The TCR's sensitivity to self peptide-MHC dictates the ability of naive CD8(+) T cells to respond to foreign antigens.

The strength with which complexes of self peptide and major histocompatibility complex (MHC) proteins are recognized by the T cell antigen receptor (TCR) dictates the homeostasis of naive CD8(+) T cells, but its effect on reactivity to foreign antigens is controversial. As expression of the negative regulator CD5 correlates with self-recognition, we studied CD5(lo) and CD5(hi) naive CD8(+) T cells. Gene-expression characteristics suggested CD5(hi) cells were better poised for reactivity and differentiation than were CD5(lo) cells, and we found that the CD5(hi) pool also exhibited more efficient clonal recruitment and expansion, as well as enhanced reactivity to inflammatory cues, during the recognition of foreign antigen. However, the recognition of complexes of foreign peptide and MHC was similar for both subsets. Thus, CD8(+) T cells with higher self-reactivity dominate the immune response to foreign antigens, with implications for T cell repertoire diversity and autoimmunity.

Transcriptional insights into the CD8(+) T cell response to infection and memory T cell formation.

After infection, many factors coordinate the population expansion and differentiation of CD8+ effector and memory T cells. Using data of unparalleled breadth from the Immunological Genome Project, we analyzed the CD8+ T cell transcriptome throughout infection to establish gene-expression signatures and identify putative transcriptional regulators. Notably, we found that the expression of key gene signatures can be used to predict the memory-precursor potential of CD8+ effector cells. Long-lived memory CD8+ cells ultimately expressed a small subset of genes shared by natural killer T and γδ T cells. Although distinct inflammatory milieu and T cell precursor frequencies influenced the differentiation of CD8+ effector and memory populations, core transcriptional signatures were regulated similarly, whether polyclonal or transgenic, and whether responding to bacterial or viral model pathogens. Our results provide insights into the transcriptional regulation that influence memory formation and CD8+ T cell immunity.

Molecular definition of the identity and activation of natural killer cells.

Using whole-genome microarray data sets of the Immunological Genome Project, we demonstrate a closer transcriptional relationship between NK cells and T cells than between any other leukocytes, distinguished by their shared expression of genes encoding molecules with similar signaling functions. Whereas resting NK cells are known to share expression of a few genes with cytotoxic CD8(+) T cells, our transcriptome-wide analysis demonstrates that the commonalities extend to hundreds of genes, many encoding molecules with unknown functions. Resting NK cells demonstrate a 'preprimed' state compared with naive T cells, which allows NK cells to respond more rapidly to viral infection. Collectively, our data provide a global context for known and previously unknown molecular aspects of NK cell identity and function by delineating the genome-wide repertoire of gene expression of NK cells in various states.

The transcriptional regulators Id2 and Id3 control the formation of distinct memory CD8+ T cell subsets.

During infection, naive CD8(+) T cells differentiate into effector cells, which are armed to eliminate pathogens, and memory cells, which are poised to protect against reinfection. The transcriptional program that regulates terminal differentiation into short-lived effector-memory versus long-lived memory cells is not clearly defined. Through the use of mice expressing reporters for the DNA-binding inhibitors Id2 and Id3, we identified Id3(hi) precursors of long-lived memory cells before the peak of T cell population expansion or upregulation of cell-surface receptors that indicate memory potential. Deficiency in Id2 or Id3 resulted in loss of distinct CD8(+) effector and memory populations, which demonstrated unique roles for these inhibitors of E-protein transcription factors. Furthermore, cytokines altered the expression of Id2 and Id3 differently, which provides insight into how external cues influence gene expression.

Impact of insulin initiation on glycaemic variability and glucose profiles in a primary healthcare Type 2 diabetes cohort: analysis of continuous glucose monitoring data from the INITIATION study.

AIM: To use continuous glucose monitoring to examine the effects of insulin initiation with glargine, with or without glulisine, on glycaemic variability and glycaemia in a cohort of people with Type 2 diabetes receiving maximum oral hypoglycaemic agents in primary healthcare. METHODS: We conducted a post hoc analysis of continuous glucose monitoring data from 89 participants at baseline and at 24 weeks after insulin commencement. Indicators of glycaemic variability (standard deviation, J-index and mean amplitude of glycaemic excursion) and glycaemia (HbA1c , mean glucose, area under the glucose-time curve) were assessed. Multi-level regression analysis was used to identify the predictors of change. RESULTS: Complete glycaemic variability data were available for 78 participants. Of these participants, 41% were women, their mean (sd) age was 59.2 (10.4) years, the median (interquartile range) diabetes duration was 10.4 (6.5, 13.3) years and the median (interquartile range) baseline HbA1c was 82.5 (71.6, 96.7) mmol/mol [9.7 (8.7, 11.0)%]. At baseline, BMI correlated negatively with standard deviation (r = -0.30) and mean amplitude of glycaemic excursion (r = -0.26), but not with J-index; HbA1c correlated with J-index (r = 0.61) but not with mean amplitude of glycaemic excursion and standard deviation. After insulin initiation the mean (sd) glucose level decreased [from 12.0 (3.0) to 8.5 (1.6) mmol/l; P < 0.001], as did the median (interquartile range) J-index [from 66.9 (47.7, 95.1) to 36.9 (27.6, 49.8) mmol/l; P < 0.001]. Baseline HbA1c correlated with a greater J-index reduction (r = -0.45; P < 0.001). The mean amplitude of glycaemic excursion and standard deviation values were unchanged. The baseline temporal profile, showing elevated postprandial morning glucose levels, was unchanged after insulin initiation, despite an overall reduction in glycaemia. CONCLUSION: Insulin initiation reduced hyperglycaemia but did not alter glycaemic variability in adults with Type 2 diabetes receiving maximum oral hypoglycaemic agents. The most significant postprandial excursions were seen in the morning, which identifies prebreakfast as the most effective target for short-acting insulin therapy.

The GALAD scoring algorithm based on AFP, AFP-L3, and DCP significantly improves detection of BCLC early stage hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of death in cirrhotic patients worldwide. The detection rate for early stage HCC remains low despite screening programs. Thus, the majority of HCC cases are detected at advanced tumor stages with limited treatment options. To facilitate earlier diagnosis, this study aims to validate the added benefit of the combination of AFP, the novel biomarkers AFP-L3, DCP, and an associated novel diagnostic algorithm called GALAD. Material and methods: Between 2007 and 2008 and from 2010 to 2012, 285 patients newly diagnosed with HCC and 402 control patients suffering from chronic liver disease were enrolled. AFP, AFP-L3, and DCP were measured using the µTASWako i30 automated immunoanalyzer. The diagnostic performance of biomarkers was measured as single parameters and in a logistic regression model. Furthermore, a diagnostic algorithm (GALAD) based on gender, age, and the biomarkers mentioned above was validated. Results: AFP, AFP-L3, and DCP showed comparable sensitivities and specifities for HCC detection. The combination of all biomarkers had the highest sensitivity with decreased specificity. In contrast, utilization of the biomarker-based GALAD score resulted in a superior specificity of 93.3 % and sensitivity of 85.6 %. In the scenario of BCLC 0/A stage HCC, the GALAD algorithm provided the highest overall AUROC with 0.9242, which was superior to any other marker combination. Conclusions: We could demonstrate in our cohort the superior detection of early stage HCC with the combined use of the respective biomarkers and in particular GALAD even in AFP-negative tumors.

Id2 influences differentiation of killer cell lectin-like receptor G1(hi) short-lived CD8+ effector T cells.

CD8(+) T cells play a crucial role in the clearance of intracellular pathogens through the generation of cytotoxic effector cells that eliminate infected cells and long-lived memory cells that provide enhanced protection against reinfection. We have previously shown that the inhibitor of E protein transcription factors, Id2, is necessary for accumulation of effector and memory CD8(+) T cells during infection. In this study, we show that CD8(+) T cells lacking Id2 did not generate a robust terminally differentiated killer cell lectin-like receptor G1 (KLRG1)(hi) effector population, but displayed a cell-surface phenotype and cytokine profile consistent with memory precursors, raising the question as to whether loss of Id2 impairs the differentiation and/or survival of effector memory cells. We found that deletion of Bim rescued Id2-deficient CD8(+) cell survival during infection. However, the dramatic reduction in KLRG1(hi) cells caused by loss of Id2 remained in the absence of Bim, such that Id2/Bim double-deficient cells form an exclusively KLRG1(lo)CD127(hi) memory precursor population. Thus, we describe a role for Id2 in both the survival and differentiation of normal CD8(+) effector and memory populations.

Real-time x-ray abnormality alerts for emergency departments using a radiographer comment model - a multisite pilot study.

INTRODUCTION: The timely communication of clinically significant image appearances to Emergency Department (ED) referrers is necessary for optimum patient care. Australian reliance on verbal communication only is time-limited, open to misinterpretation and lacks transparency. A combined radiographer alert and comment model was designed to reliably communicate image abnormalities to ED referrers in real-time. METHODS: A multidisciplinary steering group designed the model for all ED general imaging. Protocols were developed to document radiographer comments (critical, urgent and clinically significant) in patients' medical records. Critical findings were communicated directly to ED. Five NSW hospitals varying in size, complexity and population demographics piloted the model between three to twelve months during 2021-2022. Site auditors compared comments with the radiology report and designated each as True Positive (TP), False Positive (FP), indeterminate and clinically significant. Indeterminate cases were analysed by an external radiologist. Inter-observer consensus was obtained for all classifications via two independent auditors. The Positive Predictive Value (PPV), or precision of the comment, was calculated for each site. RESULTS: Radiographers (n = 69) provided comments for 1102 cases. The pooled average PPV for TP was 0.96; (0.947-0.971; 95% CI). The weighted mean error (FP comments) was 3.9%; (2.9% - 5.3%.; 95% CI). CONCLUSION: The Radiographer Comment model provided consistent levels of commenting precision and reproducibility across a range of sites with a pooled average PPV (0.96). The False Positive rate or weighted mean error (FP) of 3.9% (2.9% - 5.3%.; 95% CI) was low. IMPLICATIONS FOR FUTURE PRACTICE: A strategic, interprofessional approach in the implementation of an image alert combined with a Radiographer Comment can be adapted across a variety of hospital settings for ED and other departments.

Assessment of Treatment Outcomes in the Management of Club foot using the Ponseti Technique: A cross-sectional study.

BACKGROUND: The Ponseti technique remains the preferred method for club foot treatment. Although measures of treatment outcomes have been well documented, there is no consensus on the determinants of those outcomes. This study aims to assess treatment outcomes and the factors which can influence treatment outcomes. MATERIALS AND METHODS: This is a cross-sectional study. A total of 472 children representing 748 feet in total were recruited. Patient characteristics such as age at presentation, gender, tenotomy, walking with or without deformity, parental educational status and occupation were documented. Outcomes of care were assessed using indictors such as parents' satisfaction with the outcome of treatment and the patients' ambulation without deformity. The relationships between the determinant factors and these outcomes were explored using multivariable binary logistic regression. RESULTS: Most of the children (69.1%) were aged below 2 years. Brace compliance was very high (89.9%). The pre-treatment average Pirani scores were 3.9 ± 1.8 and 4.3 ± 1.8 for the right and left feet, respectively. Majority (88.3%) of the children achieved ambulation without deformity, whereas most (87%) of the parents were satisfied with the treatment outcomes. In total, parental satisfaction with child's treatment outcomes was lower in parents who were not formally educated odds ratio (OR) = 0.19 (95% confidence interval [CI] 0.08-0.43), but parental satisfaction was lower if the child had higher Pirani score OR = 0.77 (95% CI 0.62-0.96). Children who had more casts applied to the affected foot were more likely to walk without deformity OR = 1.24 (95% CI 1.01-1.52). CONCLUSIONS: This study revealed that treatment outcomes in children with club foot can be determined by some sociodemographic and treatment-related factors.

A network meta-analysis to compare glycaemic control in patients with type 2 diabetes treated with exenatide once weekly or liraglutide once daily in comparison with insulin glargine, exenatide twice daily or placebo.

AIMS: The glucagon-like peptide-1 receptor agonists (GLP-1 RAs) exenatide once weekly (ExQW) and liraglutide once daily (QD) are indicated to improve glycaemic control in patients with type 2 diabetes. Although glycaemic control with ExQW versus liraglutide QD 1.8 mg has been directly compared, no studies have compared ExQW with liraglutide QD 1.2 mg or determined the probable relative efficacies of various injectable therapies for glycaemic control; therefore, a network meta-analysis was performed to address these questions. METHODS: A systematic review identified randomized controlled trials of ≥24 weeks that compared ExQW, liraglutide QD (1.2 mg, 1.8 mg), insulin glargine, exenatide twice daily (ExBID), or placebo. Twenty-two studies evaluating 11 049 patients were included in the network meta-analysis. Mean differences in HbA1c relative to placebo or each other and probability rankings were estimated. RESULTS: Estimated mean differences in HbA1c versus placebo were -1.15% (95% CrI: -1.31 to -1.00) for ExQW, -1.01% (95% CrI: -1.18 to -0.85) for liraglutide 1.2 mg, and -1.18% (95% CrI: -1.32 to -1.04) for liraglutide 1.8 mg. HbA1c differences for ExQW versus liraglutide 1.2 mg and 1.8 mg were -0.14% (95% CrI: -0.34 to 0.06) and 0.03% (95% CrI: -0.14 to 0.18), respectively. The estimated mean difference in HbA1c between liraglutide 1.2 mg and 1.8 mg was 0.17% (95% CrI: 0.02-0.30). Results were consistent when adjusted for background antihyperglycaemic medications and diabetes duration. CONCLUSIONS: This network meta-analysis did not identify meaningful differences in HbA1c lowering between ExQW and both liraglutide doses, suggesting that these GLP-1 RAs have similar glycaemic effects.

Effects of HbA1c and weight reduction on blood pressure in patients with type 2 diabetes mellitus treated with exenatide*.

AIM: Treatment of patients with type 2 diabetes with glucagon-like peptide-1 (GLP-1) receptor agonist exenatide has showed improvements in glycaemic control coupled with weight loss and lowered blood pressure (BP). We examined the synergy between improved glycaemia and weight loss on BP reduction in patients treated with either exenatide twice daily (BID) or once weekly (QW). METHODS: Combining data from three controlled trials, 686 (53% male) patients [baseline mean ± SD: age 55 ± 10 years, weight 95 ± 20 kg, systolic blood pressure (SBP)/diastolic blood pressure (DBP) 130/79 ± 15/9 mmHg, HbA(1c) 8.3 ± 1.1%] treated with exenatide QW (n = 541) or BID (n = 145) were observed over 26 weeks. Using weighted means (WMs) of the longitudinal measures of HbA(1c) and weight, patients were subdivided into four groups at each visit by glycaemic and weight responses; patients who failed to reduce both HbA(1c) and weight below WMs became the reference group (R). The other three groups corresponded to patients with HbA(1c) reduction (A), weight reduction (W) and both HbA(1c) and weight reduction (AW). RESULTS: Compared with R, patients in AW, A and W groups had a significantly higher likelihood of improving SBP <130 mmHg by 88, 30 and 61%, respectively. Compared with R, patients in AW, A and W had 63, 13 and 45% higher likelihood of improving DBP <80 mmHg. CONCLUSION: Although the mechanism of BP-lowering effect of exenatide is not established, it appears that the short-term dynamics of BP is related to concomitant effects on glycaemia and body weight. These data offer a preliminary insight into the possible cardiometabolic effects of GLP-1 receptor agonism.

The effects of exenatide bid on metabolic control, medication use and hospitalization in patients with type 2 diabetes mellitus in clinical practice: a systematic review.

The objective of this systematic review was to assess the published literature on the effectiveness of exenatide twice daily (exenatide) in clinical practice, specifically its effects on haemoglobin A1c (A1C), fasting glucose (FG), weight, systolic blood pressure (SBP), medication use, hospitalization and cardiovascular disease (CVD) outcomes. A systematic literature search using the MEDLINE database of English language literature published between January 2005 and May 2011 was performed. The review included retrospective or prospective observational studies that included 100 or more patients per treatment group. A total of 15 studies meeting the inclusion criteria were identified. The studies revealed significant reductions of -0.4 to -0.9% in A1C, -10 mg/dl in FG, -2 to -11 kg in body weight and -2 to -11 mmHg in SBP. Statistically significant reductions in the use or dosage of either oral glucose-lowering medications or insulin after initiating exenatide treatment were found in every observational study that assessed medication changes, including reductions in dosage of up to 75% in sulphonylureas dosages, 22% in metformin, 66% in thiazolidinediones (TZD) or TZD combination therapy and 75% in prandial insulin. Exenatide-treated patients experienced significantly lower rates of all-cause and CVD-related hospitalization and CVD events than patients treated with other therapies overall. In this review of observational studies, exenatide initiation was associated with significant reductions in clinically relevant outcomes. Improvements in A1C, FG, weight and SBP in the observational studies in this review were consistent with improvements observed in controlled clinical trials.

Ageing and Mental Health in Canada: Perspectives from Law, Policy, and Longitudinal Research.

Canada is a relatively young, geographically-diverse country, with a larger proportion of the population aged over 65 than under 15. Increasing alongside the number of ageing Canadians is the number of older adults that live with mental health challenges. Across the life course, one in five Canadians will experience a mental health disorder with many more living with subclinical symptoms. For these individuals, their lived experience may be directly impacted by the contemporary laws and policies governing mental illness. Examining and reviewing the historical context of mental health and older adults, we provide insights into the evolving landscape of Canadian mental health law and policy, paternalistic roots in the infancy of the country, into modern foci on equity and diversity. Progressing in parallel to changes in mental health policy has been the advancement of mental health research, particularly through longitudinal studies of ageing. Although acting through different mechanisms, the evolution of Canadian mental health law, policy, and research has had, and continues to have, considerable impacts on the substantial proportion of Canadians living with mental health challenges.

The relative associations of the paediatric trauma score and revised trauma score with the severity of childhood trauma.

BACKGROUND: Children are prone to unintentional injuries and various scoring systems have been used to triage these injuries. The aim of this study is to determine the associations between paediatric trauma score (PTS), revised trauma score (RTS) and the length of hospital stay as an indicator of injury severity. METHODS: This is a descriptive cross-sectional study conducted in the University of Calabar Teaching Hospital, Calabar and National Orthopaedic Hospital, Enugu from February 2018 to March 2020. A structured questionnaire was used to collect personal, injury-specific and treatment-specific data. The relationship between PTS, RTS and the length of hospital stay was evaluated using the one-way analysis of variance (ANOVA). RESULTS: A total of 212 patients were included in the study. Majorities (129, 60%) of the injured children were male and most of the injuries were due to falls from height (54%). The mean PTS was 5.36 ± 1.9, while the mean RTS was 7.10 ± 0.9. The Pearson's product momentum correlation coefficient shows that there was weak but statistically significant correlation between the PTS and the RTS (r = 0.22, P = 0.02). The one-way ANOVA showed a statistically significant decrease in the RTS with increasing duration of hospital admission (F-statistic = 6.654, df = 3, P = 0.000). The PTS showed a less obvious decrease with no trend. CONCLUSION: In this study, the RTS showed an inverse relationship with the length of hospital stay.

Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study.

AIMS/HYPOTHESIS: Fenofibrate caused an acute, sustained plasma creatinine increase in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies. We assessed fenofibrate's renal effects overall and in a FIELD washout sub-study. METHODS: Type 2 diabetic patients (n = 9,795) aged 50 to 75 years were randomly assigned to fenofibrate (n = 4,895) or placebo (n = 4,900) for 5 years, after 6 weeks fenofibrate run-in. Albuminuria (urinary albumin/creatinine ratio measured at baseline, year 2 and close-out) and estimated GFR, measured four to six monthly according to the Modification of Diet in Renal Disease Study, were pre-specified endpoints. Plasma creatinine was re-measured 8 weeks after treatment cessation at close-out (washout sub-study, n = 661). Analysis was by intention-to-treat. RESULTS: During fenofibrate run-in, plasma creatinine increased by 10.0 µmol/l (p < 0.001), but quickly reversed on placebo assignment. It remained higher on fenofibrate than on placebo, but the chronic rise was slower (1.62 vs 1.89 µmol/l annually, p = 0.01), with less estimated GFR loss (1.19 vs 2.03 ml min(-1) 1.73 m(-2) annually, p < 0.001). After washout, estimated GFR had fallen less from baseline on fenofibrate (1.9 ml min(-1) 1.73 m(-2), p = 0.065) than on placebo (6.9 ml min(-1) 1.73 m(-2), p < 0.001), sparing 5.0 ml min(-1) 1.73 m(-2) (95% CI 2.3-7.7, p < 0.001). Greater preservation of estimated GFR with fenofibrate was observed with baseline hypertriacylglycerolaemia (n = 169 vs 491 without) alone, or combined with low HDL-cholesterol (n = 140 vs 520 without) and reductions of ≥ 0.48 mmol/l in triacylglycerol over the active run-in period (pre-randomisation) (n = 356 vs 303 without). Fenofibrate reduced urine albumin concentrations and hence albumin/creatinine ratio by 24% vs 11% (p < 0.001; mean difference 14% [95% CI 9-18]; p < 0.001), with 14% less progression and 18% more albuminuria regression (p < 0.001) than in participants on placebo. End-stage renal event frequency was similar (n = 21 vs 26, p = 0.48). CONCLUSIONS/INTERPRETATION: Fenofibrate reduced albuminuria and slowed estimated GFR loss over 5 years, despite initially and reversibly increasing plasma creatinine. Fenofibrate may delay albuminuria and GFR impairment in type 2 diabetes patients. Confirmatory studies are merited. TRIAL REGISTRATION: ISRCTN64783481.

Patient perspectives on once-weekly medications for diabetes.

AIM: to examine patient beliefs, preferences and concerns regarding a once-weekly (QW) glucose-lowering medication option. METHODS: a total of 1516 adults with type 2 diabetes drawn from a national Chronic Illness Panel completed an anonymous online survey that assessed perceived attributes of QW therapy, willingness to take an injectable QW medication and patient characteristics that might influence their willingness, such as current perceived glycaemic control and diabetes quality of life (DQOL). RESULTS: positive attitudes regarding QW medication were common, with current injection users significantly more likely than non-injection users to view beneficial aspects: greater convenience, better medication adherence, improved quality of life (QOL) and a less overwhelming sense of treatment (in all cases, p < 0.001). In all, 46.8% reported that they would likely take an injectable QW medication if recommended by their physician, with current injection users more than twice as likely as non-injection users (73.1 vs. 31.5%; p < 0.001). Greater willingness to take QW medications was associated with poorer DQOL [injection users only; odds ratio (OR) = 1.37, p < 0.01] and poorer perceived glycaemic control (non-injection users only; OR = 1.24, p < 0.05). Concerns arose about consistency of dosage over time, potential forgetfulness and cost. CONCLUSIONS: QW glucose-lowering medications are viewed positively by patients with type 2 diabetes, especially if they are current injection users or are dissatisfied with their current treatments or outcomes. Greater convenience, better medication adherence and improved QOL are commonly endorsed attributes. Clinicians may need to review both the positive attributes of QW medications as well as common patient concerns, when considering this option.

Can the Mediterranean diet lower HbA1c in type 2 diabetes? Results from a randomized cross-over study.

BACKGROUND AND AIMS: To investigate the impact of a diet modeled on the traditional Cretan Mediterranean diet on metabolic control and vascular risk in type 2 diabetes. METHODS AND RESULTS: Twenty-seven subjects (47-77 yrs) with type 2 diabetes were randomly assigned to consume either the intervention diet ad libitum or their usual diet for 12 weeks and then cross over to the alternate diet. Most of the meals and staple foods for the intervention diet were provided. Lipids, glycemic variables, blood pressure, homocysteine, C-reactive protein, plasma carotenoids and body composition (anthropometry and dual energy X-ray absorptiometry) were assessed at baseline, and at the end of both diet periods. Dietary adherence was monitored using plasma carotenoid and fatty acid (FA) analysis, complemented by diet diaries. Compared with usual diet, on the ad libitum Mediterranean intervention diet glycosylated haemoglobin fell from 7.1% (95% CI: 6.5-7.7) to 6.8% (95% CI: 6.3-7.3) (p=0.012) and diet quality improved significantly [plant:animal (g/day) food ratio increased from 1.3 (95% CI: 1.1-1.5) to 5.4 (95% CI: 4.3-6.6) (p<0.001)], plasma lycopene and lutein/zeaxanthin increased (36% and 25%, respectively), plasma saturated and trans FAs decreased, and monounsaturated FAs increased. CONCLUSION: A traditional moderate-fat Mediterranean diet improves glycemic control and diet quality in men and women with well-controlled type 2 diabetes, without adverse effects on weight.

Bursts and the efficacy of selective serotonin reuptake inhibitors.

We present a new hypothesis for the efficacy of selective serotonin reuptake inhibitors (SSRIs). We propose that SSRIs bring the response to the phasic firing of raphe nucleus cells back to normal, even though the average extracellular 5HT concentration remains low. We discuss burst firing in the raphe nuclei and use mathematical models to argue that tonic firing and phasic firing may be decoupled and may come from different mechanisms. We use a mathematical model for serotonin synthesis, release, and reuptake in terminals to illustrate the responses in terminal regions to bursts in a normal individual and in an individual with low vesicular serotonin. We then show that acute doses of SSRIs do not bring the response to bursts back to normal, but that chronic doses do return the response to normal. These model results need to be confirmed by new electrophysiological and pharmacological experiments.

Characteristics of intracerebral haemorrhage associated with COVID-19: a systematic review and pooled analysis of individual patient and aggregate data.

BACKGROUND AND PURPOSE: There are very few studies of the characteristics and causes of ICH in COVID-19, yet such data are essential to guide clinicians in clinical management, including challenging anticoagulation decisions. We aimed to describe the characteristics of spontaneous symptomatic intracerebral haemorrhage (ICH) associated with COVID-19. METHODS: We systematically searched PubMed, Embase and the Cochrane Central Database for data from patients with SARS-CoV-2 detected prior to or within 7 days after symptomatic ICH. We did a pooled analysis of individual patient data, then combined data from this pooled analysis with aggregate-level data. RESULTS: We included data from 139 patients (98 with individual data and 41 with aggregate-level data). In our pooled individual data analysis, the median age (IQR) was 60 (53-67) years and 64% (95% CI 54-73.7%) were male; 79% (95% CI 70.0-86.9%) had critically severe COVID-19. The pooled prevalence of lobar ICH was 67% (95% CI 56.3-76.0%), and of multifocal ICH was 36% (95% CI 26.4-47.0%). 71% (95% CI 61.0-80.4%) of patients were treated with anticoagulation (58% (95% CI 48-67.8%) therapeutic). The median NIHSS was 28 (IQR 15-28); mortality was 54% (95% CI 43.7-64.2%). Our combined analysis of individual and aggregate data showed similar findings. The pooled incidence of ICH across 12 cohort studies of inpatients with COVID-19 (n = 63,390) was 0.38% (95% CI 0.22-0.58%). CONCLUSIONS: Our data suggest that ICH associated with COVID-19 has different characteristics compared to ICH not associated with COVID-19, including frequent lobar location and multifocality, a high rate of anticoagulation, and high mortality. These observations suggest different underlying mechanisms of ICH in COVID-19 with potential implications for clinical treatment and trials.