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ImportanceThe presence of diabetic macular ischemia (DMI) on optical coherence tomography angiography (OCTA) images predicts diabetic retinal disease progression and visual acuity (VA) deterioration, suggesting an OCTA-based DMI evaluation can further enhance diabetic retinopathy (DR) management.ObjectiveTo investigate whether an automated binary DMI algorithm using OCTA images provides prognostic value on DR progression, diabetic macular edema (DME) development, and VA deterioration in a cohort of patients with diabetes.Design, Setting, and ParticipantsIn this cohort study, DMI assessment of superficial capillary plexus and deep capillary plexus OCTA images was performed by a previously developed deep learning algorithm. The presence of DMI was defined as images exhibiting disruption of fovea avascular zone with or without additional areas of capillary loss, while absence of DMI was defined as images presented with intact fovea avascular zone outline and normal distribution of vasculature. Patients with diabetes were recruited starting in July 2015 and were followed up for at least 4 years. Cox proportional hazards models were used to evaluate the association of the presence of DMI with DR progression, DME development, and VA deterioration. Analysis took place between June and December 2022.Main Outcomes and MeasuresDR progression, DME development, and VA deterioration.ResultsA total of 321 eyes from 178 patients were included for analysis (85 [47.75%] female; mean [SD] age, 63.39 [11.04] years). Over a median (IQR) follow-up of 50.41 (48.16-56.48) months, 105 eyes (32.71%) had DR progression, 33 eyes (10.28%) developed DME, and 68 eyes (21.18%) had VA deterioration. Presence of superficial capillary plexus–DMI (hazard ratio [HR], 2.69; 95% CI, 1.64-4.43; P P P = .003) and VA deterioration (HR, 2.12; 95% CI, 1.01-5.22; P = .04) after adjusting for age, duration of diabetes, fasting glucose, glycated hemoglobin, mean arterial blood pressure, DR severity, ganglion cell–inner plexiform layer thickness, axial length, and smoking at baseline.Conclusions and RelevanceIn this study, the presence of DMI on OCTA images demonstrates prognostic value for DR progression, DME development, and VA deterioration.

Objectives : We aim to study the viral kinetics and host inflammatory response of RSV infection in older adults, and their correlation with disease severity. Methods : We performed a prospective observational study in adults with RSV infection. We serially collected nasal-throat swabs for quantification of RSV-A and RSV-B viral load, and peripheral blood samples for measurement of cytokine/chemokine concentrations. The study endpoints were (i) requiring supplemental oxygen therapy, and (ii) non-invasive ventilation, intensive care, or died within 30 days of admission. We performed multivariable logistic regression models to identify independent variables for severe disease. Results : We enrolled 71 hospitalized patients and 10 outpatients treated for RSV infection (median age 75 years, 51% male, and 74% with comorbidities). Among hospitalized patients, 61% required supplemental oxygen therapy, and 18% had severe disease requiring non-invasive ventilation or intensive care, or died within 30 days. Inflammatory cytokine/chemokines IL-6, CXCL8/IL-8, CXCL9/MIG and CXCL10/IP-10 increased significantly during the acute phase of illness. IL-6 concentration was independently associated with severe disease after adjusting for confounding factors. RSV viral load was not associated with disease severity throughout the course of illness. Conclusion : Host inflammatory response is a major marker of severe disease in older adults with RSV infection.

Background: Intravenous ferric carboxymaltose has been shown to improve symptoms and quality of life in patients with chronic heart failure and iron deficiency. We aimed to evaluate the effect of ferric carboxymaltose, compared with placebo, on outcomes in patients who were stabilised after an episode of acute heart failure. Methods: AFFIRM-AHF was a multicentre, double-blind, randomised trial done at 121 sites in Europe, South America, and Singapore. Eligible patients were aged 18 years or older, were hospitalised for acute heart failure with concomitant iron deficiency (defined as ferritin

Summary Objective To evaluate the prevalence of self-perceived voice problems and voice-related quality of life in a nontreatment seeking older population in Hong Kong. Study Design Prospective, cross-sectional survey. Methods One hundred and one older individuals aged 65 years or above were recruited from senior citizen community centers in Hong Kong. Each participant received a face-to-face interview with the researcher. The participants were asked to report the presence of voice problems and the voice symptoms that they experienced. They were also asked to complete the Cantonese version of the Voice Handicap Index to ascertain their voice-related quality of life. Results Over one-fourth (27.7%) of participants reported having current voice problems. Perceived voice problems were found to pose significant negative impacts on the older individuals’ voice-related quality of life. The prevalence of voice problems and extent of impacts of voice-related quality of life were similar across the young-old, old-old, and the oldest-old groups of participants. Conclusion The results suggest that voice problems are common in the older population and should not be underestimated. The study urges the need to allocate more resources to provide voice-related services from the young-old group for promoting positive aging.

The zoonotic H7N9 avian influenza (AI) virus first emerged in 2013 as a low pathogenic (LPAI) strain, and has repeatedly caused human infection resulting in severe respiratory illness and a mortality of ~39% (>600 deaths) across five epidemic waves. This virus has circulated in poultry with little to no discernible clinical signs, making detection and control difficult. Contrary to published data, our group has observed a subset of specific pathogen free chickens infected with the H7N9 virus succumb to disease, showing clinical signs consistent with highly pathogenic AI (HPAI). Viral genome sequencing revealed two key mutations had occurred following infection in the haemagglutinin (HA 226 L>Q) and nucleoprotein (NP 373 A>T) proteins. We further investigated the impact of the NP mutation and demonstrated that only chickens bearing a single nucleotide polymorphism (SNP) in their IFITM1 gene were susceptible to the H7N9 virus. Susceptible chickens demonstrated a distinct loss of CD8+ T cells from the periphery as well as a dysregulation of IFNγ that was not observed for resistant chickens, suggesting a role for the NP mutation in altered T cell activation. Alternatively, it is possible that this mutation led to altered polymerase activity, as the mutation occurs in the NP 360-373 loop which has been previously show to be important in RNA binding. These data have broad ramifications for our understanding of the pathobiology of AI in chickens and humans and provide an excellent model for investigating the role of antiviral genes in a natural host species.

In this manuscript, we developed a two-fold symmetric linchpin (TSL) that converts readily available phage-displayed peptides libraries made of 20 common amino acids to genetically-encoded libraries of bicyclic peptides displayed on phage. TSL combines an aldehyde-reactive group and two thiol-reactive groups; it bridges two side chains of cysteine [C] with an N-terminal aldehyde group derived from the N-terminal serine [S], yielding a novel bicyclic topology that lacks a free N-terminus. Phage display libraries of SX1CX2X3X4X5X6X7C sequences, where X is any amino acid but Cys, were converted to a library of bicyclic TSL-[S]X1[C]X2X3X4X5X6X7[C] peptides in 45 ± 15% yield. Using this library and protein morphogen NODAL as a target, we discovered bicyclic macrocycles that specifically antagonize NODAL-induced signaling in cancer cells. At a 10 μM concentration, two discovered bicyclic peptides completely suppressed NODAL-induced phosphorylation of SMAD2 in P19 embryonic carcinoma cells. The TSL-[S]Y[C]KRAHKN[C] bicycle inhibited NODAL-induced proliferation of NODAL-TYK-nu ovarian carcinoma cells with apparent IC50 of 1 μM. The same bicycle at 10 μM concentration did not affect the growth of the control TYK-nu cells. TSL-bicycles remained stable over the course of the 72 hour-long assays in a serum-rich cell-culture medium. We further observed general stability in mouse serum and in a mixture of proteases (Pronase™) for 21 diverse bicyclic macrocycles of different ring sizes, amino acid sequences, and cross-linker geometries. TSL-constrained peptides to expand the previously reported repertoire of phage-displayed bicyclic architectures formed by cross-linking Cys side chains. We anticipate that it will aid the discovery of proteolytically stable bicyclic inhibitors for a variety of protein targets., A two-fold symmetric linchpin (TSL) converts readily available phage-displayed disulfide peptide libraries to proteolytically stable bicyclic peptides. The bicyclic phage library was screened to discover an antagonist of NODAL morphogen.

Significant global efforts have been directed towards understanding the epidemiology of highly pathogenic avian influenza (HPAI) across poultry production systems and in wild-bird reservoirs, yet understanding of disease dynamics in the village poultry setting remains limited. This article provides a detailed account of the first laboratory-confirmed outbreak of HPAI in the south-eastern provinces of Lao PDR, which occurred in a village in Sekong Province in October 2018. Perspectives from an anthropologist conducting fieldwork at the time of the outbreak, clinical and epidemiological observations by an Australian veterinarian are combined with laboratory characterization and sequencing of the virus to provide insights about disease dynamics, biosecurity, outbreak response and impediments to disease surveillance. Market-purchased chickens were considered the likely source of the outbreak. Observations highlighted the significance of a-lack-of pathognomonic clinical signs and commonness of high-mortality poultry disease with consequent importance of laboratory diagnosis. Sample submission and testing was found to be efficient, despite the village being far from the national veterinary diagnostic laboratory. Extensively raised poultry play key roles in ritual, livelihoods and nutrition of rural Lao PDR people. Unfortunately, mass mortality of chickens due to diseases such as HPAI and Newcastle disease (ND) imposes a significant burden on smallholders in Lao PDR, as in most other SE Asian countries. We observed that high mortality of chickens is perceived by locals as a new 'normal' in raising poultry; this sense of it being 'normal' is a disincentive to reporting of mortality events. Establishing effective people-centred disease-surveillance approaches with local benefit, improving market-biosecurity and veterinary-service support to control vaccine-preventable poultry diseases could all reduce mass-mortality event frequency, improve veterinary-producer relationships and increase the likelihood that mortality events are reported. Priority in each of these aspects should be on working with smallholders and local traders, appreciating and respecting their perspectives and local knowledge.

Aim To review international guidelines and to share our infection control experience during the coronavirus disease 2019 (COVID-19) pandemic at a tertiary eye centre in Hong Kong. Methods Infection control guidelines and recommendations from international ophthalmological bodies are reviewed and discussed. The measures at our hospital were drawn up as per international and local health authorities' guidelines and implemented with the collaboration of doctors, nurses and administrative staff. Results The aims of our infection control measures are to 1) minimize cross-infection within the hospital; 2) protect and support hospital staff; 3) ensure environmental control. To minimize the risk of cross-infection, outpatient attendance and elective surgery have been reduced by 40%, and general anesthesia procedures were reduced by 90%. Patients entering the hospital are screened for fever, travel history, contact and cluster history, and COVID-19 related symptoms. To protect and support hospital staff, we ensure provision of adequate personal protective equipment (PPE) and provide clear guidelines on the level of PPE needed, depending on the clinical situation. Other protective measures include provision of work uniforms, easy access to alcohol-based hand rub, opening new lunch areas, implementation of self-monitoring and self-reporting systems, and communication via online education and updates. Finally, environmental control is achieved by ensuring regular disinfection of the hospital premise, enhancing ventilation, and usage of disposable ophthalmic instruments. Conclusion Our multi-pronged approach to infection control is, so far, successful in minimizing infection risks, while allowing the maintenance of essential ophthalmic services.

Background An obstacle in influenza therapeutics development is the lack of clinical endpoints, especially in hospitalized patients. A single time-point binary outcome measure is limited by patients’ diverse clinical trajectories and low event rates. Methods A 6-point ordinal scale with ascending clinical status severity (scoring: discharged; subacute care; acute care without/with respiratory failure; intensive care unit [ICU]; death) was proposed to study outcomes of adults hospitalized with influenza. Individual patient data from 2 active surveillance cohorts’ datasets (2015/2016−2017/2018; Edmonton, Hong Kong) was used for evaluation. The impact of neuraminidase inhibitor (NAI) treatment on longitudinal ordinal outcome changes over 30 days was analyzed using mixed-effects ordinal logistic regression and group-based trajectory models. Results Patient (n = 1226) baseline characteristics included age (mean 68.0 years), virus-type (A 78.1%, B 21.9%), respiratory failure (57.2%), ICU admittance (14.4%), and NAI treatment within 5 days of illness (69.2%). Outcomes at 30 days included discharged (75.2%), subacute care (13.7%), acute care (4.5%), and death (6.6%). Two main clinical trajectories were identified, predictive by baseline scoring (mean ± SD, 4.3 ± 0.6 vs 3.5 ± 0.6, P Conclusions The ordinal outcome scale is a potentially useful clinical endpoint for influenza therapeutic trials, which could account for the diverse clinical trajectories of hospitalized patients, warranting further development.

OBJECTIVES Multiple studies have suggested that women have worse outcomes than men following mitral valve (MV) surgery—most of those studies reported on conventional sternotomy (CS) MV surgery. Therefore, we aimed to explore whether or not the minimally invasive mitral valve surgery (MIMVS) approach might mitigate a worse survival in women following MV surgery. METHODS We identified patients with isolated primary MV operations with or without tricuspid valve repair performed between 2007 and 2019. Patients were propensity score-matched across the MIMVS and CS surgical approaches. Sex was excluded from the matching process to discern whether female patients had a different likelihood of receiving minimally invasive surgery than males. A Cox proportional hazards model was fitted in the matched cohort and adjusted for the imbalance in baseline characteristics using the propensity score. RESULTS Of 956 patients (417 MIMVS, 539 CS; 424 females), the matched set comprised 342 pairs (684 patients; 296 females) of patients who were well balanced across MIMVS and CS groups with regard to preoperative clinical characteristics. We observed a 47/53% female/male ratio in the CS group and a 39/61% in the MIMVS group, P = 0.054. In both matched groups, women were older than males. A Cox model adjusted for propensity scores showed no survival difference with sex, surgical type or interaction. CONCLUSIONS Women present to the surgical team at an older age. They appear less likely to be considered for a MIMVS approach than men. Neither sex nor surgical approach was associated with worse survival in a matched sample.

Most of our understanding of the ecology and evolution of avian influenza A virus (AIV) in wild birds is derived from studies conducted in the northern hemisphere on waterfowl, with a substantial bias towards dabbling ducks. However, relevant environmental conditions and patterns of avian migration and reproduction are substantially different in the southern hemisphere. Through the sequencing and analysis of 333 unique AIV genomes collected from wild birds collected over 15 years we show that Australia is a global sink for AIV diversity and not integrally linked with the Eurasian gene pool. Rather, AIV are infrequently introduced to Australia, followed by decades of isolated circulation and eventual extinction. The number of co-circulating viral lineages varies per subtype. AIV haemagglutinin (HA) subtypes that are rarely identified at duck-centric study sites (H8-12) had more detected introductions and contemporary co-circulating lineages in Australia. Combined with a lack of duck migration beyond the Australian-Papuan region, these findings suggest introductions by long-distance migratory shorebirds. In addition, we found no evidence of directional or consistent patterns in virus movement across the Australian continent. This feature corresponds to patterns of bird movement, whereby waterfowl have nomadic and erratic rainfall-dependant distributions rather than consistent intra-continental migratory routes. Finally, we detected high levels of virus gene segment reassortment, with a high diversity of AIV genome constellations across years and locations. These data, in addition to those from other studies in Africa and South America, clearly show that patterns of AIV dynamics in the Southern Hemisphere are distinct from those in the temperate north.Author SummaryA result of the ever-growing poultry industry is a dramatic global increase in the incidence of high pathogenicity avian influenza virus outbreaks. In contrast, wild birds are believed to be the main reservoir for low pathogenic avian influenza A virus. Due to intensive research and surveillance of AIV in waterfowl in the Northern Hemisphere, we have a better understanding of AIV ecology and evolution in that region compared to the Southern Hemisphere, which are characterised by different patterns of avian migration and ecological conditions. We analysed 333 unique AIV genomes collected from wild birds in Australia to understand how Australia fits into global AIV dynamics and how viruses are maintained and dispersed within the continent of Australia. We show that the Southern Hemisphere experiences differing evolutionary dynamics to those seen in Northern Hemisphere with Australia representing a global sink for AIV.

In 2018, a 15-year-old female adolescent in Australia was infected with swine influenza A(H3N2) variant virus. The virus contained hemagglutinin and neuraminidase genes derived from 1990s-like human seasonal viruses and internal protein genes from influenza A(H1N1)pdm09 virus, highlighting the potential risk that swine influenza A virus poses to human health in Australia.

Objectives To establish a normative profile of health-related quality of life (HRQoL) for Hong Kong (HK) Chinese residents aged 18 years and above and to examine the relationship between socioeconomic characteristics and health conditions and the preference-based health index. Methods We recruited 1014 representative Cantonese-speaking residents across 18 geographical districts. The normative profiles of HRQoL were derived using established HK value sets. Mean values were computed by sex, age group, and educational attainment to obtain the EQ-5D HK normative profile for the general HK population. To explore the relationships among potential covariates (socioeconomic characteristics and health conditions) and the HK health index, a multivariable homoscedastic Tobit regression model was employed for the analysis. Results The mean index value was 0.919 using the EQ-5D-5L HK value set. Younger ages reported greater problems with anxiety or depression than did older ages, whereas older ages reported greater problems with pain or discomfort than did younger ages. Persons with higher educational attainment and those who reported higher life satisfaction reported significantly higher health index scores (P < .05). On the contrary, receiving government allowance and having experienced a serious illness were significantly associated (P < .05) with a lower health index. Conclusions The norm values fully represent the societal preferences of the HK population, and knowledge of societal preferences can enable policy makers to allocate resources and prioritize service planning. The study was conducted with the EuroQol International EQ-5D-5L Valuation Protocol and therefore enabled us to compare the EQ-5D-5L values with other countries to facilitate understanding of societal preferences in different jurisdictions.

Financial markets are noisy learning environments. We propose an approach that regularizes the Temporal Convolutional Network using a supervised autoencoder, which we term the Supervised Temporal Autoencoder (STAE). We show that the addition of the auxiliary reconstruction task is beneficial to the primary supervised learning task in the context of stock return time-series forecasting. We also show that STAE is able to learn features directly from transformed price series, alleviating the need for handcrafted features. The autoencoder also improves interpretability as users can observe output of the decoder and inspect features retained by the network.

In this manuscript, we developed a Two-fold Symmetric Linchpin (TSL) that converts readily available phage display peptides libraries made of 20 common amino acids to genetically-encoded libraries of bicyclic peptides displayed on phage. TSL combines an aldehyde-reactive group and two thiol-reactive groups; it bridges two side chains of cysteine [C] with an N-terminal aldehyde group derived from the N-terminal serine [S], yielding a novel bicyclic topology that lacks a free N-terminus. Phage display libraries of SX1CX2X3X4X5X6X7C sequences, where Xi is any amino acids but Cys, were converted to a library of bicyclic TSL-[S]X1[C]X2X3X4X5X6X7[C] peptides in 45 ± 15% yield. Using this library and protein morphogen NODAL as a target, we discovered bicyclic macrocycles that specifically antagonize NODAL-induced signaling in cancer cells. At a 10 µM concentration, two discovered bicyclic peptides completely suppressed NODAL-induced phosphorylation of SMAD2 in P19 embryonic carcinoma. The TSL-[S]Y[C]KRAHKN[C] bicycle inhibited NODAL-induced proliferation of NODAL-Tky-nu ovarian carcinoma cells with apparent IC50 1 µM. The same bicycle at 10 µM concentration did not affect the growth of the control Tky-nu cells. TSL-bicycles remained stable over the course of the 72 hour-long assays in a serum-rich cell-culture medium. We further observed general stability in mouse serum and in a mixture of proteases (PronaseTM) for 33 diverse bicyclic macrocycles of different ring sizes, amino acid sequences, and cross-linker geometries. TSL-constrained peptides expand the previously reported repertoire of phage display bicyclic architectures formed by cross-linking Cys side chains. We anticipate that it will aid the discovery of proteolytically stable bicyclic inhibitors for a variety of protein targets.