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Background Although electromyogram (EMG) pattern recognition (PR) for multifunctional upper limb prosthesis control has been reported for decades, the clinical benefits have rarely been examined. The study purposes were to: 1) compare self-report and performance outcomes of a transradial amputee immediately after training and one week after training of direct myoelectric control and EMG pattern recognition (PR) for a two-degree-of-freedom (DOF) prosthesis, and 2) examine the change in outcomes one week after pattern recognition training and the rate of skill acquisition in two subjects with transradial amputations. Methods In this cross-over study, participants were randomized to receive either PR control or direct control (DC) training of a 2 DOF myoelectric prosthesis first. Participants were 2 persons with traumatic transradial (TR) amputations who were 1 DOF myoelectric users. Outcomes, including measures of dexterity with and without cognitive load, activity performance, self-reported function, and prosthetic satisfaction were administered immediately and 1 week after training. Speed of skill acquisition was assessed hourly. One subject completed training under both PR control and DC conditions. Both subjects completed PR training and testing. Outcomes of test metrics were analyzed descriptively. Results Comparison of the two control strategies in one subject who completed training in both conditions showed better scores in 2 (18%) dexterity measures, 1 (50%) dexterity measure with cognitive load, and 1 (50%) self-report functional measure using DC, as compared to PR. Scores of all other metrics were comparable. Both subjects showed decline in dexterity after training. Findings related to rate of skill acquisition varied considerably by subject. Conclusions Outcomes of PR and DC for operating a 2-DOF prosthesis in a single subject cross-over study were similar for 74% of metrics, and favored DC in 26% of metrics. The two subjects who completed PR training showed decline in dexterity one week after training ended. Findings related to rate of skill acquisition varied considerably by subject. This study, despite its small sample size, highlights a need for additional research quantifying the functional and clinical benefits of PR control for upper limb prostheses.

A large body of literature details the deleterious effects of everyday discrimination on health, focusing on stress processes after discrimination occurs. In contrast, less work has investigated what occurs prior to encountering discrimination when a person expects it. Using a 10-day daily diary design, the current study examined predictors and outcomes of anticipated discrimination. Participants included 341 U.S. adults aged 19-74 years (29% racial minorities, 68% women). Multiple regression examined predictors of anticipated and reported discrimination. Further, two-level multilevel models evaluated anticipated discrimination predicting discrimination occurrence, appraisals, affect, and physical symptoms. Results showed that discrimination was anticipated on 21% of days; racial minorities and people with more prior exposure to discrimination anticipated more daily discrimination than White participants and those with lower prior exposure. People who anticipated discrimination more often than others reported more daily discrimination and perceived discrimination as more stressful but also perceived greater control over the events. They additionally had relatively larger upticks in physical symptoms on days when discrimination occurred-but no differences in discrimination-related affect-compared to people who anticipated discrimination less frequently. Within-persons, anticipating discrimination on a given day (versus not) was associated with greater likelihood of reporting discrimination occurred later that day and greater perceived stress severity, but no differences in perceived control, affect, or physical symptoms. In sum, anticipated discrimination was fairly common in daily life, and individual differences in anticipated discrimination were linked to more perceived daily discrimination, higher perceived stress severity, and more discrimination-related physical symptoms.

Although environmental factors, mainly nutrition and UV-B radiation, have been considered major determinants of vitamin D status, they have only explained a modest proportion of the variation in serum 25-hydroxyvitamin D. We aimed to study the seasonal impact of genetic factors on serum 25-hydroxyvitamin D concentrations. 204 same-sex twins, aged 39-85 years and living at northern latitude 60 degrees, were recruited from the Swedish Twin Registry. Serum 25-hydroxyvitamin D was analysed by high-pressure liquid chromatography and mass spectrometry. Genetic modelling techniques estimated the relative contributions of genetic, shared and individual-specific environmental factors to the variation in serum vitamin D. The average serum 25-hydroxyvitamin D concentration was 84.8 nmol/l (95% CI 81.0-88.6) but the seasonal variation was substantial, with 24.2 nmol/l (95% CI 16.3-32.2) lower values during the winter as compared to the summer season. Half of the variability in 25-hydroxyvitamin D during the summer season was attributed to genetic factors. In contrast, the winter season variation was largely attributable to shared environmental influences (72%; 95% CI 48-86%), i.e., solar altitude. Individual-specific environmental influences were found to explain one fourth of the variation in serum 25-hydroxyvitamin D independent of season. There exists a moderate genetic impact on serum vitamin D status during the summer season, probably through the skin synthesis of vitamin D. Further studies are warranted to identify the genes impacting on vitamin D status.

Recent research indicates a favourable influence of postmenopausal hormone therapy (HT) if initiated early, but not late, on subclinical atherosclerosis. However, the clinical relevance of timing of HT initiation for hard end points such as stroke remains to be determined. Further, no previous research has considered the timing of initiation of HT in relation to haemorrhagic stroke risk. The importance of the route of administration, type, active ingredient, and duration of HT for stroke risk is also unclear. We aimed to assess the association between HT and risk of stroke, considering the timing of initiation, route of administration, type, active ingredient, and duration of HT. Data on HT use reported by the participants in 5 population-based Swedish cohort studies, with baseline investigations performed during the period 1987-2002, were combined in this observational study. In total, 88,914 postmenopausal women who reported data on HT use and had no previous cardiovascular disease diagnosis were included. Incident events of stroke (ischaemic, haemorrhagic, or unspecified) and haemorrhagic stroke were identified from national population registers. Laplace regression was employed to assess crude and multivariable-adjusted associations between HT and stroke risk by estimating percentile differences (PDs) with 95% confidence intervals (CIs). The fifth and first PDs were calculated for stroke and haemorrhagic stroke, respectively. Crude models were adjusted for age at baseline only. The final adjusted models included age at baseline, level of education, smoking status, body mass index, level of physical activity, and age at menopause onset. Additional variables evaluated for potential confounding were type of menopause, parity, use of oral contraceptives, alcohol consumption, hypertension, dyslipidaemia, diabetes, family history of cardiovascular disease, and cohort. During a median follow-up of 14.3 years, 6,371 first-time stroke events were recorded; of these, 1,080 were haemorrhagic. Following multivariable adjustment, early initiation (<5 years since menopause onset) of HT was associated with a longer stroke-free period than never use (fifth PD, 1.00 years; 95% CI 0.42 to 1.57), but there was no significant extension to the time period free of haemorrhagic stroke (first PD, 1.52 years; 95% CI -0.32 to 3.37). When considering timing as a continuous variable, the stroke-free and the haemorrhagic stroke-free periods were maximal if HT was initiated approximately 0-5 years from the onset of menopause. If single conjugated equine oestrogen HT was used, late initiation of HT was associated with a shorter stroke-free (fifth PD, -4.41 years; 95% CI -7.14 to -1.68) and haemorrhagic stroke-free (first PD, -9.51 years; 95% CI -12.77 to -6.24) period than never use. Combined HT when initiated late was significantly associated with a shorter haemorrhagic stroke-free period (first PD, -1.97 years; 95% CI -3.81 to -0.13), but not with a shorter stroke-free period (fifth PD, -1.21 years; 95% CI -3.11 to 0.68) than never use. Given the observational nature of this study, the possibility of uncontrolled confounding cannot be excluded. Further, immortal time bias, also related to the observational design, cannot be ruled out. When initiated early in relation to menopause onset, HT was not associated with increased risk of incident stroke, regardless of the route of administration, type of HT, active ingredient, and duration. Generally, these findings held also for haemorrhagic stroke. Our results suggest that the initiation of HT 0-5 years after menopause onset, as compared to never use, is associated with a decreased risk of stroke and haemorrhagic stroke. Late initiation was associated with elevated risks of stroke and haemorrhagic stroke when conjugated equine oestrogen was used as single therapy. Late initiation of combined HT was associated with haemorrhagic stroke risk.

Alzheimer’s disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%. We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These ‘subtypes’ were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes. Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of ‘typical AD’ and a revisiting of tau pathological staging. Systematic characterization of longitudinal tau variability in human Alzheimer’s disease using an unbiased subtyping algorithm reveals four trajectories of tau deposition with distinct clinical features.

The Swedish Twin Registry was first established in the late 1950s. Today it includes more than 170,000 twins--in principle, all twins born in Sweden since 1886. In this article we describe some ongoing and recently completed projects based on the registry. In particular, we describe recent efforts to screen all twins born between 1959 and 1985, and young twin pairs when they turn 9 and 12 years of age. For these studies, we present initial frequencies of common conditions and exposures.The Swedish Twin Registry was first established in the late 1950s. Today it includes more than 170,000 twins--in principle, all twins born in Sweden since 1886. In this article we describe some ongoing and recently completed projects based on the registry. In particular, we describe recent efforts to screen all twins born between 1959 and 1985, and young twin pairs when they turn 9 and 12 years of age. For these studies, we present initial frequencies of common conditions and exposures.

PurposeRitlecitinib, an inhibitor of Janus kinase 3 and tyrosine kinase expressed in hepatocellular carcinoma family kinases, is in development for inflammatory diseases. This study assessed the impact of ritlecitinib on drug transporters using a probe drug and endogenous biomarkers.MethodsIn vitro transporter-mediated substrate uptake and inhibition by ritlecitinib and its major metabolite were evaluated. Subsequently, a clinical drug interaction study was conducted in 12 healthy adult participants to assess the effect of ritlecitinib on pharmacokinetics of rosuvastatin, a substrate of breast cancer resistance protein (BCRP), organic anion transporting polypeptide 1B1 (OATP1B1), and organic anion transporter 3 (OAT3). Plasma concentrations of coproporphyrin I (CP-I) and pyridoxic acid (PDA) were assessed as endogenous biomarkers for OATP1B1 and OAT1/3 function, respectively.ResultsIn vitro studies suggested that ritlecitinib can potentially inhibit BCRP, OATP1B1 and OAT1/3 based on regulatory cutoffs. In the subsequent clinical study, coadministration of ritlecitinib decreased rosuvastatin plasma exposure area under the curve from time 0 to infinity (AUCinf) by  ~ 13% and maximum concentration (Cmax) by  ~ 27% relative to rosuvastatin administered alone. Renal clearance was comparable in the absence and presence of ritlecitinib coadministration. PK parameters of AUCinf and Cmax for CP-I and PDA were also similar regardless of ritlecitinib coadministration.ConclusionRitlecitinib does not inhibit BCRP, OATP1B1, and OAT3 and is unlikely to cause a clinically relevant interaction through these transporters. Furthermore, our findings add to the body of evidence supporting the utility of CP-I and PDA as endogenous biomarkers for assessment of OATP1B1 and OAT1/3 transporter activity.

Diet may be associated with risk of dementia and Alzheimer disease (AD). The authors examined the association between fruit and vegetable consumption in midlife and risk for all types of dementia and AD. Participants were 3,779 members of the Swedish Twin Registry who completed a diet questionnaire approximately 30 years before cognitive screening and full clinical evaluation for dementia as part of the study of dementia in Swedish Twins (HARMONY) study. Among the participants, 355 twins were diagnosed with dementia. Among these, 81 twin pairs were discordant for dementia (50 discordant for AD). Data were analyzed with logistic regression for the entire sample using generalized estimating equations to adjust for relatedness of twins and with conditional logistic regression for the co-twin control design. In fully adjusted models, a medium or great proportion of fruits and vegetables in the diet, compared with no or small, was associated with a decreased risk of dementia and AD. This effect was observed among women and those with angina. Similar, but nonsignificant, odds ratios were found in the co-twin control analyses. The findings suggest that higher fruit and vegetable consumption may reduce the risk of dementia, especially among women and those with angina pectoris in midlife.

The interrogation of proteomes (\"proteomics\") in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology and medicine. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 µL of serum or plasma). Our current assay measures 813 proteins with low limits of detection (1 pM median), 7 logs of overall dynamic range (~100 fM-1 µM), and 5% median coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding signature of DNA aptamer concentrations, which is quantified on a DNA microarray. Our assay takes advantage of the dual nature of aptamers as both folded protein-binding entities with defined shapes and unique nucleotide sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to rapidly discover unique protein signatures characteristic of various disease states. We describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine.

A large body of literature details the deleterious effects of everyday discrimination on health, focusing on stress processes after discrimination occurs. In contrast, less work has investigated what occurs prior to encountering discrimination when a person expects it. Using a 10-day daily diary design, the current study examined predictors and outcomes of anticipated discrimination. Participants included 341 U.S. adults aged 19-74 years (29% racial minorities, 68% women). Multiple regression examined predictors of anticipated and reported discrimination. Further, two-level multilevel models evaluated anticipated discrimination predicting discrimination occurrence, appraisals, affect, and physical symptoms. Results showed that discrimination was anticipated on 21% of days; racial minorities and people with more prior exposure to discrimination anticipated more daily discrimination than White participants and those with lower prior exposure. People who anticipated discrimination more often than others reported more daily discrimination and perceived discrimination as more stressful but also perceived greater control over the events. They additionally had relatively larger upticks in physical symptoms on days when discrimination occurred-but no differences in discrimination-related affect-compared to people who anticipated discrimination less frequently. Within-persons, anticipating discrimination on a given day (versus not) was associated with greater likelihood of reporting discrimination occurred later that day and greater perceived stress severity, but no differences in perceived control, affect, or physical symptoms. In sum, anticipated discrimination was fairly common in daily life, and individual differences in anticipated discrimination were linked to more perceived daily discrimination, higher perceived stress severity, and more discrimination-related physical symptoms.