Comparison of the Physical Function Trajectories in Three Birth Cohorts of Chinese Older Adults: A 14-Year Longitudinal Study.

OBJECTIVES: It remains uncertain whether the favorable trend of reduction in physical disabilities has become reversed in the recent-born cohorts of older adults. This study aimed to compare the rate of decline with time in self-reported Instrumental Activity of Daily Living (IADL) difficulties, objective measurement of gait speed and grip strength, in three birth cohorts of Chinese older adults. DESIGN: A prospective cohort study. SETTING AND PARTICIPANTS: Four thousand Chinese older adults aged 65 years or above in three birth cohorts (1934-1938, 1929-1933, 1905-1928) were recruited from the community in Hong Kong. MEASUREMENTS: Grip strength, gait speed and IADL difficulties were measured between 2001 to 2017. Joint models were used to examine the trajectories of grip strength, gait speed and IADL difficulties over time, and the interaction effect of age-by-cohort (or also age2-by-cohort) was also examined. RESULTS: The recently born cohort (1934 - 1938) had worse grip strength and more IADL difficulties at the same age than the earlier two cohorts (1929 - 1933; 1905 - 1928). Furthermore, the most recently born cohort also followed a more rapid decline longitudinally with a greater decline observed in gait speed, grip strength and IADL difficulties for women whereas a greater decline in grip strength and IADL difficulties for men. CONCLUSIONS: The continuous improvement of physical limitations in old age may have halted and there appears to be a reversal of this favourable trend in the recent born cohort of older adults living in Hong Kong.

Impact of COVID-19 on the sleep-wake patterns of preschool children.

OBJECTIVE: To explore the impact of the COVID-19 pandemic on the sleep-wake patterns of preschool children. METHODS: A cohort of preschoolers established before the COVID-19 pandemic was invited to participate in this study. Data including children's demographics, their own and parental sleep-wake patterns, physical activities, and screen time were collected through an online questionnaire from August to September 2020. A comparison was made on the collected data from the same cohort of children before and during the pandemic. RESULTS: The cohort which was established before the pandemic consisted of 3720 preschoolers. For this current study, 642 (17%) participated, and 497 (13%) children who fulfilled the eligibility criteria were included in the final analysis. They showed a delay in their bedtime and wake time on both weekdays and weekends with a 15-30 min increase in nocturnal sleep duration. However, with a reduction in nap time, the average daily sleep duration was shortened by 16.3 ± 64.3 min (p < 0.001) and 27.5 ± 72.9 min (p < 0.001) during weekdays and weekends, respectively. Screen time was increased while outdoor activity duration was decreased. Parental sleep/wake times were also delayed with an increase in sleep duration. Children's sleep habits were associated with screen time and parental sleep/wake patterns. CONCLUSION: Despite school suspension during the COVID-19 pandemic, preschoolers were not sleeping longer. Screen time and parental sleep/wake patterns were the major factors driving the preschoolers' sleep habits. Health education is required to control screen time in children and to promote sleep hygiene among all family members.

Real-world treatment sequencing and survival in previously treated advanced renal cell carcinoma patients receiving nivolumab monotherapy: a UK retrospective cohort study.

BACKGROUND: The CheckMate 025 trial established nivolumab monotherapy as one of the standards of care in previously treated advanced or metastatic renal cell carcinoma (aRCC). However, supporting real-world data is lacking. This study investigated characteristics, treatment sequences and clinical outcomes of patients who received nivolumab monotherapy for previously treated aRCC in the UK. METHODS: This was a retrospective cohort study of aRCC patients treated with nivolumab at second line or later (2L +) at 4 UK oncology centres. Eligible patients commenced nivolumab (index date) between 01 March 2016 and 30 June 2018 (index period). Study data were extracted from medical records using an electronic case report form. Data cut-off (end of follow-up) was 31 May 2019. RESULTS: In total, 151 patients were included with median follow-up of 15.2 months. Mean age was 66.9 years, male preponderance (72.2%), and mostly Eastern Cooperative Oncology Group performance status grade 0-1 (71.5%). Amongst 112 patients with a known International Metastatic RCC Database Consortium score, distribution between favourable, intermediate, and poor risk categories was 20.5%, 53.6%, and 25.9% respectively. The majority of patients (n = 109; 72.2%) received nivolumab at 2L, and these patients had a median overall survival (OS) of 23.0 months [95% confidence interval: 17.2, not reached]. All patients who received nivolumab at 2L had received TKIs at 1L. Amongst the 42 patients (27.8%) who received nivolumab in third line or later (3L +) the median OS was 12.4 months [95% CI: 8.8, 23.2]. The most common reasons for nivolumab discontinuation were disease progression (2L: 61.2%; 3L: 68.8%) and adverse events (2L: 34.7%; 3L: 28.1%). CONCLUSION: This study provides real-world evidence on the characteristics, treatment sequences, and outcomes of aRCC patients who received 2L + nivolumab monotherapy in the UK. Nivolumab-specific survival outcomes were similar to those achieved in the CheckMate 025 trial.

Beam particle identification and tagging of incompletely stripped heavy beams with HEIST.

A challenge preventing successful inverse kinematics measurements with heavy nuclei that are not fully stripped is identifying and tagging the beam particles. For this purpose, the HEavy ISotope Tagger (HEIST) has been developed. HEIST utilizes two micro-channel plate timing detectors to measure the time-of-flight, a multi-sampling ion chamber to measure energy loss, and a high-purity germanium detector to identify isomer decays and calibrate the isotope identification system. HEIST has successfully identified 198Pb and other nearby nuclei at energies of about 75 MeV/A. In the experiment discussed, a typical cut containing 89% of all 198Pb80+ in the beam had a purity of 86%. We examine the issues of charge state contamination. The observed charge state populations of these ions are presented and, using an adjusted beam energy, are well described by the charge state model GLOBAL.

The SπRIT time projection chamber.

The Superconducting Analyzer for MUlti-particles from RAdioIsotope (SAMURAI) Pion-Reconstruction and Ion-Tracker Time Projection Chamber (SπRIT TPC) was designed to enable measurements of heavy ion collisions with the SAMURAI spectrometer at the RIKEN radioactive isotope beam factory and provides constraints on the equation of state of neutron-rich nuclear matter. The SπRIT TPC has a 50.5 cm drift length and an 86.4 × 134.4 cm2 pad plane with 12 096 pads that are equipped with the generic electronics for TPCs. The SπRIT TPC allows for an excellent reconstruction of particles and provides isotopic resolution for pions and other light charged particles across a wide range of energy losses and momenta. The details of the SπRIT TPC are presented, along with discussion of the TPC performance based on cosmic rays and charged particles emitted in heavy ion collisions.

Probing the Symmetry Energy with the Spectral Pion Ratio.

Many neutron star properties, such as the proton fraction, reflect the symmetry energy contributions to the equation of state that dominate when neutron and proton densities differ strongly. To constrain these contributions at suprasaturation densities, we measure the spectra of charged pions produced by colliding rare isotope tin (Sn) beams with isotopically enriched Sn targets. Using ratios of the charged pion spectra measured at high transverse momenta, we deduce the slope of the symmetry energy to be 42

Observation of the Exotic Isotope

A ^{13}F resonance was observed following a charge-exchange reaction between a fast ^{13}O beam and a ^{9}Be target. The resonance was found in the invariant-mass distribution of 3p+^{10}C events and probably corresponds to a 5/2^{+} excited state. The ground state was also expected to be populated, but was not resolved from the background. The observed level decays via initial proton emissions to both the ground and first 2^{+} state of ^{12}O, which subsequently undergo 2p decay. In addition, there may also be a significant proton decay branch to the second 2^{+} level in ^{12}O. The wave function associated with the observed level may be collectivized due to coupling to the continuum as is it located just above the threshold for proton decay to the 2_{2}^{+} state of ^{12}O.

Electronic collection of patient-reported outcomes following discharge after surgery: systematic review.

BACKGROUND: Little is known about the electronic collection and clinical feedback of patient-reported outcomes (ePROs) following surgical discharge. This systematic review summarized the evidence on the collection and uses of electronic systems to collect PROs after discharge from hospital after surgery. METHOD: Systematic searches of MEDLINE, Embase, PsycINFO, CINAHL and Cochrane Central were undertaken from database inception to July 2019 using terms for 'patient reported outcomes', 'electronic', 'surgery' and 'at home'. Primary research of all study designs was included if they used electronic systems to collect PRO data in adults after hospital discharge following surgery. Data were collected on the settings, patient groups and specialties, ePRO systems (including features and functions), PRO data collected, and integration with health records. RESULTS: Fourteen studies were included from 9474 records, including two RCTs and six orthopaedic surgery studies. Most studies (9 of 14) used commercial ePRO systems. Six reported types of electronic device were used: tablets or other portable devices (3 studies), smartphones (2), combination of smartphones, tablets, portable devices and computers (1). Systems had limited features and functions such as real-time clinical feedback (6 studies) and messaging service for patients with care teams (3). No study described ePRO system integration with electronic health records to support clinical feedback. CONCLUSION: There is limited reporting of ePRO systems in the surgical literature, and ePRO systems lack integration with hospital clinical systems. Future research should describe the ePRO system and ePRO questionnaires used, and challenges encountered during the study, to support efficient upscaling of ePRO systems using tried and tested approaches.

First Observation of the Four-Proton Unbound Nucleus

^{18}Mg was observed, for the first time, by the invariant-mass reconstruction of ^{14}O+4p events. The ground-state decay energy and width are E_{T}=4.865(34) MeV and Γ=115(100) keV, respectively. The observed momentum correlations between the five particles are consistent with two sequential steps of prompt 2p decay passing through the ground state of ^{16}Ne. The invariant-mass spectrum also provides evidence for an excited state at an excitation energy of 1.84(14) MeV, which is likely the first excited 2^{+} state. As this energy exceeds that for the 2^{+} state in ^{20}Mg, this observation provides an argument for the demise of the N=8 shell closure in nuclei far from stability. However, in open systems this classical argument for shell strength is compromised by Thomas-Ehrman shifts.

Association of technologically assisted integrated care with clinical outcomes in type 2 diabetes in Hong Kong using the prospective JADE Program: A retrospective cohort analysis.

BACKGROUND: Diabetes outcomes are influenced by host factors, settings, and care processes. We examined the association of data-driven integrated care assisted by information and communications technology (ICT) with clinical outcomes in type 2 diabetes in public and private healthcare settings. METHODS AND FINDINGS: The web-based Joint Asia Diabetes Evaluation (JADE) platform provides a protocol to guide data collection for issuing a personalized JADE report including risk categories (1-4, low-high), 5-year probabilities of cardiovascular-renal events, and trends and targets of 4 risk factors with tailored decision support. The JADE program is a prospective cohort study implemented in a naturalistic environment where patients underwent nurse-led structured evaluation (blood/urine/eye/feet) in public and private outpatient clinics and diabetes centers in Hong Kong. We retrospectively analyzed the data of 16,624 Han Chinese patients with type 2 diabetes who were enrolled in 2007-2015. In the public setting, the non-JADE group (n = 3,587) underwent structured evaluation for risk factors and complications only, while the JADE (n = 9,601) group received a JADE report with group empowerment by nurses. In a community-based, nurse-led, university-affiliated diabetes center (UDC), the JADE-Personalized (JADE-P) group (n = 3,436) received a JADE report, personalized empowerment, and annual telephone reminder for reevaluation and engagement. The primary composite outcome was time to the first occurrence of cardiovascular-renal diseases, all-site cancer, and/or death, based on hospitalization data censored on 30 June 2017. During 94,311 person-years of follow-up in 2007-2017, 7,779 primary events occurred. Compared with the JADE group (136.22 cases per 1,000 patient-years [95% CI 132.35-140.18]), the non-JADE group had higher (145.32 [95% CI 138.68-152.20]; P = 0.020) while the JADE-P group had lower event rates (70.94 [95% CI 67.12-74.91]; P < 0.001). The adjusted hazard ratios (aHRs) for the primary composite outcome were 1.22 (95% CI 1.15-1.30) and 0.70 (95% CI 0.66-0.75), respectively, independent of risk profiles, education levels, drug usage, self-care, and comorbidities at baseline. We reported consistent results in propensity-score-matched analyses and after accounting for loss to follow-up. Potential limitations include its nonrandomized design that precludes causal inference, residual confounding, and participation bias. CONCLUSIONS: ICT-assisted integrated care was associated with a reduction in clinical events, including death in type 2 diabetes in public and private healthcare settings.

Optimizing the design of invasive placebo interventions in randomized controlled trials.

BACKGROUND: Placebo-controlled trials play an important role in the evaluation of healthcare interventions. However, they can be challenging to design and deliver for invasive interventions, including surgery. In-depth understanding of the component parts of the treatment intervention is needed to ascertain what should, and should not, be delivered as part of the placebo. Assessment of risk to patients and strategies to ensure that the placebo effectively mimics the treatment are also required. To date, no guidance exists for the design of invasive placebo interventions. This study aimed to develop a framework to optimize the design and delivery of invasive placebo interventions in RCTs. METHODS: A preliminary framework was developed using published literature to: expand the scope of an existing typology, which facilitates the deconstruction of invasive interventions; and identify placebo optimization strategies. The framework was refined after consultation with key stakeholders in surgical trials, consensus methodology and medical ethics. RESULTS: The resulting DITTO framework consists of five stages: deconstruct treatment intervention into constituent components and co-interventions; identify critical surgical element(s); take out the critical element(s); think risk, feasibility and role of placebo in the trial when considering remaining components; and optimize placebo to ensure effective blinding of patients and trial personnel. CONCLUSION: DITTO considers invasive placebo composition systematically, accounting for risk, feasibility and placebo optimization. Use of the framework can support the design of high-quality RCTs, which are needed to underpin delivery of healthcare interventions.

ANTECEDENTES: Los ensayos controlados con placebo juegan un papel importante en la evaluación de las intervenciones sanitarias. Sin embargo, pueden ser difíciles de diseñar e implementar en el caso de intervenciones invasivas, incluida la cirugía. Se necesita un conocimiento profundo de los componentes de la intervención terapéutica (para determinar qué se debe y qué no se debe administrar como parte del placebo). También se precisa de una evaluación del riesgo para los pacientes y de las estrategias para garantizar que el placebo imite el tratamiento de forma efectiva. Hasta la fecha no existen guías para el diseño de intervenciones invasivas con placebo. Este estudio tuvo como objetivo desarrollar un marco para optimizar el diseño y la práctica de intervenciones invasivas con placebo dentro en los ensayos clínicos aleatorizados (ECA). MÉTODOS: Utilizando la literatura publicada, se desarrolló un marco preliminar para i) ampliar el alcance de los modelos existentes para facilitar la deconstrucción de las actuaciones invasivas, y ii) identificar estrategias para optimizar el placebo. El marco se perfeccionó tras consultar con partes interesadas ​​en ensayos quirúrgicos, metodología de consenso y ética médica. RESULTADOS: El marco DITTO resultantes consiste en cinco etapas: Etapa 1: deconstrucción de la intervención de tratamiento en sus componentes esenciales y co-intervenciones; Etapa 2: identificar el(los) elemento(s) quirúrgico(s) básico(s); Etapa 3: eliminar el(los) elemento(s) básico(s); Etapa 4: considerar el riesgo, la viabilidad y el papel del placebo en el ensayo al tener en cuenta los demás componentes; y Etapa 5: optimizar el placebo para garantizar el cegamiento efectivo de los pacientes y del personal del ensayo. CONCLUSIÓN: DITTO considera de forma sistemática la naturaleza invasiva del placebo, teniendo en cuenta el riesgo, la viabilidad y la optimización del placebo. El uso de este marco de referencia puede ayudar al diseño de ECAs de alta calidad, necesarios para afianzar la implementación de intervenciones sanitarias.

Integration of biochemical and topographic cues for the formation and spatial distribution of invadosomes in nasopharyngeal epithelial cells.

Invadosomes are invasive protrusions generated by cells which can secrete matrix metalloproteinases for focal digestion of extracellular matrix. They also aid invasive cancer cells in their transmigration through vascular endothelium. However, how the physical and chemical cues in a three-dimensional (3D) system signal the spatial localization of invadosomes remains largely unknown. Here we study the topographic guidance of invadosome formation in invasive nasopharyngeal cells under the stimulation of an inflammatory cytokine, TGF-ß1, using engineered gratings with different width and depth. We first report that TGF-ß1 can act as an external signal to upregulate the formation of invadosomes with a random distribution on a plane 2D surface. When the cells were seeded on parallel 3D gratings of 5 µm width and 1 µm depth, most of the invadosomes aligned to the edges of the gratings, indicating a topographic cue to the control of invadosome localization. While the number of invadosomes per cell were not upregulated when the cells were seeded on 3D topography, guidance of invadosomes localization to edges is correlated with cell migration directionality on 1 µm deep gratings. Invadosomes preferentially form at edges when the cells move at a lower speed and are guided along narrow gratings. The invadosomes forming at 3D edges also have a longer half-life than those forming on a plane surface. These data suggest that there are integrated biochemical and 3D geometric cues underlying the spatial regulation of invasive structures so as to elicit efficient invasion or metastasis of cells. STATEMENT OF SIGNIFICANCE: Nasopharyngeal cells were integrated with the biological cues and matrix topography to govern the activity and spatial distribution of invadosomes. The biochemical induction of invadosome formation by TGF-ß1 in nasopharyngeal cells was observed. When the cells were seeded on parallel 3D gratings, most of the invadosomes aligned to the edges of the gratings due to topographical induced invadosome localization. While the number of invadosomes per cell were not upregulated, guidance of invadosomes localization to edges is correlated with cell migration directionality on 1 µm deep gratings. Invadosomes preferentially form at edges with a higher stability when the cells are guided along narrow gratings. The integrated biochemical and 3D geometric cues could elicit efficient invasion or metastasis of cells.

Changes in tuberculosis epidemiology, United States, 1993-2017.

BACKGROUND: After 20 years of steady decline, the pace of decline of tuberculosis (TB) incidence in the United States has slowed.METHODS: Trends in TB incidence rates and case counts since 1993 were assessed using national US surveillance data. Patient characteristics reported during 2014-2017 were compared with those for 2010-2013.RESULTS: TB rates and case counts slowed to an annual decline of respectively 2.2% (95%CI -3.4 to -1.0) and 1.5% (95%CI -2.7 to -0.3) since 2012, with decreases among US-born persons and no change among non-US-born persons. Overall, persons with TB diagnosed during 2014-2017 were older, more likely to have combined pulmonary and extra-pulmonary disease than extra-pulmonary disease alone, more likely to be of non-White race, and less likely to have human immunodeficiency virus infection, or cavitary pulmonary disease. During 2014-2017, non-US-born persons with TB were more likely to have diabetes mellitus, while the US-born were more likely to have smear-positive TB and use non-injecting drugs.CONCLUSION: Changes in epidemiologic trends are likely to affect TB incidence in the coming decades. The Centers for Disease Control and Prevention has called for increased attention to TB prevention through the detection and treatment of latent tuberculous infection.

First Observation of Unbound

The structure of the extremely proton-rich nucleus _{8}^{11}O_{3}, the mirror of the two-neutron halo nucleus _{3}^{11}Li_{8}, has been studied experimentally for the first time. Following two-neutron knockout reactions with a ^{13}O beam, the ^{11}O decay products were detected after two-proton emission and used to construct an invariant-mass spectrum. A broad peak of width ∼3.4 MeV was observed. Within the Gamow coupled-channel approach, it was concluded that this peak is a multiplet with contributions from the four lowest ^{11}O resonant states: J^{π}=3/2_{1}^{-}, 3/2_{2}^{-}, 5/2_{1}^{+}, and 5/2_{2}^{+}. The widths and configurations of these states show strong, nonmonotonic dependencies on the depth of the p-^{9}C potential. This unusual behavior is due to the presence of a broad threshold resonant state in ^{10}N, which is an analog of the virtual state in ^{10}Li in the presence of the Coulomb potential. After optimizing the model to the data, only a moderate isospin asymmetry between ground states of ^{11}O and ^{11}Li was found.

Update on the Hong Kong Reference Framework for Hypertension Care for Adults in Primary Care Settings-review of evidence on the definition of high blood pressure and goal of therapy.

The Hong Kong Reference Framework for Hypertension Care for Adults in Primary Care Settings is updated regularly to ensure it reflects the latest medical development and best practice. In 2017, guidelines from the United States included a major change, adopting the lower blood pressure values of 130/80 mm Hg in defining hypertension, in contrast to the prevailing international consensus of 140/90 mm Hg. After thorough review of the literature and international guidelines, the Advisory Group on Hong Kong Reference Framework for Care of Diabetes and Hypertension in Primary Care Settings (Advisory Group) recommends that the definition of hypertension adopted in the Reference Framework should remain unchanged as a blood pressure of ≥140/90 mm Hg, as there is currently inadequate evidence and lack of general consensus to support such change in Hong Kong. The Advisory Group agrees on individualised treatment goals, and recommends that the initial blood pressure goal for individuals with uncomplicated hypertension should be <140/90 mm Hg; for those who can tolerate it, the goal should be ≤130/80 mm Hg. A lower blood pressure is advisable for young or overweight/obese patients, smokers, and patients with other cardiovascular risk factors.

Outcomes of Stent Retriever versus Aspiration-First Thrombectomy in Ischemic Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND: There is ongoing debate regarding the optimal first-line thrombectomy technique for large-vessel occlusion. PURPOSE: We performed a systematic review and meta-analysis of comparative studies on stent retriever-first and aspiration-first thrombectomy. DATA SOURCES: We searched Ovid MEDLINE, PubMed, and EMBASE from 2009 to February 2018. STUDY SELECTION: Two reviewers independently selected the studies. The primary end point was successful reperfusion (TICI 2b/3). DATA ANALYSIS: Random-effects meta-analysis was used for analysis. DATA SYNTHESIS: Eighteen studies including 2893 patients were included. There was no significant difference in the rate of final successful reperfusion (83.9% versus 83.3%; OR = 0.87; 95% CI, 0.62%-1.27%) or good functional outcome (mRS 0-2) at 90 days (OR = 1.07; 95% CI, 0.80-1.44) between the stent-retriever thrombectomy and aspiration groups. The stent-retriever thrombectomy-first group achieved a statistically significant higher TICI 2b/3 rate after the first-line device than the aspiration-first group (74.9% versus 66.4%; OR = 1.53; 95% CI, 1.14%-2.05%) and resulted in lower use of a rescue device (19.9% versus 32.5%; OR = 0.36; 95% CI, 0.14%-0.90%). The aspiration-first approach resulted in a statistically shorter groin-to-reperfusion time (weighted mean difference, 7.15 minutes; 95% CI, 1.63-12.67 minutes). There was no difference in the number of passes, symptomatic intracerebral hemorrhage, vessel dissection or perforation, and mortality between groups. LIMITATIONS: Most of the included studies were nonrandomized. There was significant heterogeneity in some of the outcome variables. CONCLUSIONS: Stent-retriever thrombectomy-first and aspiration-first thrombectomy were associated with comparable final reperfusion rates and functional outcome. Stent-retriever thrombectomy was superior in achieving reperfusion as a stand-alone first-line technique, with lower use of rescue devices but a longer groin-to-reperfusion time.