The corona contracts in a black-hole transient.

The geometry of the accretion flow around stellar-mass black holes can change on timescales of days to months1-3. When a black hole emerges from quiescence (that is, it 'turns on' after accreting material from its companion) it has a very hard (high-energy) X-ray spectrum produced by a hot corona4,5 positioned above its accretion disk, and then transitions to a soft (lower-energy) spectrum dominated by emission from the geometrically thin accretion disk, which extends to the innermost stable circular orbit6,7. Much debate persists over how this transition occurs and whether it is driven largely by a reduction in the truncation radius of the disk8,9 or by a reduction in the spatial extent of the corona10,11. Observations of X-ray reverberation lags in supermassive black-hole systems12,13 suggest that the corona is compact and that the disk extends nearly to the central black hole14,15. Observations of stellar-mass black holes, however, reveal equivalent (mass-scaled) reverberation lags that are much larger16, leading to the suggestion that the accretion disk in the hard-X-ray state of stellar-mass black holes is truncated at a few hundreds of gravitational radii from the black hole17,18. Here we report X-ray observations of the black-hole transient MAXI J1820+07019,20. We find that the reverberation time lags between the continuum-emitting corona and the irradiated accretion disk are 6 to 20 times shorter than previously seen. The timescale of the reverberation lags shortens by an order of magnitude over a period of weeks, whereas the shape of the broadened iron K emission line remains remarkably constant. This suggests a reduction in the spatial extent of the corona, rather than a change in the inner edge of the accretion disk.

Outcome and feasibility of radiotherapy bridging in large B-cell lymphoma patients receiving CD19 CAR T in the UK.

Radiotherapy (RT) has potential synergistic effects with chimeric antigen receptor (CAR) T but is not widely used as bridging therapy due to logistical challenges and lack of standardised protocols. We analysed RT bridging in a multicentre national cohort of large B-cell lymphoma patients approved for 3L axicabtagene ciloleucel or tisagenlecleucel across 12 UK centres. Of 763 approved patients, 722 were leukapheresed, 717 had data available on bridging therapy. 169/717 (24%) received RT bridging, 129 as single modality and 40 as combined modality treatment (CMT). Of 169 patients, 65.7% had advanced stage, 36.9% bulky disease, 86.5% elevated LDH, 41.7% international prognostic index (IPI) ≥3 and 15.2% double/triple hit at the time of approval. Use of RT bridging varied from 11% to 32% between centres and increased over time. Vein-to-vein time and infusion rate did not differ between bridging modalities. RT-bridged patients had favourable outcomes with 1-year progression-free survival (PFS) of 56% for single modality and 47% for CMT (1-year PFS 43% for systemic bridging). This is the largest cohort of LBCL patients receiving RT bridging prior to CAR T reported to date. Our results show that RT bridging can be safely and effectively used even in advanced stage and high-risk disease, with low dropout rates and excellent outcomes.

Did the UK's public health shielding policy protect the clinically extremely vulnerable during the COVID-19 pandemic in Wales? Results of EVITE Immunity, a linked data retrospective study.

INTRODUCTION: The UK shielding policy intended to protect people at the highest risk of harm from COVID-19 infection. We aimed to describe intervention effects in Wales at 1 year. METHODS: Retrospective comparison of linked demographic and clinical data for cohorts comprising people identified for shielding from 23 March to 21 May 2020; and the rest of the population. Health records were extracted with event dates between 23 March 2020 and 22 March 2021 for the comparator cohort and from the date of inclusion until 1 year later for the shielded cohort. RESULTS: The shielded cohort included 117,415 people, with 3,086,385 in the comparator cohort. The largest clinical categories in the shielded cohort were severe respiratory condition (35.5%), immunosuppressive therapy (25.9%) and cancer (18.6%). People in the shielded cohort were more likely to be female, aged ≥50 years, living in relatively deprived areas, care home residents and frail. The proportion of people tested for COVID-19 was higher in the shielded cohort (odds ratio [OR] 1.616; 95% confidence interval [CI] 1.597-1.637), with lower positivity rate incident rate ratios 0.716 (95% CI 0.697-0.736). The known infection rate was higher in the shielded cohort (5.9% vs 5.7%). People in the shielded cohort were more likely to die (OR 3.683; 95% CI: 3.583-3.786), have a critical care admission (OR 3.339; 95% CI: 3.111-3.583), hospital emergency admission (OR 2.883; 95% CI: 2.837-2.930), emergency department attendance (OR 1.893; 95% CI: 1.867-1.919) and common mental disorder (OR 1.762; 95% CI: 1.735-1.789). CONCLUSION: Deaths and healthcare utilisation were higher amongst shielded people than the general population, as would be expected in the sicker population. Differences in testing rates, deprivation and pre-existing health are potential confounders; however, lack of clear impact on infection rates raises questions about the success of shielding and indicates that further research is required to fully evaluate this national policy intervention.

Realist analysis of whether emergency departments with primary care services generate 'provider-induced demand'.

BACKGROUND: It is not known whether emergency departments (EDs) with primary care services influence demand for non-urgent care ('provider-induced demand'). We proposed that distinct primary care services in EDs encourages primary care demand, whereas primary care integrated within EDs may be less likely to cause additional demand. We aimed to explore this and explain contexts (C), mechanisms (M) and outcomes (O) influencing demand. METHODS: We used realist evaluation methodology and observed ED service delivery. Twenty-four patients and 106 staff members (including Clinical Directors and General Practitioners) were interviewed at 13 EDs in England and Wales (240 hours of observations across 30 days). Field notes from observations and interviews were analysed by creating 'CMO' configurations to develop and refine theories relating to drivers of demand. RESULTS: EDs with distinct primary care services were perceived to attract demand for primary care because services were visible, known or enabled direct access to health care services. Other influencing factors included patients' experiences of accessing primary care, community care capacity, service design and population characteristics. CONCLUSIONS: Patient, local-system and wider-system factors can contribute to additional demand at EDs that include primary care services. Our findings can inform service providers and policymakers in developing strategies to limit the effect of potential influences on additional demand when demand exceeds capacity.

Production performance and nitrogen metabolism in dairy cows fed supplemental blends of rumen undegradable protein and rumen-protected amino acids in low- compared with high-protein diets containing corn distillers grains.

Feeding corn dried distillers grains with solubles (DDGS) in low crude protein (CP) diets could limit N waste in lactating cows. However, it also could possibly reduce metabolizable AA supply, especially Lys, and compromise milk production. Therefore, the objective of this study was to evaluate the effects of feeding supplemental blends of rumen undegradable protein (RUP) and rumen-protected (RP) AA in a low compared with high CP diet containing corn DDGS on milk production and selected measures of N utilization. Six multiparous Holstein cows (619.3 ± 49.8 kg of body weight; 26.8 ± 6.2 d in milk) were subjected to a split-plot, 3 × 3 Latin square design (21-d periods) with dietary CP content [low (14.6%; LP) or high (16.6%; HP)] as the whole-plot factor, and blend of RUP and RP-AA [control (CON), no supplement; blend A (0.11 kg/cow per d); or blend B (0.45 kg/cow per d)] as the sub-plot factor. All diets contained 10% corn DDGS; blends of RUP and RP-AA were top-dressed during morning feeding. There was no dietary CP content × supplemental blend interaction for all measured variables. Nutrient (dry matter, organic matter, neutral detergent fiber, acid detergent fiber, and CP), milk and milk component yields, and feed and apparent N efficiency did not differ for cows fed the low- compared with the high-protein diet. However, apparent total-tract CP digestibility, blood and milk urea-N concentrations, and urinary excretion (g/d) of N and urea-N were lower for cows fed the low-protein compared with the high-protein diet. There was no supplemental blend effect on nutrient intake and apparent total-tract digestibility, and milk and milk component yields. Except for a tendency for total urinary purine derivative excretion and microbial N flow to be lower for cows fed blend B compared with CON but not blend A, there was no supplemental blend effect on measures of N utilization. Both dietary CP content and supplemental blend of RUP and RP-AA had a marginal effect on the plasma free AA profile. In summary, reducing dietary CP content in diets containing corn DDGS had no effect on lactation performance, possibly accounting for the lack of a positive response following the provision of supplemental blends of RUP and RP-AA. However, reducing dietary CP content resulted in a decrease in blood and milk urea-N concentrations, and urinary excretion of N and urea-N, suggestive of an improvement in the efficiency of N use.

Mortality risk among women exposed to violence in Brazil: a population-based exploratory analysis.

OBJECTIVES: The objective of this study was to estimate mortality risk among women exposed to violence in Brazil using population-based data. STUDY DESIGN: This study used a linked database containing nearly 800,000 violence (against women) notifications and 16,500 associated deaths over the period 2011-2016. METHODS: Aggregate age-standardized population-based rates of mortality were built to estimate risk ratios (RRs) at the national and state level, and for different forms of violence and causes of death, as well as type of offender involved, and across various characteristics of the women. RRs compared the rate of mortality among women exposed to violence with that in the general population of women - excess mortality due to violence was also derived from this comparison. The analysis was divided into two time periods (2011-13 and 2014-16). RESULTS: During 2014-16, women exposed to violence had an estimated mortality risk that was 8.3 [95% confidence interval (CI): 8.2-8.5] times higher than that of the general woman population, and an estimated 100 women died on a weekly basis as a direct or indirect consequence of exposure to violence. Higher (all-cause) mortality risk was associated with physical violence and violence that involved repetition and that was self-inflicted. The risk of mortality increased when the cause of death involved external causes (RR: 51.2, 95% CI: 49.6-52.8). When death was attributable to (i) non-communicable diseases and (ii) communicable, maternal, neonatal, and nutritional diseases, the risk was 5.4 [95% CI: 5.3-5.6] and 6.7 [95% CI: 6.1-7.2] times, respectively. Women at greatest (all-cause) mortality risk include white and multiracial (parda) and single women in the age group 10-29 years, who live in the northeast part of the country. When the offender was a partner/ex., women aged 10-19 years showed the greatest (all-cause) mortality risk at 16.9 [95% CI: 13.9-19.8] times. Higher risk was also observed within the age group 30-59 years when death was attributable to external causes (RR: 74.6, 95% CI: 71.3-77.9). For younger women and girls, there was a clear gradient in (all-cause) mortality risk, with those living in the poorest municipalities at greater risk. Age-specific mortality risk also showed significant variation within and across states. CONCLUSIONS: This analysis suggests that most women exposed to violence will likely experience an increased risk of mortality, regardless of her place of residence, age group, racial/ethnic background, marital status situation, and socio-economic status. The estimated RRs are only an approximation given the design of this analysis and should be interpreted with caution.

[A protocol for light therapy in bipolar disorder]. / Protocol voor lichttherapie bij bipolaire stoornis.

BACKGROUND: There is no national protocol for the use of light therapy in bipolar depression.
AIM: The chronotherapy collaboration group of the Foundation for Bipolar Disorders intended to write a protocol for light therapy in bipolar depressive episodes.
METHOD: Narrative review of several systematic reviews, two clinician's guides and deliberation with the sub-commission Guidelines of the Dutch Ophthalmologic Society.
RESULTS: The following indication was established: depressive episode, with or without seasonal features, in bipolar I or II disorder, including subsyndromal (depressive) seasonal complaints. The list of relative contra-indications (pre-existent retinal illnesses, systemic illnesses with effect on the retina and use of photosensitive medication) was shortened. In this case the medical professional discusses the possibility of an ophthalmologic consultation with the patient. Use of a mood stabilizer/antimanic medication in order to prevent mania or a mixed episode is only necessary in a depressive episode in bipolar I, but not in bipolar II disorder. Standard treatment is 10.000 lux white light during 30 minutes in the morning.
CONCLUSION: There is sufficient evidence to propose light therapy in a bipolar depressive episode with or without seasonal features.

Systems based analysis of human embryos and gene networks involved in cell lineage allocation.

BACKGROUND: Little is understood of the molecular mechanisms involved in the earliest cell fate decision in human development, leading to the establishment of the trophectoderm (TE) and inner cell mass (ICM) stem cell population. Notably, there is a lack of understanding of how transcriptional networks arise during reorganisation of the embryonic genome post-fertilisation. RESULTS: We identified a hierarchical structure of preimplantation gene network modules around the time of embryonic genome activation (EGA). Using network models along with eukaryotic initiation factor (EIF) and epigenetic-associated gene expression we defined two sets of blastomeres that exhibited diverging tendencies towards ICM or TE. Analysis of the developmental networks demonstrated stage specific EIF expression and revealed that histone modifications may be an important epigenetic regulatory mechanism in preimplantation human embryos. Comparison to published RNAseq data confirmed that during EGA the individual 8-cell blastomeres are transcriptionally primed for the first lineage decision in development towards ICM or TE. CONCLUSIONS: Using multiple systems biology approaches to compare developmental stages in the early human embryo with single cell transcript data from blastomeres, we have shown that blastomeres considered to be totipotent are not transcriptionally equivalent. Furthermore we have linked the developmental interactome to individual blastomeres and to later cell lineage. This has clinical implications for understanding the impact of fertility treatments and developmental programming of long term health.

Study protocol of a multicenter randomized controlled trial of mindfulness-based cognitive therapy and treatment as usual in bipolar disorder.

BACKGROUND: Despite multiple pharmacological interventions, many people with bipolar disorder (BD) experience substantial residual mood symptoms, even in the absence of severe mood episodes, which have a negative impact on the course of illness and quality of life. Limited data are available on how to optimize treatment for BD, especially for those who suffer from persistent and residual depressive symptoms. Preliminary evidence suggests Mindfulness-Based Cognitive Therapy (MBCT) as a psychological treatment option for BD. This study aims to investigate whether adding MBCT to treatment as usual (TAU) will result in symptomatic and functional improvements in adults with BD compared to TAU alone. METHODS/DESIGN: This study is a prospective, evaluator blinded, multicenter, randomized controlled trial of MBCT + TAU and TAU alone in 160 adults with bipolar type I and type II. Assessments will be conducted at baseline (T0), mid-treatment (Tmid), and at 3 (T1), 6 (T2), 9 (T3), 12 (T4), and 15 (T5) months follow-up. Primary outcome is post-treatment severity of depressive symptoms (Inventory of Depressive Symptomatology- Clinician administered). Secondary outcomes are severity of (hypo) manic symptoms, anxiety, relapse rates, overall functioning, positive mental health, and cost-effectiveness. As possible mediators will be assessed rumination of negative affect, dampening and rumination of positive affect, mindfulness skills, and self-compassion. DISCUSSION: This study will provide valuable insight into the (cost-)effectiveness of MBCT on clinician- and self-rated symptoms of BD, relapse rates, positive mental health, and overall functioning. TRIAL REGISTRATION: NCT03507647 . Registered 25th of April 2018.

Optical pupillometry in traumatic brain injury: neurological pupil index and its relationship with intracranial pressure through significant event analysis.

Primary Objective: Treatment paradigms for traumatic brain injury (TBI) rely on invasive monitoring of intracranial pressure (ICP) for planning intervention. Optical pupillometry is a non-invasive, objective monitoring method, measuring parameters of pupillary response and displaying a scalar value - a neurological pupil index (NPi). An impaired response on NPi has been tentatively correlated with ICP, through analysis of mean/peak NPi and ICP readings. We sought to evaluate this relationship more closely. Research Design: Prospective observational. Methods and Procedures: We obtained hourly pupillometry readings, alongside ICP values, from 40 patients with TBI requiring invasive ICP monitoring. Significant events were identified for analysis based on the significant aberration of ICP or NPi. Main Outcomes and Results: On average, individuals experienced a few significant events. There was a weak relationship between ICP events and a preceding NPi event. The results show that there is a weak but statistically insignificant relationship between NPi and ICP, where reduced pupil reactivity may indicate a raised ICP. The strength of this trend appears to diminish post-decompressive surgery. Conclusions: Whilst pupillometry may not be a reliable surrogate marker for ICP, NPi may still prove to be a useful tool in a multimodal prognostic assessment of the patient with acute brain injury.

Switch from BAK-preserved to preservative-free latanoprost decreases anterior chamber flare in POAG patients.

PURPOSE: To validate the hypothesis that BAK induces low-grade inflammation in the anterior chamber, we designed a study to investigate whether switching from BAK-preserved to preservative-free latanoprost in patients with primary open-angle glaucoma (POAG) would reduce the flare levels. PATIENTS: Forty-one eyes of twenty-two patients with primary open-angle glaucoma treated with BAK-preserved latanoprost for at least 6 months as monotherapy were included. Exclusion criteria included any use of topical eye drops other than latanoprost, pseudoexfoliation and pigment dispersion glaucoma, wearing of contact lenses and intraocular surgery in the past year. METHODS: At the start of the study, we measured baseline flare values. We then switched all patients to preservative-free latanoprost. After 1, 2, and 3 months, a routine ophthalmological examination was performed and flare measurement repeated. RESULTS: Thirty-three eyes were followed up throughout the entire 3-month period. One month after the switch to preservative-free latanoprost, a statistically significant mean drop in flare of - 0.96 ph/ms (P = 0.025) was observed. Mean flare decreased further by - 1.31 ph/ms (P = 0.0027) after 2 months and by - 1.25 ph/ms (P = 0.0041) after 3 months. CONCLUSION: The switch from BAK-preserved to preservative-free latanoprost induced a statistically significant reduction in mean flare value. Whereas our previous study showed an increase in flare when initiating treatment with BAK-preserved eye drops, this study shows a decrease in flare upon cessation of BAK-preserved drugs. The combined evidence from the two studies strongly suggests that in humans BAK exerts its effects not only on the ocular surface, but also at the level of the anterior chamber.

Folate supplementation to prevent birth abnormalities: evaluating a community-based participatory action plan for refugees and migrant workers on the Thailand-Myanmar border.

OBJECTIVES: Preconception folic acid (PFA) taken at least 3 months before conception can decrease the incidence of neural tube defects (NTDs) by approximately 46%. NTDs contribute significantly to neonatal morbidity and mortality in migrant and refugee populations on the Thailand-Myanmar border (incidence 1.57/1000 live births). This audit aimed to assess uptake of PFA among migrant and refugee women, evaluate knowledge about PFA among local healthcare workers and implement a participatory community intervention to increase PFA uptake and decrease NTD incidence in this population. STUDY DESIGN: A mixed-methods baseline evaluation was followed by an intervention involving health worker education and a community outreach program. A follow-up audit was performed 18 months post-intervention. METHODS: Data were gathered via surveys, short interviews and focus group discussions. The intervention program included community-based workshops, production and distribution of printed flyers and posters, and outreach to various local organisations. RESULTS: Uptake of PFA was <2% both before and after the intervention. Despite a substantial increase in local healthcare worker knowledge of PFA, no significant improvement in PFA uptake after the intervention was detected. Most pregnancies in this local community sample were reported to be unplanned. CONCLUSIONS: High rates of NTDs with low PFA uptake remains a major public health challenge in this transient population. Results indicate that improved health worker knowledge alone is not sufficient to enhance PFA uptake in this population. Integration of PFA education within expanded family planning programs and broad-based food fortification may be more effective.

Directed Change in TNFα Specificity to Create DR5 Antagonists.

Death receptor 5 (DR5) is a promising target for antitumor therapy due to its high expression on different tumor cells. Resistance of various tumor cells against TRAIL, a natural ligand for the death receptors, reduces its therapeutic potential and prompts the search for novel agonists at these receptors. Previous screening across the combinatorial peptide library yielded a peptide sequence KVVLTHR that specifically binds DR5. Incorporation of this sequence into TNFα resulted in binding DR5 with mutant protein TNFα-mut and appearance of cytotoxicity against lymphoma cells.

High-resolution magnetic resonance imaging reveals nuclei of the human amygdala: manual segmentation to automatic atlas.

The amygdala is composed of multiple nuclei with unique functions and connections in the limbic system and to the rest of the brain. However, standard in vivo neuroimaging tools to automatically delineate the amygdala into its multiple nuclei are still rare. By scanning postmortem specimens at high resolution (100-150µm) at 7T field strength (n = 10), we were able to visualize and label nine amygdala nuclei (anterior amygdaloid, cortico-amygdaloid transition area; basal, lateral, accessory basal, central, cortical medial, paralaminar nuclei). We created an atlas from these labels using a recently developed atlas building algorithm based on Bayesian inference. This atlas, which will be released as part of FreeSurfer, can be used to automatically segment nine amygdala nuclei from a standard resolution structural MR image. We applied this atlas to two publicly available datasets (ADNI and ABIDE) with standard resolution T1 data, used individual volumetric data of the amygdala nuclei as the measure and found that our atlas i) discriminates between Alzheimer's disease participants and age-matched control participants with 84% accuracy (AUC=0.915), and ii) discriminates between individuals with autism and age-, sex- and IQ-matched neurotypically developed control participants with 59.5% accuracy (AUC=0.59). For both datasets, the new ex vivo atlas significantly outperformed (all p < .05) estimations of the whole amygdala derived from the segmentation in FreeSurfer 5.1 (ADNI: 75%, ABIDE: 54% accuracy), as well as classification based on whole amygdala volume (using the sum of all amygdala nuclei volumes; ADNI: 81%, ABIDE: 55% accuracy). This new atlas and the segmentation tools that utilize it will provide neuroimaging researchers with the ability to explore the function and connectivity of the human amygdala nuclei with unprecedented detail in healthy adults as well as those with neurodevelopmental and neurodegenerative disorders.

A systematic review of the analgesic efficacy of cannabinoid medications in the management of acute pain.

BACKGROUND: Cannabinergic medications have been postulated to demonstrate efficacy in the management of pain. The aim of this systematic review was to assess the analgesic efficacy and adverse effects of cannabinoids when used for the management of acute pain. METHODS: A systematic review was performed by searching the MEDLINE, EMBASE and CENTRAL databases, and the World Health Organization International Clinical Trials Registry Platform for human randomized controlled trials that assessed the analgesic efficacy of cannabinoids compared to placebo or active comparators. The reported outcomes for analgesic efficacy and adverse effects in included studies were qualitatively analysed. RESULTS: Seven studies, including 611 patients were included in the systematic review. In five studies, cannabinoids were found to provide equivalent analgesia to placebo, in one study the analgesia provided by cannabinoids was superior to placebo, and in one study cannabinoids provided analgesia that was inferior to that provided by placebo. No synergistic or additive analgesic effect was observed when cannabinoids were used in combination with opioids. In five of the seven studies, certain adverse effects were more frequent with cannabinoid treatment than with placebo or active comparator. CONCLUSION: On the basis of the available randomized controlled trial evidence, cannabinoids have no role in the management of acute pain.

Effect of summer daylight exposure and genetic background on growth in growth hormone-deficient children.

The response to growth hormone in humans is dependent on phenotypic, genetic and environmental factors. The present study in children with growth hormone deficiency (GHD) collected worldwide characterised gene-environment interactions on growth response to recombinant human growth hormone (r-hGH). Growth responses in children are linked to latitude, and we found that a correlate of latitude, summer daylight exposure (SDE), was a key environmental factor related to growth response to r-hGH. In turn growth response was determined by an interaction between both SDE and genes known to affect growth response to r-hGH. In addition, analysis of associated networks of gene expression implicated a role for circadian clock pathways and specifically the developmental transcription factor NANOG. This work provides the first observation of gene-environment interactions in children treated with r-hGH.

High educational performance is a distinctive feature of bipolar disorder: a study on cognition in bipolar disorder, schizophrenia patients, relatives and controls.

BACKGROUND: Schizophrenia is associated with lower intelligence and poor educational performance relative to the general population. This is, to a lesser degree, also found in first-degree relatives of schizophrenia patients. It is unclear whether bipolar disorder I (BD-I) patients and their relatives have similar lower intellectual and educational performance as that observed in schizophrenia. METHOD: This cross-sectional study investigated intelligence and educational performance in two outpatient samples [494 BD-I patients, 952 schizophrenia spectrum (SCZ) patients], 2231 relatives of BD-I and SCZ patients, 1104 healthy controls and 100 control siblings. Mixed-effects and regression models were used to compare groups on intelligence and educational performance. RESULTS: BD-I patients were more likely to have completed the highest level of education (odds ratio 1.88, 95% confidence interval 1.66-2.70) despite having a lower IQ compared to controls (ß = -9.09, S.E. = 1.27, p < 0.001). In contrast, SCZ patients showed both a lower IQ (ß = -15.31, S.E. = 0.86, p < 0.001) and lower educational levels compared to controls. Siblings of both patient groups had significantly lower IQ than control siblings, but did not differ on educational performance. IQ scores did not differ between BD-I parents and SCZ parents, but BD-I parents had completed higher educational levels. CONCLUSIONS: Although BD-I patients had a lower IQ than controls, they were more likely to have completed the highest level of education. This contrasts with SCZ patients, who showed both intellectual and educational deficits compared to healthy controls. Since relatives of BD-I patients did not demonstrate superior educational performance, our data suggest that high educational performance may be a distinctive feature of bipolar disorder patients.

Evidence that small molecule enhancement of ß-hexosaminidase activity corrects the behavioral phenotype in Dutch APP(E693Q) mice through reduction of ganglioside-bound Aß.

Certain mutant Alzheimer's amyloid-ß (Aß) peptides (that is, Dutch mutant APP(E693Q)) form complexes with gangliosides (GAß). These mutant Aß peptides may also undergo accelerated aggregation and accumulation upon exposure to GM2 and GM3. We hypothesized that increasing ß-hexosaminidase (ß-hex) activity would lead to a reduction in GM2 levels, which in turn, would cause a reduction in Aß aggregation and accumulation. The small molecule OT1001 is a ß-hex-targeted pharmacological chaperone with good bioavailability, blood-brain barrier penetration, high selectivity for ß-hex and low cytotoxicity. Dutch APP(E693Q) transgenic mice accumulate oligomeric Aß as they age, as well as Aß oligomer-dose-dependent anxiety and impaired novel object recognition (NOR). Treatment of Dutch APP(E693Q) mice with OT1001 caused a dose-dependent increase in brain ß-hex levels up to threefold over those observed at baseline. OT1001 treatment was associated with reduced anxiety, improved learning behavior in the NOR task and dramatically reduced GAß accumulation in the subiculum and perirhinal cortex, both of which are brain regions required for normal NOR. Pharmacological chaperones that increase ß-hex activity may be useful in reducing accumulation of certain mutant species of Aß and in preventing the associated behavioral pathology.

Sex differences in elite swimming with advanced age are less than marathon running.

The sex difference in marathon performance increases with finishing place and age of the runner but whether this occurs among swimmers is unknown. The purpose was to compare sex differences in swimming velocity across world record place (1st-10th), age group (25-89 years), and event distance. We also compared sex differences between freestyle swimming and marathon running. The world's top 10 swimming times of both sexes for World Championship freestyle stroke, backstroke, breaststroke, and butterfly events and the world's top 10 marathon times in 5-year age groups were obtained. Men were faster than women for freestyle (12.4 ± 4.2%), backstroke (12.8 ± 3.0%), and breaststroke (14.5 ± 3.2%), with the greatest sex differences for butterfly (16.7 ± 5.5%). The sex difference in swimming velocity increased across world record place for freestyle (P < 0.001), breaststroke, and butterfly for all age groups and distances (P < 0.001) because of a greater relative drop-off between first and 10th place for women. The sex difference in marathon running increased with the world record place and the sex difference for marathon running was greater than for swimming (P < 0.001). The sex difference in swimming increased with world record place and age, but was less than for marathon running. Collectively, these results suggest more depth in women's swimming than marathon running.