A multi-population phenome-wide association study of genetically-predicted height in the Million Veteran Program.

BACKGROUND: Height has been associated with many clinical traits but whether such associations are causal versus secondary to confounding remains unclear in many cases. To systematically examine this question, we performed a Mendelian Randomization-Phenome-wide association study (MR-PheWAS) using clinical and genetic data from a national healthcare system biobank. METHODS AND FINDINGS: Analyses were performed using data from the US Veterans Affairs (VA) Million Veteran Program in non-Hispanic White (EA, n = 222,300) and non-Hispanic Black (AA, n = 58,151) adults in the US. We estimated height genetic risk based on 3290 height-associated variants from a recent European-ancestry genome-wide meta-analysis. We compared associations of measured and genetically-predicted height with phenome-wide traits derived from the VA electronic health record, adjusting for age, sex, and genetic principal components. We found 345 clinical traits associated with measured height in EA and an additional 17 in AA. Of these, 127 were associated with genetically-predicted height at phenome-wide significance in EA and 2 in AA. These associations were largely independent from body mass index. We confirmed several previously described MR associations between height and cardiovascular disease traits such as hypertension, hyperlipidemia, coronary heart disease (CHD), and atrial fibrillation, and further uncovered MR associations with venous circulatory disorders and peripheral neuropathy in the presence and absence of diabetes. As a number of traits associated with genetically-predicted height frequently co-occur with CHD, we evaluated effect modification by CHD status of genetically-predicted height associations with risk factors for and complications of CHD. We found modification of effects of MR associations by CHD status for atrial fibrillation/flutter but not for hypertension, hyperlipidemia, or venous circulatory disorders. CONCLUSIONS: We conclude that height may be an unrecognized but biologically plausible risk factor for several common conditions in adults. However, more studies are needed to reliably exclude horizontal pleiotropy as a driving force behind at least some of the MR associations observed in this study.

Urban-rural disparities in acceptance of human papillomavirus vaccination among women in Can Tho, Vietnam.

Background: In Vietnam, cervical cancer is a significant public health concern for women. Unfortunately, despite the availability of the HPV vaccine, low vaccination rates persist. Objectives: This study investigates the discrepancy between urban and rural areas in the willingness to receive HPV vaccination with or without fees. Methods: A cross-sectional study was conducted on a sample of 648 women aged between 15 and 49, living in two urban and two rural Vietnamese districts of Can Tho, between May and December 2021. Results: The overall vaccination rate was 4%, with urban women having a higher rate of 4.9% compared to rural women at 3.1%. Among unvaccinated women, those from rural areas expressed a significantly higher desire to receive the free vaccine (91.4%) than urban women (84.4%). However, the intention to vaccinate declined when rural women and urban women were advised to pay the cost (63.4% and 57.1%, respectively). A strong correlation was found between a positive attitude and intention for vaccination, irrespective of its price or free availability. Education and access to information about the HPV vaccine were also identified as the most significant factors influencing the intention to vaccination among urban and rural women. Conclusion: The low HPV vaccination rates among women aged 15-49 living in both urban and rural regions of Vietnam are a notable public health concern. These outcomes emphasize the critical need for effective programs of vaccine laterization, as an introduction to the offer of affordable and accessible HPV vaccines for women in Can Tho, Vietnam.

Knowledge and awareness of COVID-19 among Indonesian migrant workers in the Greater China Region.

OBJECTIVES: Migrant workers are one of the most vulnerable population groups during the coronavirus disease 2019 (COVID-19) pandemic. This study investigated knowledge and awareness of COVID-19 among Indonesian migrant workers (IMWs) in Macao (SAR), Hong Kong (SAR), and Taiwan. STUDY DESIGN: This was a cross-sectional study. METHODS: Data were collected through an online survey in February and March 2020 to gain information on (1) participants' sociodemographic characteristics, (2) experience and awareness regarding COVID-19 information, and (3) knowledge and understanding of COVID-19. A series of Chi-squared, t-test, and logistic regression analyses were conducted. RESULTS: The survey was completed by 491 participants (92.1% female). Knowledge of COVID-19 was obtained from multiple sources, including a large proportion from online social media. However, participants who obtained information from their employer, local social networks, and migrant organisations answered a greater number of questions correctly. One-third of participants reported receiving hoax, fake news, and incorrect information and obtained information from unverified sources. Participants were most interested in information about how to cure COVID-19, and 57.8% knew that no specific drug or vaccine was currently available. Almost all participants correctly identified fever and wearing a facemask as the main COVID-19 symptom and prevention strategy, respectively. Participants with senior high school or higher education and who worked as domestic or care workers had a greater knowledge of COVID-19 than their counterparts. CONCLUSIONS: Public health communication strategies using multiple channels, including employers and community organisations, would help to minimise COVID-19 knowledge gaps. In addition, it is recommended that digital literacy content is added to public health campaigns.

Branded versus generic drug use in chronic disease management in Hong Kong-perspectives of health care professionals and the general public.

INTRODUCTION: The aim of the present study was to evaluate the understanding of generic substitution among health care professionals and members of the general public ("general public") in Hong Kong. METHODS: This cross-sectional descriptive study was performed by using a self-completed anonymous questionnaire from March 2015 to May 2017. The questionnaire included demographic data, knowledge of generic drugs, experiences of generic substitution, and views on policy. RESULTS: A total of 2106 general public, 73 doctors, 22 nurses, and 50 pharmacists responded the questionnaire. In all, 41.2% of the general public was aware that generic drugs have the same active ingredients. Although a majority of the health care professionals knew that generic drugs have the same active ingredients (doctors: 79.5%; nurses: 86.4%; pharmacists: 98.0%), many were unaware of bioequivalence (doctors: 37.0%; nurses: 18.2%; pharmacists: 50.0%). "Efficacy" was ranked as the primary concern among all groups; a substantial portion of respondents reported experiencing adverse drug reactions upon generic substitution (general public: 26.6%; doctors: 23.3%; nurses: 9.1%; pharmacists: 42.0%). At least half of the general public, nurses, and pharmacists considered that patients should be given a choice for generic substitution. However, fewer than one-fifth of doctors and nurses and approximately one-third of pharmacists considered that patient consent was needed prior to generic substitution, compared with approximately two-thirds of the general public. CONCLUSION: The knowledge and perception of generic substitution remains low, both in the general public and among health care professionals. This knowledge deficit could potentially lead to different perspectives among stakeholders regarding generic substitution.

Value of the portal venous phase in evaluation of treated hepatocellular carcinoma following transcatheter arterial chemoembolisation.

AIM: To evaluate the utility of the portal venous phase on multiphasic computed tomography (CT) after treatment of hepatocellular carcinoma (HCC) with trans-arterial chemoembolisation (TACE). MATERIALS AND METHODS: This was a retrospective review of patients who underwent TACE for HCC between 1 April 2012 and 21 December 2014, with appropriate multiphasic, pre- and post-procedural CT examinations. The maximum non-contrast, arterial phase, and portal venous phase attenuation values of the tumour and tumour bed were evaluated within a region of interest (ROI), with values adjusted against background hepatic parenchyma. Linear regression analyses were performed for both the arterial and venous phases, to assess the level of enhancement and to determine if the venous phase had additional value in this setting. RESULTS: A total of 86 cases from 51 patients were reviewed. All pre-procedural CT examinations of lesions demonstrated arterial phase enhancement with portal venous and delayed phase washout compatible with HCC. The post-procedural CT examinations following TACE revealed expected decreased arterial enhancement. Sixty-five cases (76%) showed persistent non-enhancement on the portal venous phase following embolisation therapy. A total of 21 cases (24%), however, demonstrated progressive portal venous hyper enhancement. Linear regression analysis demonstrated a statistical significance between the difference in maximal arterial and portal venous enhancement in these cases. CONCLUSION: Following TACE, the treated lesion may demonstrate portal venous phase hyper-enhancement within the tumour bed. As such, full attention should be given to these images for comprehensive evaluation of tumour response following treatment.

Restoring speech following total removal of the larynx by a learned transformation from sensor data to acoustics.

Total removal of the larynx may be required to treat laryngeal cancer: speech is lost. This article shows that it may be possible to restore speech by sensing movement of the remaining speech articulators and use machine learning algorithms to derive a transformation to convert this sensor data into an acoustic signal. The resulting "silent speech," which may be delivered in real time, is intelligible and sounds natural. The identity of the speaker is recognisable. The sensing technique involves attaching small, unobtrusive magnets to the lips and tongue and monitoring changes in the magnetic field induced by their movement.

A cross-sectional study of the knowledge, attitude, and practice of patients aged 50 years or above towards herpes zoster in an out-patient setting.

INTRODUCTION: There has been limited research on the knowledge of and attitudes about herpes zoster in the Hong Kong population. This study aimed to investigate the knowledge, attitude, and practice of patients aged 50 years or above towards herpes zoster and its vaccination. METHODS: This was a cross-sectional study in the format of a structured questionnaire interview carried out in Sai Ying Pun Jockey Club General Outpatient Clinic in Hong Kong. Knowledge of herpes zoster and its vaccination was assessed, and patient attitudes to and concerns about the disease were evaluated. Factors that affected a decision about vaccination against herpes zoster were investigated. RESULTS: A total of 408 Hong Kong citizens aged 50 years or above were interviewed. Multiple regression analysis revealed that number of correct responses regarding knowledge about herpes zoster was positively correlated with educational attainment (B=0.313, P=0.026) and history of herpes zoster (B=0.408, P=0.038), and negatively correlated with age (B= -0.042, P<0.001) and male gender (B= -0.396, P=0.029). Answers to several questions revealed a sizable number of misconceptions about the disease. Among all respondents, 35% stated that they were worried about getting the disease, and 17% would consider vaccination against herpes zoster. CONCLUSIONS: Misconceptions about herpes zoster were notable in this study. More health education is needed to improve the understanding and heighten awareness of herpes zoster among the general public. Although the majority of participants indicated that herpes zoster would have a significant impact on their health, a relatively smaller proportion was actually worried about getting the disease. Further studies on this topic should be encouraged to gauge the awareness and knowledge of herpes zoster among broader age-groups.

Development and pre-testing of a rehabilitation planning consultation for head-and-neck cancer.

BACKGROUND: In contrast with other major chronic conditions such as heart disease and stroke, cancer care does not routinely integrate evidence-based rehabilitation services within the standard continuum. The objectives of the present project were to develop a rehabilitation planning consultation (rpc) for survivors of head-and-neck (hn) cancer, to test its feasibility, and to make refinements. METHODS: Using intervention mapping, the rpc-alpha was developed by examining potential theoretical methods and practical applications relative to the program objectives. During feasibility testing, a single case series was conducted with survivors of hn cancer who had completed their cancer treatment within the preceding 11 months; iterative refinements were made after each case. RESULTS: The rpc-alpha was led by a rehabilitation professional and was based on self-management principles. The initial consultation included instruction in a global cognitive strategy, goal-setting, introduction to available resources, action planning, and coping planning. A follow-up consultation was conducted a few weeks later. Of 9 participants recruited, 5 completed post-intervention assessments. Participants reported that the rpc helped them to make rehabilitation plans. CONCLUSIONS: The rpc was feasible to use and satisfactory to a small group of hn cancer survivors. A pilot test of the refined version is in process.

Frequency of motor alterations detected through manometry in patients with esophageal symptoms and scleroderma. / Frecuencia de alteraciones motoras detectadas por manometría en pacientes con síntomas esofágicos y esclerodermia.

BACKGROUND: Scleroderma can present with esophageal involvement causing important morbidity. AIMS: To describe the manometric findings and clinical characteristics of patients with scleroderma and esophageal symptoms. MATERIALS AND METHODS: Patients with scleroderma and esophageal symptoms were evaluated through esophageal manometry within the time frame of one year. Descriptive statistics were carried out and the continuous variables were expressed as means and standard deviation. Frequencies were expressed as percentages. RESULTS: The study included 24 female patients with a mean age of 53.5 years and mean disease progression of 7.84 years. The most frequent findings were short and hypotonic lower esophageal sphincter (mean length 1.58cm and mean tone 9.49mmHg) and ineffective esophageal motility (mean non-transmitted waves 92.91%, mean effective primary peristalsis 40.05%, and mean amplitude 13.11mmHg). The most frequent symptom was dysphagia. CONCLUSIONS: Scleroderma is associated with lower esophageal sphincter alterations and symptomatic ineffective esophageal motility.

Drosophila KASH-domain protein Klarsicht regulates microtubule stability and integrin receptor localization during collective cell migration.

During collective migration of the Drosophila embryonic salivary gland, cells rearrange to form a tube of a distinct shape and size. Here, we report a novel role for the Drosophila Klarsicht-Anc-Syne Homology (KASH) domain protein Klarsicht (Klar) in the regulation of microtubule (MT) stability and integrin receptor localization during salivary gland migration. In wild-type salivary glands, MTs became progressively stabilized as gland migration progressed. In embryos specifically lacking the KASH domain containing isoforms of Klar, salivary gland cells failed to rearrange and migrate, and these defects were accompanied by decreased MT stability and altered integrin receptor localization. In muscles and photoreceptors, KASH isoforms of Klar work together with Klaroid (Koi), a SUN domain protein, to position nuclei; however, loss of Koi had no effect on salivary gland migration, suggesting that Klar controls gland migration through novel interactors. The disrupted cell rearrangement and integrin localization observed in klar mutants could be mimicked by overexpressing Spastin (Spas), a MT severing protein, in otherwise wild-type salivary glands. In turn, promoting MT stability by reducing spas gene dosage in klar mutant embryos rescued the integrin localization, cell rearrangement and gland migration defects. Klar genetically interacts with the Rho1 small GTPase in salivary gland migration and is required for the subcellular localization of Rho1. We also show that Klar binds tubulin directly in vitro. Our studies provide the first evidence that a KASH-domain protein regulates the MT cytoskeleton and integrin localization during collective cell migration.

Intracranial EEG correlates of implicit relational inference within the hippocampus.

Drawing inferences from past experiences enables adaptive behavior in future situations. Inference has been shown to depend on hippocampal processes. Usually, inference is considered a deliberate and effortful mental act which happens during retrieval, and requires the focus of our awareness. Recent fMRI studies hint at the possibility that some forms of hippocampus-dependent inference can also occur during encoding and possibly also outside of awareness. Here, we sought to further explore the feasibility of hippocampal implicit inference, and specifically address the temporal evolution of implicit inference using intracranial EEG. Presurgical epilepsy patients with hippocampal depth electrodes viewed a sequence of word pairs, and judged the semantic fit between two words in each pair. Some of the word pairs entailed a common word (e.g., "winter-red," "red-cat") such that an indirect relation was established in following word pairs (e.g., "winter-cat"). The behavioral results suggested that drawing inference implicitly from past experience is feasible because indirect relations seemed to foster "fit" judgments while the absence of indirect relations fostered "do not fit" judgments, even though the participants were unaware of the indirect relations. A event-related potential (ERP) difference emerging 400 ms post-stimulus was evident in the hippocampus during encoding, suggesting that indirect relations were already established automatically during encoding of the overlapping word pairs. Further ERP differences emerged later post-stimulus (1,500 ms), were modulated by the participants' responses and were evident during encoding and test. Furthermore, response-locked ERP effects were evident at test. These ERP effects could hence be a correlate of the interaction of implicit memory with decision-making. Together, the data map out a time-course in which the hippocampus automatically integrates memories from discrete but related episodes to implicitly influence future decision making.

Validation of the BETA-2 Score: An Improved Tool to Estimate Beta Cell Function After Clinical Islet Transplantation Using a Single Fasting Blood Sample.

The beta score, a composite measure of beta cell function after islet transplantation, has limited sensitivity because of its categorical nature and requires a mixed-meal tolerance test (MMTT). We developed a novel score based on a single fasting blood sample. The BETA-2 score used stepwise forward linear regression incorporating glucose (in millimoles per liter), C-peptide (in nanomoles per liter), hemoglobin A1c (as a percentage) and insulin dose (U/kg per day) as continuous variables from the original beta score data set (n = 183 MMTTs). Primary and secondary analyses assessed the score's ability to detect glucose intolerance (90-min MMTT glucose ≥8 mmol/L) and insulin independence, respectively. A validation cohort of islet transplant recipients (n = 114 MMTTs) examined 12 mo after transplantation was used to compare the score's ability to detect these outcomes. The BETA-2 score was expressed as follows (range 0-42): [Formula: see text] A score <20 and ≥15 detected glucose intolerance and insulin independence, respectively, with >82% sensitivity and specificity. The BETA-2 score demonstrated greater discrimination than the beta score for these outcomes (p < 0.05). Using a fasting blood sample, the BETA-2 score estimates graft function as a continuous variable and shows greater discrimination of glucose intolerance and insulin independence after transplantation versus the beta score, allowing frequent assessments of graft function. Studies examining its utility to track long-term graft function are required.

The influence of precompression on elasticity of thyroid nodules estimated by ultrasound shear wave elastography.

OBJECTIVES: To investigate the influence of variations in resting pressure (precompression) on thyroid ultrasound supersonic shear wave elastography (SWE). METHODS: Thirty-five normal thyroid glands (Norm), 55 benign hyperplastic nodules (BHN), and 17 papillary thyroid cancers (PTC) in 96 subjects underwent thyroid SWE. Four precompression levels were applied manually by the operator, ranging from A (baseline, 0 % strain) to D (high, 22-30 % strain). SWE results at each precompression level were compared using ANOVA tests with P < 0.05 indicating significance. RESULTS: SWE indices were highest in PTC, followed by BHN and Norm at each precompression level (P < 0.05). All tissue types showed successive increases in SWE results as precompression increased, although the rate was higher for PTC than BHN and Norm (Ps < 0.05). SWE values (kPa) of Norm, BHN, and PTC at baseline precompression (A) were 10.3 ± 3.3, 17.7 ± 7.6, and 22.2 ± 11.9 compared with 21.1 ± 4.2, 42.3 ± 16.0, and 97.6 ± 46.8 at high precompression (D). SWE index differences between precompression levels A and D were 10.8 kPa for Norm, 24.6 kPa for BHN, and 75.4 kPa for PTC. CONCLUSION: PTCs show greater SWE stiffening than BHN as precompression rises. Precompression effects on thyroid nodules are not negligible and may account for wide discrepancies in published SWE discriminatory performance results for thyroid malignancy. KEY POINTS: • Increases in resting pressure (precompression) applied by the operator increases thyroid stiffness. • Papillary cancers show greater increases in stiffness (strain hardening) than benign nodules. • Precompression may affect the diagnostic performance of shearwave elastography for thyroid malignancy.

Cytoskeletal motor-driven active self-assembly in in vitro systems.

Molecular motor-driven self-assembly has been an active area of soft matter research for the past decade. Because molecular motors transform chemical energy into mechanical work, systems which employ molecular motors to drive self-assembly processes are able to overcome kinetic and thermodynamic limits on assembly time, size, complexity, and structure. Here, we review the progress in elucidating and demonstrating the rules and capabilities of motor-driven active self-assembly. We focus on the types of structures created and the degree of control realized over these structures, and discuss the next steps necessary to achieve the full potential of this assembly mode which complements robotic manipulation and passive self-assembly.

Controlling self-assembly of microtubule spools via kinesin motor density.

Active self-assembly, in which non-thermal energy is consumed by the system to put together building blocks, allows the creation of non-equilibrium structures and active materials. Microtubule spools assembled in gliding assays are one example of such non-equilibrium structures, capable of storing bending energies on the order of 10(5) kT. Although these structures arise spontaneously in experiments, the origin of microtubule spooling has long been debated. Here, using a stepwise kinesin gradient, we demonstrate that spool assembly can be controlled by the surface density of kinesin motors, showing that pinning of microtubules due to dead motors plays a dominant role in spool initiation.

The effect of oxidative stress on the bursopentin peptide structure: a theoretical study.

Bursopentin (BP(5), H-Cys(1)-Lys(2)-Arg(3)-Val(4)-Tyr(5)-OH), found in the bursa Fabricius of the chicken, is a pentapeptide that protects the organism from oxidative stress by reducing the intracellular generation of reactive oxygen species. Hydrogen abstraction, a common oxidative reaction occurring in proteins, often results in the formation of d amino acid residues. To study the effect of this phenomenon on the structure of bursopentin, each of its residues were converted from the l configuration to the d configuration, and the structures of these peptide epimers were compared to that of the wild-type bursopentin. The conformations, secondary structures, compactness and hydrogen bonding of bursopentin were compared to its epimers using molecular dynamics simulations and first principles quantum chemical computations. It was discovered that the repulsion between the side chains of Lys(2) and Arg(3) influenced the conformation of the peptide regardless of the configuration of these residues. Epimerisation of the Val(4) and Tyr(5) caused a reduction in the compactness of bursopentin. In all cases, the occurrence of a turn structure was relatively high, especially when Arg(3) was in the d configuration. Thermodynamic analysis of the epimerisation process showed that the formation of d amino acid residues is favourable.

B-Raf mutation: a key player in molecular biology of cancer.

B-Raf is one of the more commonly mutated proto-oncogenes implicated in the development of cancers. In this review, we consider the mechanisms and clinical impacts of B-Raf mutations in cancer and discuss the implications for the patient in melanoma, thyroid cancer and colorectal cancer, where B-Raf mutations are particularly common.

Tracking the mechanism of fibril assembly by simulated two-dimensional ultraviolet spectroscopy.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of plaque deposits in the human brain. The main component of these plaques consists of highly ordered structures called amyloid fibrils, formed by the amyloid ß-peptide (Aß). The mechanism connecting Aß and AD is yet undetermined. In a previous study, a coarse-grained united-residue model and molecular dynamics simulations were used to model the growth mechanism of Aß amyloid fibrils. On the basis of these simulations, a dock/lock mechanism was proposed, in which Aß fibrils grow by adding monomers at either end of an amyloid fibril template. To examine the structures in the early time-scale formation and growth of amyloid fibrils, simulated two-dimensional ultraviolet spectroscopy is used. These early structures are monitored in the far ultraviolet regime (λ = 190-250 nm) in which the computed signals originate from the backbone nπ* and ππ* transitions. These signals show distinct cross-peak patterns that can be used, in combination with molecular dynamics, to monitor local dynamics and conformational changes in the secondary structure of Aß-peptides. The protein geometry-correlated chiral xxxy signal and the non-chiral combined signal xyxy-xyyx were found to be sensitive to, and in agreement with, a dock/lock pathway.

The multiple stressor effect in zebrafish embryos from simultaneous exposure to ionising radiation and cadmium.

Living organisms are exposed to a mixture of environmental stressors, and the resultant effects are referred to as multiple stressor effects. In the present work, we studied the multiple stressor effect in embryos of the zebrafish (Danio rerio) from simultaneous exposure to ionising radiation (alpha particles) and cadmium through quantification of apoptotic signals at 24 h postfertilisation (hpf) revealed by vital dye acridine orange staining. For each set of experiments, 32-40 dechorionated embryos were deployed, which were divided into four groups each having 8-10 embryos. The four groups of embryos were referred to as (1) the control group (C), which received no further treatments after dechorionation; (2) the Cd-dosed and irradiated group (CdIr), which was exposed to 100 µM Cd from 5 to 24 hpf, and also received about 4.4 mGy from alpha particles at 5 hpf; (3) the irradiated group (Ir), which received about 4.4 mGy from alpha particles at 5 hpf; and (4) the Cd-dosed group (Cd), which was exposed to 100 µM Cd from 5 to 24 hpf. In general, the CdIr, Ir and Cd groups had more apoptotic signals than the C group. Within the 12 sets of experimental results, two showed significant synergistic effects, one showed a weakly synergistic effect and nine showed additive effects. The multiple stressor effect of 100 µM Cd with ~4.4 mGy alpha-particle radiation resulted in an additive or synergistic effect, but no antagonistic effect. The failure to identify significant synergistic effects for some sets of data, and thus their subsequent classification as additive effects, might be a result of the relatively small magnitude of the synergistic effects. The results showed that the radiation risk could be perturbed by another environmental stressor such as a heavy metal, and as such a realistic human radiation risk assessment should in general take into account the multiple stressor effects.