11 years. Severely obese 5-year-old children had a 50.3% (43.1 to 57.4%) chance of remaining severely obese. There were no substantial differences between sexes. Nondeprived obese 5-year-old boys had a lower probability of remaining obese than deprived obese boys: -21.8% (-40.4 to -3.2%). This association was not observed in obese 5-year-old girls, in whom the nondeprived group had a probability of remaining obese 7% higher (-15.2 to 29.2%). The sex difference in this interaction of deprivation and baseline weight status was therefore -28.8% (-59.3 to 1.6%). CONCLUSIONS: We have demonstrated that ordinal logistic regression can be an informative approach to predict the chances of a child changing to, or from, an unhealthy weight status. This approach is easy to interpret and could be applied to any longitudinal data set with an ordinal outcome.

Open-label randomized non-inferiority trial of a fixed-dose combination of glimepiride and atorvastatin for the treatment of people whose Type 2 diabetes is uncontrolled on metformin.

AIMS: To evaluate, in a randomized, open-label study, the non-inferiority of a bioequivalent fixed-dose combination of glimepiride and atorvastatin vs. separately co-administered tablets in people with Type 2 diabetes mellitus. METHODS: Participants with HbA1c ≥ 53 to < 80 mmol/mol (≥ 7.0 to < 9.5%), average fasting blood glucose > 7.0 mmol/l, who were on metformin for ≥ 3 months, were randomized to combination (n = 215) or co-administered glimepiride and atorvastatin (n = 212) once daily for 20 weeks. Up-titration of glimepiride (1-4 mg) and atorvastatin (10-20 mg) were based on average fasting blood glucose and LDL cholesterol, respectively. Co-primary endpoints were change from baseline to week 20 in HbA1c and LDL cholesterol. RESULTS: Non-inferiority was demonstrated for both co-primary endpoints: the upper limits of 95% CIs for differences (combination-reference) were less than the prespecified margins of 3.3 mmol/mol (0.3%) for change from baseline in HbA1c [difference 0.1 mmol/mol (95% CI -1.6, 1.9); 0.01% (95% CI -0.15, 0.17)] and 6% for percentage change from baseline in LDL cholesterol [difference 0.87% (95% CI -2.47, 4.21)]. Similar proportions of participants on combination and reference had treatment-emergent adverse events (64 vs. 61%). More participants on combination had hypoglycaemia (21 vs. 13%); most events were considered by the treating physician to be unrelated to study drug. CONCLUSIONS: The combination was non-inferior to separately co-administered tablets and the safety profile was consistent with the known profiles of glimepiride and atorvastatin. The observed increase in hypoglycaemia on the combination cannot be explained, but may be attributable to non-systematic collectiof glucose readings and may have been influenced by reporting bias in this open-label trial.

Cross-sectional Association between Walking Pace and Sleep-disordered Breathing.

Sleep-disordered breathing is an important comorbidity for several diseases, including stroke. Initial screening tools comprise simple yes/no questions about known risk factors for sleep-disordered breathing, e.g., obesity, sex. But walking speed has not been investigated in this context. We examined the cross-sectional association between walking pace and sleep-disordered breathing in the population-level Multi-Ethnic Study of Atherosclerosis. A sample of 2912 men and 3213 women (46-87 years) reported perceived walking pace outside their homes. A walking pace<0.89 m/s was deemed "slow", with ≥ 0.89 m/s considered "average/brisk" according to validated thresholds. Sample prevalences were: sleep apnoea (3.5%), self-reported apnoeas (8.4%), loud snoring (20.5%), daytime tiredness (22.2%) and slow-walking pace (26.9%). The 95% CI risk differences (multivariable-adjusted) for slow vs. faster walking pace were; sleep apnoea (0.4-2.5%), self-reported apnoeas (0.1-3.8%), loud snoring (1.2-8.3%), and daytime tiredness (3.0-7.8%). Risk differences were similar between sexes. The multivariable-adjusted risk ratio indicated that slower walkers had 1.5 (95% CI: 1.0 to 2.1) times the risk of sleep apnoea vs. faster walkers. In conclusion, a slower walking speed was associated with a greater prevalence of sleep-disordered breathing, independently from other common screening factors. Therefore, a simple walking speed question may help consolidate screening for this disorder.

The effects of evening bright light exposure on subsequent morning exercise performance.

We investigated the effects of evening bright light on the circadian timing of core temperature and morning exercise performance under conditions of high thermal stress. At 20:00 h, 8 males were exposed to a standardised light protocol and thereafter to either polychromatic bright light (2,500 lux at 50 cm, BL) or no light (0 lux, NL) for 30 min. The following morning, intermittent cycling exercise was undertaken followed by a 10 km time-trial in an environmental chamber set to 35°C and 60% relative humidity. Core body temperature was measured throughout. Data were analysed using a within-subjects model and presented as mean±SD. Time of the sleep-trough in core temperature occurred ~1.75 h later following BL (P=0.07). Prior to time-trial, core temperature was 0.27±0.42°C lower in BL (95%CI: -0.02 to 0.57, P=0.07). The time-trial was completed 1.43±0.63 min (0.98-1.87) faster in BL (P=0.001). Post time-trial, intestinal temperature was 38.21±0.56°C (37.84-38.57) in BL compared to 38.64±0.42°C (38.34-38.93) in NL (P=0.10). These data provide the first evidence that a 30-min exposure to bright light prior to sleep can influence exercise performance under hot conditions during the subsequent early morning.