St Joseph's Health Centre

BACKGROUND: Once-daily injections of parathyroid hormone or its amino-terminal fragments increase bone formation and bone mass without causing hypercalcemia, but their effects on fractures are unknown. METHODS: We randomly assigned 1637 postmenopausal women with prior vertebral fractures to receive 20 or 40 microg of parathyroid hormone (1-34) or placebo, administered subcutaneously by the women daily. We obtained vertebral radiographs at base line and at the end of the study (median duration of observation, 21 months) and performed serial measurements of bone mass by dual-energy x-ray absorptiometry. RESULTS: New vertebral fractures occurred in 14 percent of the women in the placebo group and in 5 percent and 4 percent, respectively, of the women in the 20-microg and 40-microg parathyroid hormone groups; the respective relative risks of fracture in the 20-microg and 40-microg groups, as compared with the placebo group, were 0.35 and 0.31 (95 percent confidence intervals, 0.22 to 0.55 and 0.19 to 0.50). New nonvertebral fragility fractures occurred in 6 percent of the women in the placebo group and in 3 percent of those in each parathyroid hormone group (relative risk, 0.47 and 0.46, respectively [95 percent confidence intervals, 0.25 to 0.88 and 0.25 to 0.861). As compared with placebo, the 20-microg and 40-microg doses of parathyroid hormone increased bone mineral density by 9 and 13 more percentage points in the lumbar spine and by 3 and 6 more percentage points in the femoral neck; the 40-microg dose decreased bone mineral density at the shaft of the radius by 2 more percentage points. Both doses increased total-body bone mineral by 2 to 4 more percentage points than did placebo. Parathyroid hormone had only minor side effects (occasional nausea and headache). CONCLUSIONS: Treatment of postmenopausal osteoporosis with parathyroid hormone (1-34) decreases the risk of vertebral and nonvertebral fractures; increases vertebral, femoral, and total-body bone mineral density; and is well tolerated. The 40-microg dose increased bone mineral density more than the 20-microg dose but had similar effects on the risk of fracture and was more likely to have side effects.

Aging is associated with progressive loss of neuromuscular function that often leads to progressive disability and loss of independence. The term sarcopenia is now commonly used to describe the loss of skeletal muscle mass and strength that occurs in concert with biological aging. By the seventh and eighth decade of life, maximal voluntary contractile strength is decreased, on average, by 20-40% for both men and women in proximal and distal muscles. Although age-associated decreases in strength per unit muscle mass, or muscle quality, may play a role, the majority of strength loss can be accounted for by decreased muscle mass. Multiple factors lead to the development of sarcopenia and the associated impact on function. Loss of skeletal muscle fibers secondary to decreased numbers of motoneurons appears to be a major contributing influence, but other factors, including decreased physical activity, altered hormonal status, decreased total caloric and protein intake, inflammatory mediators, and factors leading to altered protein synthesis, must also be considered. The prevalence of sarcopenia, which may be as high as 30% for those >/=60 yr, will increase as the percentage of the very old continues to grow in our populations. The link between sarcopenia and disability among elderly men and women highlights the need for continued research into the development of the most effective interventions to prevent or at least partially reverse sarcopenia, including the role of resistance exercise and other novel pharmacological and nutritional interventions.

It has long been theorised that there are two temporally distinct forms of self-reference: extended self-reference linking experiences across time, and momentary self-reference centred on the present. To characterise these two aspects of awareness, we used functional magnetic resonance imaging (fMRI) to examine monitoring of enduring traits ('narrative' focus, NF) or momentary experience ('experiential' focus, EF) in both novice participants and those having attended an 8 week course in mindfulness meditation, a program that trains individuals to develop focused attention on the present. In novices, EF yielded focal reductions in self-referential cortical midline regions (medial prefrontal cortex, mPFC) associated with NF. In trained participants, EF resulted in more marked and pervasive reductions in the mPFC, and increased engagement of a right lateralised network, comprising the lateral PFC and viscerosomatic areas such as the insula, secondary somatosensory cortex and inferior parietal lobule. Functional connectivity analyses further demonstrated a strong coupling between the right insula and the mPFC in novices that was uncoupled in the mindfulness group. These results suggest a fundamental neural dissociation between two distinct forms of self-awareness that are habitually integrated but can be dissociated through attentional training: the self across time and in the present moment.

Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD-abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions.

STUDY DESIGN: Systematic review of clinical measurement. OBJECTIVE: To find and synthesize evidence on the psychometric properties and usefulness of the neck disability index (NDI). BACKGROUND: The NDI is the most commonly used outcome measure for neck pain, and a synthesis of knowledge should provide a deeper understanding of its use and limitations. METHODS AND MEASURES: Using a standard search strategy (1966 to September 2008) and 4 databases (Medline, CINAHL, Embase, and PsychInfo), a structured search was conducted and supplemented by web and hand searching. In total, 37 published primary studies, 3 reviews, and 1 in-press paper were analyzed. Pairs of raters conducted data extraction and critical appraisal using structured tools. Ranking of quality and descriptive synthesis were performed. RESULTS: Horizon estimation suggested the potential for 1 missed paper. The agreement between raters on quality assessments was high(kappa = 0.82). Half of the studies reached a quality level greater than 70%. Failures to report clear psychometric objectives/hypotheses or to rationalize the sample size were the most common design flaws. Studies often focused on less clinically applicable properties, like construct validity or group reliability, than transferable data, like known group differences or absolute reliability (standard error of measurement [SEM] or minimum detectable change [MDC]). Most studies suggest that the NDI has acceptable reliability, although intraclass correlation coefficients (ICCs) range from 0.50 to 0.98. Longer test intervals and the definition of stable can influence reliability estimates. A number of high-quality published (Korean, Dutch, Spanish, French, Brazilian Portuguese) and commercially supported translations are available. The NDI is considered a 1-dimensional measure that can be interpreted as an interval scale. Some studies question these assumptions. The MDC is around 5/50 for uncomplicated neck pain and up to 10/50 for cervical radiculopathy. The reported clinically important difference (CID) is inconsistent across different studies ranging from 5/50 to 19/50. The NDI is strongly correlated (>0.70) to a number of similar indices and moderately related to both physical and mental aspects of general health. CONCLUSION: The NDI has sufficient support and usefulness to retain its current status as the most commonly used self-report measure for neck pain. More studies of CID in different clinical populations and the relationship to subjective/work/function categories are required.

BACKGROUND: A strategy of mechanical ventilation that limits airway pressure and tidal volume while permitting hypercapnia has been recommended for patients with the acute respiratory distress syndrome. The goal is to reduce lung injury due to overdistention. However, the efficacy of this approach has not been established. METHODS: Within 24 hours of intubation, patients at high risk for the acute respiratory distress syndrome were randomly assigned to either pressure- and volume-limited ventilation (limited-ventilation group), with the peak inspiratory pressure maintained at 30 cm of water or less and the tidal volume at 8 ml per kilogram of body weight or less, or to conventional ventilation (control group), with the peak inspiratory pressure allowed to rise as high as 50 cm of water and the tidal volume at 10 to 15 ml per kilogram. All other ventilatory variables were similar in the two groups. RESULTS: A total of 120 patients with similar clinical features underwent randomization (60 in each group). The patients in the limited-ventilation and control groups were exposed to different mean (+/-SD) tidal volumes (7.2+/-0.8 vs. 10.8+/-1.0 ml per kilogram, respectively; P<0.001) and peak inspiratory pressures (23.6+/-5.8 vs. 34.0+/-11.0 cm of water, P<0.001). Mortality was 50 percent in the limited-ventilation group and 47 percent in the control group (relative risk, 1.07; 95 percent confidence interval, 0.72 to 1.57; P=0.72). In the limited-ventilation group, permissive hypercapnia (arterial carbon dioxide tension, >50 mm Hg) was more common (52 percent vs. 28 percent, P=0.009), more marked (54.4+/-18.8 vs. 45.7+/-9.8 mm Hg, P=0.002), and more prolonged (146+/-265 vs. 25+/-22 hours, P=0.017) than in the control group. The incidence of barotrauma, the highest multiple-organ-dysfunction score, and the number of episodes of organ failure were similar in the two groups; however, the numbers of patients who required paralytic agents (23 vs. 13, P=0.05) and dialysis for renal failure (13 vs. 5, P= 0.04) were greater in the limited-ventilation group than in the control group. CONCLUSIONS: In patients at high risk for the acute respiratory distress syndrome, a strategy of mechanical ventilation that limits peak inspiratory pressure and tidal volume does not appear to reduce mortality and may increase morbidity.

OBJECTIVE: The goal of this study was to develop a reliable and valid tool for quantifying patient-rated wrist pain and disability. DESIGN: Survey, tool development, reliability, and validity study. SETTING: Upper extremity unit. PARTICIPANTS: One hundred members of the International Wrist Investigators were surveyed by mail to assist in development of the scale. Patients with distal radius (n = 64) or scaphoid (n = 35) fractures were enrolled in a reliability study, and 101 patients with distal radius fractures were enrolled in a validity study. INTERVENTION: Information from the expert survey, biomechanical literature, and patient interviews was used as a basis for item generation and definition of structural limitations for a scale that would be practical in the clinic. Patients with distal radius or scaphoid fractures completed the Patient-Rated Wrist Evaluation (PRWE) on two occasions to determine test-retest reliability. Patients with distal radius fractures (n = 101) completed the PRWE and the SF-36 and were tested with traditional impairment measures at baseline and at two, three, and six months after fracture to determine construct and criterion validity. MAIN OUTCOME MEASURES: Reliability coefficients (ICCs) and validity correlations (Pearson product moment correlations). RESULTS: Patient opinions on pain and on ability to do activities of daily living and work were thought to be the most important dimensions to include in subjective outcome tools. Brevity and simplicity were seen as essential in the clinic environment. A fifteen-item questionnaire (the PRWE) was designed to measure wrist pain and disability. Test-retest reliability was excellent (ICCs > 0.90). Validity assessment demonstrated that the instrument detected significant differences over time (p < 0.01) and was appropriately correlated with alternate forms of assessing parameters of pain and disability. CONCLUSIONS: The PRWE provides a brief, reliable, and valid measure of patient-rated pain and disability.

OBJECTIVE: To utilize the diagnostic criteria of frontal lobe dementia (FLD). METHODS: We studied 12 patients with FLD diagnosed clinically, with radiological confirmation in 10 and autopsy confirmation in 2; sixteen patients with Alzheimer's disease matched for stage and severity to FLD and 11 patients with depressive dementia were used as control groups. A 24-item Frontal Behavioral Inventory (FBI) using the most relevant behavioral manifestations of FLD was administered in these populations. RESULTS: FLD patient scores on the FBI were much higher compared with control groups (AD and DD). Item analysis showed loss of insight, indifference, distractibility, personal neglect and apathy as the most frequent negative symptoms. Perseveration, disinhibition, inappropriateness, impulsivity, and irresponsibility were the most significant positive symptoms. An operational definition of FLD included a minimum FBI score of 27. Only one false positive was shown in the depressive group and none among the AD group, indicating little overlap between patient groups, and a high discriminating value of the FBI. CONCLUSIONS: The FBI appears to be a useful diagnostic instrument and a method to operate the behavioral criteria of FLD. Further prospective studies are warranted to establish validity.

PurposeGenetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides a comprehensive testing platform that has the potential to streamline genetic assessments, but there are limited comparative data to guide its clinical use.MethodsWe prospectively recruited 103 patients from pediatric non-genetic subspecialty clinics, each with a clinical phenotype suggestive of an underlying genetic disorder, and compared the diagnostic yield and coverage of WGS with those of conventional genetic testing.ResultsWGS identified diagnostic variants in 41% of individuals, representing a significant increase over conventional testing results (24%; P = 0.01). Genes clinically sequenced in the cohort (n = 1,226) were well covered by WGS, with a median exonic coverage of 40 × ±8 × (mean ±SD). All the molecular diagnoses made by conventional methods were captured by WGS. The 18 new diagnoses made with WGS included structural and non-exonic sequence variants not detectable with whole-exome sequencing, and confirmed recent disease associations with the genes PIGG, RNU4ATAC, TRIO, and UNC13A.ConclusionWGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort.

Tau is a hallmark pathology of Alzheimer's disease, and animal models have suggested that tau spreads from cell to cell through neuronal connections, facilitated by β-amyloid (Aβ). We test this hypothesis in humans using an epidemic spreading model (ESM) to simulate tau spread, and compare these simulations to observed patterns measured using tau-PET in 312 individuals along Alzheimer's disease continuum. Up to 70% of the variance in the overall spatial pattern of tau can be explained by our model. Surprisingly, the ESM predicts the spatial patterns of tau irrespective of whether brain Aβ is present, but regions with greater Aβ burden show greater tau than predicted by connectivity patterns, suggesting a role of Aβ in accelerating tau spread. Altogether, our results provide evidence in humans that tau spreads through neuronal communication pathways even in normal aging, and that this process is accelerated by the presence of brain Aβ.

Recovery from emotional challenge and increased tolerance of negative affect are both hallmarks of mental health. Mindfulness training (MT) has been shown to facilitate these outcomes, yet little is known about its mechanisms of action. The present study employed functional MRI (fMRI) to compare neural reactivity to sadness provocation in participants completing 8 weeks of MT and waitlisted controls. Sadness resulted in widespread recruitment of regions associated with self-referential processes along the cortical midline. Despite equivalent self-reported sadness, MT participants demonstrated a distinct neural response, with greater right-lateralized recruitment, including visceral and somatosensory areas associated with body sensation. The greater somatic recruitment observed in the MT group during evoked sadness was associated with decreased depression scores. Restoring balance between affective and sensory neural networks-supporting conceptual and body based representations of emotion-could be one path through which mindfulness reduces vulnerability to dysphoric reactivity.

OBJECTIVES: To compare the efficacy and safety of unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs) and to examine current controversies in the treatment of venous thromboembolism (VTE) (ie, setting, product type, and frequency of administration). METHODS: Data were abstracted from MEDLINE, HEALTH, previous reviews, personal files, clinical experts, and conference abstracts. Randomized controlled trials of patients diagnosed with acute VTE that compared LMWHs with UFH were included. Independent duplicate assessment was done for methodological quality and data extraction. Data are reported as pooled relative risks (RRs) and 95% confidence intervals (CIs) comparing LMWHs with UFH as determined by the random effects model. RESULTS: Thirteen studies were included. There was no statistically significant difference in risk between UFH and LMWHs for recurrent VTE (RR, 0.85 [95% CI, 0.65-1.12]), pulmonary embolism (RR, 1.02 [95% CI, 0.64-1.62]), major bleeding (RR, 0.63 [95% CI, 0.37-1.05]), minor bleeding (RR, 1.18 [95% CI, 0.87-1.61]), and thrombocytopenia (RR, 0.85 [95% CI, 0.45-1.62]). There was a statistically significant difference for risk of total mortality (RR, 0.76 [95% CI, 0.59-0.98]) in favor of LMWHs. Inpatient treatment may reduce the risk of major bleeding vs outpatient therapy. Once-daily therapy is as safe and effective as twice-daily therapy when compared indirectly. Different products could not be statistically compared, but qualitative analysis shows that there are no apparent differences in efficacy and safety. CONCLUSIONS: Low-molecular-weight heparins are at least as effective as UFH in preventing recurrent VTE. It is unlikely that LMWHs are superior in the treatment of VTE, but they do show a statistically significant decrease in total mortality. No differences were seen in the development of recurrent VTE dependent on treatment setting. There were no apparent differences between once-daily and twice-daily therapy or among products. Inpatient therapy may be associated with less major bleeding; therefore, if LMWHs are given in the outpatient setting, patients should be rigorously monitored.

We previously demonstrated the essential role of the flt-1 gene in regulating the development of the cardiovascular system. While the inactivation of the flt-1 gene leads to a very severe disorganization of the vascular system, the primary defect at the cellular level was unknown. Here we report a surprising finding that it is an increase in the number of endothelial progenitors that leads to the vascular disorganization in flt-1(-/-) mice. At the early primitive streak stage (prior to the formation of blood islands), hemangioblasts are formed much more abundantly in flt-1(-/-) embryos. This increase is primarily due to an alteration in cell fate determination among mesenchymal cells, rather than to increased proliferation, migration or reduced apoptosis of flt-1(-/-) hemangioblasts. We further show that the increased population density of hemangioblasts is responsible for the observed vascular disorganization, based on the following observations: (1) both flt-1(-/-) and flt-1(+/+) endothelial cells formed normal vascular channels in chimaeric embryos; (2) wild-type endothelial cells formed abnormal vascular channels when their population density was significantly increased; and (3) in the absence of wild-type endothelial cells, flt-1(-/-) endothelial cells alone could form normal vascular channels when sufficiently diluted in a developing embryo. These results define the primary defect in flt-1(-/-) embryos at the cellular level and demonstrate the importance of population density of progenitor cells in pattern formation.

OBJECTIVE: To evaluate the long-term efficacy of acarbose, an alpha-glucosidase inhibitor, in improving glycemic control in patients with non-insulin-dependent diabetes mellitus. DESIGN: A 1-year, multicenter, randomized, double-blind, placebo-controlled study. SETTING: Seven university-affiliated, community-based, tertiary care diabetes clinics. PATIENTS: 354 patients with non-insulin-dependent diabetes mellitus were recruited; 77 were being treated with diet alone, 83 with diet and metformin, 103 with diet and sulfonylurea, and 91 with diet and insulin. Patients in each treatment group were randomly assigned to either acarbose or placebo for 1 year. Eighty-seven percent of patients receiving acarbose and 92% of those receiving placebo were included in the efficacy analysis (n = 316). MEASUREMENTS: At baseline and at 3-month intervals, levels of hemoglobin A1c (HbA1c), fasting and postprandial plasma glucose, fasting and postprandial serum C-peptide, and fasting serum lipids were measured. RESULTS: Compared with placebo, acarbose treatment caused a significant decrease in the mean postprandial plasma glucose peak (90 minutes) in all four groups (19.0 +/- 0.4 mmol/L to 15.5 +/- 0.4 mmol/L; P < 0.001). Analysis of the postprandial plasma glucose incremental area under the curve showed that the change from baseline to the end of the treatment period differed for placebo and acarbose recipients by 4.73 mmol.h/L in the diet alone group (P < 0.001), 2.06 mmol.h/L in the metformin group (P = 0.01), 2.65 mmol.h/L in the sulfonylurea group (P < 0.001), and 3.13 mmol.h/L in the insulin group (P = 0.001). Corresponding decreases in HbA1c levels occurred; these were 0.9% in the diet alone group (P = 0.005), 0.8% in the metformin group (P = 0.011), 0.9% in the sulfonylurea group (P = 0.002), and 0.4% in the insulin group (P = 0.077). Acarbose did not significantly affect mean serum C-peptide or mean serum lipid levels. CONCLUSIONS: Acarbose improved long-term glycemic control in patients with non-insulin-dependent diabetes mellitus regardless of concomitant antidiabetic medication.

BACKGROUND: Across Europe, Canada, and the United States, 22-43 % of transgender (trans) people report a history of suicide attempts. We aimed to identify intervenable factors (related to social inclusion, transphobia, or sex/gender transition) associated with reduced risk of past-year suicide ideation or attempt, and to quantify the potential population health impact. METHODS: The Trans PULSE respondent-driven sampling (RDS) survey collected data from trans people age 16+ in Ontario, Canada, including 380 who reported on suicide outcomes. Descriptive statistics and multivariable logistic regression models were weighted using RDS II methods. Counterfactual risk ratios and population attributable risks were estimated using model-standardized risks. RESULTS: Among trans Ontarians, 35.1 % (95 % CI: 27.6, 42.5) seriously considered, and 11.2 % (95 % CI: 6.0, 16.4) attempted, suicide in the past year. Social support, reduced transphobia, and having any personal identification documents changed to an appropriate sex designation were associated with large relative and absolute reductions in suicide risk, as was completing a medical transition through hormones and/or surgeries (when needed). Parental support for gender identity was associated with reduced ideation. Lower self-reported transphobia (10(th) versus 90(th) percentile) was associated with a 66 % reduction in ideation (RR = 0.34, 95 % CI: 0.17, 0.67), and an additional 76 % reduction in attempts among those with ideation (RR = 0.24; 95 % CI: 0.07, 0.82). This corresponds to potential prevention of 160 ideations per 1000 trans persons, and 200 attempts per 1,000 with ideation, based on a hypothetical reduction of transphobia from current levels to the 10(th) percentile. CONCLUSIONS: Large effect sizes were observed for this controlled analysis of intervenable factors, suggesting that interventions to increase social inclusion and access to medical transition, and to reduce transphobia, have the potential to contribute to substantial reductions in the extremely high prevalences of suicide ideation and attempts within trans populations. Such interventions at the population level may require policy change.

Using the adiabatic approximation, which assumes that the tracer concentration in parenchymal tissue changes slowly relative to that in capillaries, we derived a time-domain, closed-form solution of the tissue homogeneity model. This solution, which is called the adiabatic solution, is similar in form to those of two-compartment models. Owing to its simplicity, the adiabatic solution can be used in CBF experiments in which kinetic data with only limited time resolution or signal-to-noise ratio, or both, are obtained. Using computer simulations, we investigated the accuracy and the precision of the parameters in the adiabatic solution for values that reflect 2H-labeled water (D2O) clearance from the brain (see Part II). It was determined that of the three model parameters, (1) the vascular volume (Vi), (2) the product of extraction fraction and blood flow (EF), and (3) the clearance rate constant (kadb), only the last one could be determined accurately, and therefore CBF must be determined from this parameter only. From the error analysis of the adiabatic solution, it was concluded that for the D2O clearance experiments described in Part II, the coefficient of variation of CBF was approximately 7% in gray matter and 22% in white matter.

Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by a decline in cognitive functions with no validated disease modifying treatment. It is critical for timely treatment to detect AD in its earlier stage before clinical manifestation. Mild cognitive impairment (MCI) is an intermediate stage between cognitively normal older adults and AD. To predict conversion from MCI to probable AD, we applied a deep learning approach, multimodal recurrent neural network. We developed an integrative framework that combines not only cross-sectional neuroimaging biomarkers at baseline but also longitudinal cerebrospinal fluid (CSF) and cognitive performance biomarkers obtained from the Alzheimer's Disease Neuroimaging Initiative cohort (ADNI). The proposed framework integrated longitudinal multi-domain data. Our results showed that 1) our prediction model for MCI conversion to AD yielded up to 75% accuracy (area under the curve (AUC) = 0.83) when using only single modality of data separately; and 2) our prediction model achieved the best performance with 81% accuracy (AUC = 0.86) when incorporating longitudinal multi-domain data. A multi-modal deep learning approach has potential to identify persons at risk of developing AD who might benefit most from a clinical trial or as a stratification approach within clinical trials.

OBJECTIVE: To evaluate the effects of therapeutic heparin compared with prophylactic heparin among moderately ill patients with covid-19 admitted to hospital wards. DESIGN: Randomised controlled, adaptive, open label clinical trial. SETTING: 28 hospitals in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and US. PARTICIPANTS: 465 adults admitted to hospital wards with covid-19 and increased D-dimer levels were recruited between 29 May 2020 and 12 April 2021 and were randomly assigned to therapeutic dose heparin (n=228) or prophylactic dose heparin (n=237). INTERVENTIONS: Therapeutic dose or prophylactic dose heparin (low molecular weight or unfractionated heparin), to be continued until hospital discharge, day 28, or death. MAIN OUTCOME MEASURES: The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to an intensive care unit, assessed up to 28 days. The secondary outcomes included all cause death, the composite of all cause death or any mechanical ventilation, and venous thromboembolism. Safety outcomes included major bleeding. Outcomes were blindly adjudicated. RESULTS: . At 28 days, the primary composite outcome had occurred in 37/228 patients (16.2%) assigned to therapeutic heparin and 52/237 (21.9%) assigned to prophylactic heparin (odds ratio 0.69, 95% confidence interval 0.43 to 1.10; P=0.12). Deaths occurred in four patients (1.8%) assigned to therapeutic heparin and 18 patients (7.6%) assigned to prophylactic heparin (0.22, 0.07 to 0.65; P=0.006). The composite of all cause death or any mechanical ventilation occurred in 23 patients (10.1%) assigned to therapeutic heparin and 38 (16.0%) assigned to prophylactic heparin (0.59, 0.34 to 1.02; P=0.06). Venous thromboembolism occurred in two patients (0.9%) assigned to therapeutic heparin and six (2.5%) assigned to prophylactic heparin (0.34, 0.07 to 1.71; P=0.19). Major bleeding occurred in two patients (0.9%) assigned to therapeutic heparin and four (1.7%) assigned to prophylactic heparin (0.52, 0.09 to 2.85; P=0.69). CONCLUSIONS: In moderately ill patients with covid-19 and increased D-dimer levels admitted to hospital wards, therapeutic heparin was not significantly associated with a reduction in the primary outcome but the odds of death at 28 days was decreased. The risk of major bleeding appeared low in this trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT04362085.

The rate of motor unit (MU) loss and its influence on the progression of sarcopenia is not well understood. Therefore, the main purpose of this study was to estimate and compare numbers of MUs in the tibialis anterior (TA) of young men ( approximately 25 years) and two groups of older men ( approximately 65 years and >/=80 years). Decomposition-enhanced spike-triggered averaging was used to collect surface and intramuscular electromyographic signals during isometric dorsiflexions at 25% of maximum voluntary contraction. The mean surface-MU potential size was divided into the maximum M wave to calculate the motor unit number estimate (MUNE). The MUNE was significantly reduced in the old (91) compared to young (150) men, and further reduced in the very old men (59). Despite the smaller MUNE at age 65, strength was not reduced until beyond 80 years. This suggests that age-related MU loss in the TA does not limit function until a critical threshold is reached.

In Alzheimer's diseases (AD), tau pathology is strongly associated with cognitive decline. Preclinical evidence suggests that tau spreads across connected neurons in an activity-dependent manner. Supporting this, cross-sectional AD studies show that tau deposition patterns resemble functional brain networks. However, whether higher functional connectivity is associated with higher rates of tau accumulation is unclear. Here, we combine resting-state fMRI with longitudinal tau-PET in two independent samples including 53 (ADNI) and 41 (BioFINDER) amyloid-biomarker defined AD subjects and 28 (ADNI) vs. 16 (BioFINDER) amyloid-negative healthy controls. In both samples, AD subjects show faster tau accumulation than controls. Second, in AD, higher fMRI-assessed connectivity between 400 regions of interest (ROIs) is associated with correlated tau-PET accumulation in corresponding ROIs. Third, we show that a model including baseline connectivity and tau-PET is associated with future tau-PET accumulation. Together, connectivity is associated with tau spread in AD, supporting the view of transneuronal tau propagation.