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Meta‐analyses showed that non‐dipping of nocturnal blood pressure on ambulatory blood pressure monitoring (ABPM) was associated with adverse cardiovascular prognosis. However, these prognostic studies were mainly conducted in Caucasian and Japanese populations. Whether this association applies to Chinese patients remained uninvestigated. A total of 1199 Chinese patients with hypertension undergoing ABPM between January 2012 and December 2014 were recruited retrospectively from five public hypertension referral clinics in Hong Kong. Patients were followed up for a mean 6.42 years for cardiovascular morbidity and mortality and all‐cause mortality. Time to event of different dipping patterns was compared by Kaplan‐Meier curves. Hazard ratios (HR) were obtained by Cox proportional hazard models with patient demographics and confounding factors adjusted in multivariate regression. A total of 163 end point events occurred in the period. Normal dipping was observed in 446 patients (37.2%), non‐dipping in 490 (40.9%), reverse dipping in 161 (13.4%), and extreme dipping in 102 (8.5%). Kaplan‐Meier analyses showed inferior survival in non‐dippers and reverse dippers for total cardiovascular events and coronary events but not cerebrovascular events. After adjusting for confounding factors, Cox regressions showed HRs 1.166 (CI 0.770‐1.764) and 1.173 (CI 0.681‐2.021) in non‐dippers and reverse dippers for total cardiovascular events, and HRs 1.320 (CI 0.814‐2.141) and 1.476 (CI 0.783‐2.784) for coronary events. Nocturnal blood pressure non‐dipping, and to a greater extent reverse dipping, demonstrated adverse cardiovascular prognosis in a cohort of Chinese patients with hypertension in Hong Kong. Further focused studies on cerebrovascular events and reverse dippers were warranted to refine risk stratification.

Antibody (Ab)-dependent and-independent activation of the duck complement (C') system were studied. Ab-independent C' activity exhibited characteristics similar to those of the mammalian alternative C' pathway (ACP), including the selective lysis of rabbit erythrocytes (RRBC), a requirement for Mg2+, but not Ca2+, depletion of activity by zymosan, and lack of sensitivity to the mammalian C1 inhibitor carrageenan. Measurement of C' activity using antisera against sheep erythrocytes (SRBC) revealed that duck Abs activate C' by a pathway resembling the mammalian classical pathway (CCP) requiring both Ca2+ and Mg2+. Ab-dependent and-independent activities were further distinguishable by their kinetics of lysis and sensitivities to heat. Duck Abs were also found to activate C' in normal and carrageenantreated serum by a mechanism that requires only Mg2+, and thus resembles the ACP. However, this Ab-dependent ACP-like activity exhibits patterns of ionic strength dependence and ontogeny which are clearly different from those of the conventional ACP and CCP. These findings indicate that duck C' can be activated by three mechanisms: Ab-mediated activation of the CCP, and Ab-mediated and Ab-independent activation of the ACP. Duck Ab responses to SRBC and RRBC were followed by direct agglutination, antiglobulin agglutination, and activation of the CCP and ACP. While the C' -activating abilities of duck anti-SRBC Abs persisted through a 3-month programme of inoculation, the anti-RRBC response lost its ability to activate C' after 2 weeks.

Breast cancer is the most common cancer in reproductive age women. The aim of this study is to assess the knowledge, attitude and intention on fertility preservation among women diagnosed to have breast cancer. This is a multi-centre cross-sectional questionnaire study. Reproductive age women diagnosed with breast cancer attending Oncology, Breast Surgery and Gynaecology Clinics and support groups were invited to participate. Women filled in paper or electronic form of the questionnaire. 461 women were recruited and 421 women returned the questionnaire. Overall, 181/410 (44.1%) women had heard of fertility preservation. Younger age and higher education level were significantly associated with increased awareness of fertility preservation . Awareness and acceptance of the different fertility preservation methods in reproductive age women with breast cancer was suboptimal. However, 46.1% women felt that their fertility concerns affected their decision for cancer treatment in some way.

Recurrent urinary tract infections (rUTIs) are extremely common, with ~ 25% of all women experiencing a recurrence within 1 year of their original infection. Escherichia coli ST131 is a globally dominant multidrug resistant clone associated with high rates of rUTI. Here, we show the dynamics of an ST131 population over a 5-year period from one elderly woman with rUTI since the 1970s. Using whole genome sequencing, we identify an indigenous clonal lineage (P1A) linked to rUTI and persistence in the fecal flora, providing compelling evidence of an intestinal reservoir of rUTI. We also show that the P1A lineage possesses substantial plasmid diversity, resulting in the coexistence of antibiotic resistant and sensitive intestinal isolates despite frequent treatment. Our longitudinal study provides a unique comprehensive genomic analysis of a clonal lineage within a single individual and suggests a population-wide resistance mechanism enabling rapid adaptation to fluctuating antibiotic exposure. Recurrent urinary tract infections occur in ~ 25% of women. Here, Beatson and colleagues use whole genome sequencing to track the dynamics of an E. coli ST131 clone in a single patient over a 5-year period. This study provides unique insights into pathogen evolution during recurrent urinary infection.

Dysregulation of vascular stiffness and cellular metabolism occurs early in pulmonary hypertension (PH). However, the mechanisms by which biophysical properties of the vascular extracellular matrix (ECM) relate to metabolic processes important in PH remain undefined. In this work, we examined cultured pulmonary vascular cells and various types of PH-diseased lung tissue and determined that ECM stiffening resulted in mechanoactivation of the transcriptional coactivators YAP and TAZ (WWTR1). YAP/TAZ activation modulated metabolic enzymes, including glutaminase (GLS1), to coordinate glutaminolysis and glycolysis. Glutaminolysis, an anaplerotic pathway, replenished aspartate for anabolic biosynthesis, which was critical for sustaining proliferation and migration within stiff ECM. In vitro, GLS1 inhibition blocked aspartate production and reprogrammed cellular proliferation pathways, while application of aspartate restored proliferation. In the monocrotaline rat model of PH, pharmacologic modulation of pulmonary vascular stiffness and YAP-dependent mechanotransduction altered glutaminolysis, pulmonary vascular proliferation, and manifestations of PH. Additionally, pharmacologic targeting of GLS1 in this model ameliorated disease progression. Notably, evaluation of simian immunodeficiency virus-infected nonhuman primates and HIV-infected subjects revealed a correlation between YAP/TAZ-GLS activation and PH. These results indicate that ECM stiffening sustains vascular cell growth and migration through YAP/TAZ-dependent glutaminolysis and anaplerosis, and thereby link mechanical stimuli to dysregulated vascular metabolism. Furthermore, this study identifies potential metabolic drug targets for therapeutic development in PH.

This cross-sectional study aimed to compare the change in spinal posture, mechanical stiffness, and motor control of the thoracolumbar spine in individuals who were asymptomatic and those with chronic nonspecific low back pain (LBP) of flexion pattern (FP) or active extension pattern (AEP) during pushing and pulling tasks performed in standing. The real-time thoracolumbar posture, mechanical stiffness, electromyographic amplitude and synergy between specified trunk muscle pairs (Internal Oblique and Multifidus, Rectus Abdominis and Erector Spinae, Internal Oblique and Rectus Abdominis, Multifidus and Erector Spinae) were analysed during quiet standing, standing pushing and pulling tasks against a load standardized at 15% of the individual body weight in a total of 39 individuals (asymptomatic, n = 14; FP, n = 11; AEP, n = 14). Pulling task resulted in greater lumbar posterior translation ( p  = 0.009) and Rectus Abdominis activity ( p  = 0.006), but smaller lumbar lordosis ( p  < 0.001) when compared to pushing task. Pulling task also resulted smaller lumbar lordosis ( p  < 0.001) and thoracic kyphosis ( p  = 0.003) comparing to upright standing. AEP group showed a significantly greater amplitude of their Internal Oblique activity when compared to those who were asymptomatic across all tasks ( p  = 0.001). Findings suggested that pulling manoeuvre in standing produced greater shear at the lumbar spine than that of pushing manoeuvre. Individuals with low back pain executed the low-load push/pull tasks with the motor strategy largely comparable to asymptomatic group. Future studies investigating the cumulative effect of repetitive push/pull loadings on the movement and motor control of the spine are warranted to better understand the long-term impacts on spinal health.

Mutations in IDH1 and IDH2 (encoding isocitrate dehydrogenase 1 and 2) drive the development of gliomas and other human malignancies. Mutant IDH1 induces epigenetic changes that promote tumorigenesis, but the scale and reversibility of these changes are unknown. Here, using human astrocyte and glioma tumorsphere systems, we generate a large-scale atlas of mutant-IDH1-induced epigenomic reprogramming. We characterize the reversibility of the alterations in DNA methylation, the histone landscape, and transcriptional reprogramming that occur following IDH1 mutation. We discover genome-wide coordinate changes in the localization and intensity of multiple histone marks and chromatin states. Mutant IDH1 establishes a CD24 + population with a proliferative advantage and stem-like transcriptional features. Strikingly, prolonged exposure to mutant IDH1 results in irreversible genomic and epigenetic alterations. Together, these observations provide unprecedented high-resolution molecular portraits of mutant-IDH1-dependent epigenomic reprogramming. These findings have substantial implications for understanding of mutant IDH function and for optimizing therapeutic approaches to targeting IDH-mutant tumors. This study uses human astrocytes and glioma tumorspheres to generate an atlas of mutant-IDH1-induced epigenomic reprogramming. The findings have implications for understanding mutant IDH function and for optimizing approaches to target IDH-mutant tumors.

The identification of autoantigens remains a critical challenge for understanding and treating autoimmune diseases. Autoimmune polyendocrine syndrome type 1 (APS1), a rare monogenic form of autoimmunity, presents as widespread autoimmunity with T and B cell responses to multiple organs. Importantly, autoantibody discovery in APS1 can illuminate fundamental disease pathogenesis, and many of the antigens found in APS1 extend to more common autoimmune diseases. Here, we performed proteome-wide programmable phage-display (PhIP-Seq) on sera from a cohort of people with APS1 and discovered multiple common antibody targets. These novel APS1 autoantigens exhibit tissue-restricted expression, including expression in enteroendocrine cells, pineal gland, and dental enamel. Using detailed clinical phenotyping, we find novel associations between autoantibodies and organ-restricted autoimmunity, including a link between anti-KHDC3L autoantibodies and premature ovarian insufficiency, and between anti-RFX6 autoantibodies and diarrheal-type intestinal dysfunction. Our study highlights the utility of PhIP-Seq for extensively interrogating antigenic repertoires in human autoimmunity and the importance of antigen discovery for improved understanding of disease mechanisms. The immune system uses antibodies to fight microbes that cause disease. White blood cells pump antibodies into the bloodstream, and these antibodies latch onto bacteria and viruses, targeting them for destruction. But sometimes, the immune system gets it wrong. In autoimmune diseases, white blood cells mistakenly make antibodies that target the body's own tissues. Detecting these 'autoantibodies' in the blood can help doctors to diagnose autoimmune diseases. But the identities and targets of many autoantibodies remain unknown. In one rare disease, called autoimmune polyendocrine syndrome type 1 (APS-1), a faulty gene makes the immune system much more likely to make autoantibodies. People with this disease can develop an autoimmune response against many different healthy organs. Although APS-1 is rare, some of the autoantibodies made by individuals with the disease are the same as the ones in more common autoimmune diseases, like type 1 diabetes. Therefore, investigating the other autoantibodies produced by individuals with APS-1 could reveal the autoantibodies driving other autoimmune diseases. Autoantibodies bind to specific regions of healthy proteins, and one way to identify them is to use hundreds of thousands of tiny viruses in a technique called proteome-wide programmable phage-display, or PhIP-Seq. Each phage carries one type of protein segment. When mixed with blood serum from a patient, the autoantibodies stick to the phages that carry the target proteins for that autoantibody. These complexes can be isolated using biochemical techniques. Sequencing the genes of these phages then reveals the identity of the autoantibodies’ targets. Using this technique, Vazquez et al successfully pulled 23 known autoantibodies from the serum of patients with APS-1. Then, experiments to search for new targets began. This revealed many new autoantibodies, targeting proteins found only in specific tissues. They included one that targets a protein found on cells in the gut, and another that targets a protein found on egg cells in the ovaries. Matching the PhIP-Seq data to patient symptoms confirmed that these new antibodies correlate with the features of specific autoimmune diseases. For example, patients with antibodies that targeted the gut protein were more likely to have gut symptoms, while patients with antibodies that targeted the egg cell protein were more likely to have problems with their ovaries. Further investigations using PhIP-Seq could reveal the identities of even more autoantibodies. This might pave the way for new antibody tests to diagnose autoimmune diseases and identify tissues at risk of damage. This could be useful not only for people with APS-1, but also for more common autoimmune diseases that target the same organs.

The Human Proteome Organization (HUPO) launched the Human Proteome Project (HPP) in 2010, creating an international framework for global collaboration, data sharing, quality assurance and enhancing accurate annotation of the genome-encoded proteome. During the subsequent decade, the HPP established collaborations, developed guidelines and metrics, and undertook reanalysis of previously deposited community data, continuously increasing the coverage of the human proteome. On the occasion of the HPP’s tenth anniversary, we here report a 90.4% complete high-stringency human proteome blueprint. This knowledge is essential for discerning molecular processes in health and disease, as we demonstrate by highlighting potential roles the human proteome plays in our understanding, diagnosis and treatment of cancers, cardiovascular and infectious diseases. The Human Proteome Project (HPP) was launched in 2010 to enhance accurate annotation of the genome-encoded proteome. Ten years later, the HPP releases its first blueprint of the human proteome, annotating 90% of all known proteins at high-stringency and discussing the implications of proteomics for precision medicine.

Background MedSense is an electronic hand hygiene compliance monitoring system that provides Infection Control Practitioners with continuous access to hand hygiene compliance information by monitoring Moments 1 and 4 of the WHO \"My 5 Moments for Hand Hygiene\" guidelines. Unlike previous electronic monitoring systems, MedSense operates in open cubicles with multiple beds and does not disrupt existing workflows. Methods This study was conducted in a 6-bed neurosurgical intensive care unit with technical development and evaluation phases. Healthcare workers (HCWs) wore an electronic device in the style of an identity badge to detect hand hygiene opportunities and compliance. We compared the compliance determined by the system and an infection control nurse. At the same time, the system assessed compliance by time of day, day of week, work shift, professional category of HCWs, and individual subject, while the workload of HCWs was monitored by measuring the amount of time they spent in patient zones. Results During the three-month evaluation phase, the system identified 13,694 hand hygiene opportunities from 17 nurses, 3 physiotherapists, and 1 healthcare assistant, resulting in an overall compliance of 35.1% for the unit. The per-indication compliance for Moment 1, 4, and simultaneous 1 and 4 were 21.3% (95%CI: 19.0, 23.6), 39.6% (95%CI: 37.3, 41.9), and 49.2% (95%CI: 46.6, 51.8), respectively, and were all statistically significantly different (p < 0.001). In the four 20-minute sessions when hand hygiene was monitored concurrently by the system and infection control nurse, the compliance were 88.9% and 95.6% respectively (p = 0.34), and the activity indices were 11.1 and 12.9 opportunities per hour, respectively. The hours from 12:00 to 14:00 had a notably lower compliance (21.3%, 95%CI: 17.2, 25.3) than nearly three quarters of the other periods of the day (p < 0.001). Nurses who used shared badges had significantly (p < 0.01) lower compliance (23.7%, 95%CI: 17.8, 29.6) than both the registered nurses (36.1%, 95%CI: 34.2, 37.9) and nursing officers (34.0%, 95%CI: 31.1, 36.9) who used named badges. Conclusion MedSense provides an unobtrusive and objective measurement of hand hygiene compliance. The information is important for staff training by the infection control team and allocation of manpower by hospital administration.