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Purpose We compared the incidence of venous thromboembolism (VTE) among Asian populations with localized colorectal cancer undergoing curative resection with and without the use of pharmacological thromboprophylaxis (PTP). Methods A comprehensive literature search was undertaken to identify relevant studies published from January 1, 1980 to February 28, 2022. The inclusion criteria were patients who underwent primary tumor resection for localized nonmetastatic colorectal cancer; an Asian population or studies conducted in an Asian country; randomized controlled trials, case-control studies, or cohort studies; and the incidence of symptomatic VTE, deep vein thrombosis, and/or pulmonary embolism as the primary study outcomes. Data were pooled using a random-effects model. This study was registered in PROSPERO on October 11, 2020 (No. CRD42020206793). Results Seven studies (2 randomized controlled trials and 5 observational cohort studies) were included, encompassing 5,302 patients. The overall incidence of VTE was 1.4%. The use of PTP did not significantly reduce overall VTE incidence: 1.1% (95% confidence interval [CI], 0%–3.1%) versus 1.9% (95% CI, 0.3%–4.4%; P=0.55). Similarly, PTP was not associated with significantly lower rates of symptomatic VTE, proximal deep vein thrombosis, or pulmonary embolism. Conclusion The benefit of PTP in reducing VTE incidence among Asian patients undergoing curative resection for localized colorectal cancer has not been clearly established. The decision to administer PTP should be evaluated on a case-by-case basis and with consideration of associated bleeding risks.

Introduction: Bilateral breast cancers (BBC) diagnosed at an interval apart are uncommon. While metastatic staging guidelines are established in patients with unilateral breast cancer, its role in BBC diagnosed at an interval apart is unclear. We aim to identify the subgroup who would benefit from metastatic staging at contralateral cancer diagnosis. Methods: Eligible patients were divided into three categories: (A) ipsilateral invasive cancer and contralateral ductal carcinoma in situ (DCIS), (B) bilateral invasive cancers and (C) ipsilateral DCIS and contralateral invasive cancer and reviewed retrospectively. We excluded patients with bilateral DCIS, synchronous BBC diagnosed within 6 months from first cancer, patients who were stage IV at first cancer diagnosis and patients with recurrence prior to contralateral cancer. Results: Of 4516 newly diagnosed breast cancer patients, 79 patients were included. Systemic metastasis occurred in 15.6% of patients in Group B. Having nodal positivity of either cancer which were diagnosed ≤30 months apart and nodal positivity of only the contralateral cancer when diagnosed >30 months apart was significantly associated with systemic metastasis (p = 0.0322). Conclusions: Both the nodal status and a 30 months cut-off time interval between the two cancers can be used to identify patients who will benefit from metastatic staging. This finding requires validation in larger studies.

Background: Forearm fractures are the most common paediatric fractures. While successful management in the preadolescent is often conservative, outcomes in adolescents have greatly improved with intramedullary Titanium Elastic Nail System (TENS) and rigid plate fixation. However, there have been no objective criteria for determining when TENS may be used in adolescents. This study aimed to compare the modified method of Sauvegrain et al. (2005) for skeletal age scoring against chronological age to predict treatment outcomes in adolescents with a forearm fracture treated by TENS and subsequently determine the skeletal age limits of TENS in adolescents. Patients and methods: This was a single-centre retrospective study of adolescents aged 10–16 years with an isolated, complete diaphyseal forearm fracture managed surgically from January 2014 to 2018. The modified Sauvegrain method provided skeletal age scoring via elbow radiographs. Functional outcomes were classified into good and poor groups by considering the treatment complication, range of motion and functional ability at the final review one year after intervention. Results: There were 128 TENS patients, comprising 15 females and 113 males. On average, males displayed older skeletal age than chronological age with a mean (SD) difference of 1.29 (1.03) years (p

Abstract Background We aimed to explore the three-way interaction among age, gender, and kidney function on the risk of all-cause mortality and cardiovascular mortality among patients with type 2 diabetes (T2D). Methods In a retrospective cohort study, patients aged > 40 years with T2D with serum creatinine and urine albumin measured from 2013 to 2019 were included from a multi-institutional diabetes registry. The exposure was estimated glomerular filtration rate (eGFR), outcomes were all-cause mortality (primary outcome) and cardiovascular disease (CVD) mortality (secondary outcome). We applied multivariable cox proportional hazards regression analysis to compute the association between eGFR and mortality. Results A total of 36,556 patients were followed for up to 6 years during which 2492 (6.82%) died from all causes, and 690 (1.9%) died from CVD. We observed a significant three-way interaction (p = 0.021) among age (younger,

Abstract Background Advances in four-dimensional flow cardiovascular magnetic resonance (4D flow CMR) have allowed quantification of left ventricular (LV) and right ventricular (RV) blood flow. We aimed to (1) investigate age and sex differences of 4D flow CMR-derived LV and RV relative flow components and kinetic energy (KE) parameters indexed to end-diastolic volume (KEiEDV) in healthy subjects; and (2) assess the effects of age and sex on these parameters. Methods We performed 4D flow analysis in 163 healthy participants (42% female; mean age 43 ± 13 years) of a prospective registry study (NCT03217240) who were free of cardiovascular diseases. Relative flow components (direct flow, retained inflow, delayed ejection flow, residual volume) and multiple phasic KEiEDV (global, peak systolic, average systolic, average diastolic, peak E-wave, peak A-wave) for both LV and RV were analysed. Results Compared with men, women had lower median LV and RV residual volume, and LV peak and average systolic KEiEDV, and higher median values of RV direct flow, RV global KEiEDV, RV average diastolic KEiEDV, and RV peak E-wave KEiEDV. ANOVA analysis found there were no differences in flow components, peak and average systolic, average diastolic and global KEiEDV for both LV and RV across age groups. Peak A-wave KEiEDV increased significantly (r = 0.458 for LV and 0.341 for RV), whereas peak E-wave KEiEDV (r = − 0.355 for LV and − 0.318 for RV), and KEiEDV E/A ratio (r = − 0.475 for LV and − 0.504 for RV) decreased significantly, with age. Conclusion These data using state-of-the-art 4D flow CMR show that biventricular flow components and kinetic energy parameters vary significantly by age and sex. Age and sex trends should be considered in the interpretation of quantitative measures of biventricular flow. Clinical trial registration https://www.clinicaltrials.gov . Unique identifier: NCT03217240.

Recent reviews highlighted low-intensity transcranial focused ultrasound (TUS) as a promising new tool for non-invasive neuromodulation in basic and applied sciences. Our preregistered double-blind within-subjects study (N = 152) utilized TUS targeting the right prefrontal cortex, which, in earlier work, was found to positively enhance self-reported global mood, decrease negative states of self-reported emotional conflict (anxiety/worrying), and modulate related midfrontal functional magnetic resonance imaging activity in affect regulation brain networks. To further explore TUS effects on objective physiological and behavioral variables, we used a virtual T-maze task that has been established in prior studies to measure motivational conflicts regarding whether participants execute approach versus withdrawal behavior (with free-choice responses via continuous joystick movements) while allowing to record related electroencephalographic data such as midfrontal theta activity (MFT). MFT, a reliable marker of conflict representation on a neuronal level, was of particular interest to us since it has repeatedly been shown to explain related behavior, with relatively low MFT typically preceding approach-like risky behavior and relatively high MFT typically preceding withdrawal-like risk aversion. Our central hypothesis is that TUS decreases MFT in T-maze conflict situations and thereby increases approach and reduces withdrawal. Results indicate that TUS led to significant MFT decreases, which significantly explained increases in approach behavior and decreases in withdrawal behavior. This study expands TUS evidence on a physiological and behavioral level with a large sample size of human subjects, suggesting the promise of further research based on this distinct TUS-MFT-behavior link to influence conflict monitoring and its behavioral consequences. Ultimately, this can serve as a foundation for future clinical work to establish TUS interventions for emotional and motivational mental health.

BackgroundPulmonary artery (PA) strain is associated with structural and functional alterations of the vessel and is an independent predictor of cardiovascular events. The relationship of PA strain to metabolomics in participants without cardiovascular disease is unknown.MethodsIn the current study, community-based older adults, without known cardiovascular disease, underwent simultaneous cine cardiovascular magnetic resonance (CMR) imaging, clinical examination, and serum sampling. PA global longitudinal strain (GLS) analysis was performed by tracking the change in distance from the PA bifurcation to the pulmonary annular centroid, using standard cine CMR images. Circulating metabolites were measured by cross-sectional targeted metabolomics analysis.ResultsAmong n = 170 adults (mean age 71 ± 6.3 years old; 79 women), mean values of PA GLS were 16.2 ± 4.4%. PA GLS was significantly associated with age (β = −0.13, P = 0.017), heart rate (β = −0.08, P = 0.001), dyslipidemia (β = −2.37, P = 0.005), and cardiovascular risk factors (β = −2.49, P = 0.001). Alanine (β = −0.007, P = 0.01) and proline (β = −0.0009, P = 0.042) were significantly associated with PA GLS after adjustment for clinical risk factors. Medium and long-chain acylcarnitines were significantly associated with PA GLS (C12, P = 0.027; C12-OH/C10-DC, P = 0.018; C14:2, P = 0.036; C14:1, P = 0.006; C14, P = 0.006; C14-OH/C12-DC, P = 0.027; C16:3, P = 0.019; C16:2, P = 0.006; C16:1, P = 0.001; C16:2-OH, P = 0.016; C16:1-OH/C14:1-DC, P = 0.028; C18:1-OH/C16:1-DC, P = 0.032).ConclusionBy conventional CMR, PA GLS was associated with aging and vascular risk factors among a contemporary cohort of older adults. Metabolic pathways involved in PA stiffness may include gluconeogenesis, collagen synthesis, and fatty acid oxidation.

BackgroundPrior studies have shown disparities in the uptake of cardioprotective newer glucose-lowering drugs (GLDs), including sodium-glucose cotranwsporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1a). This study aimed to characterize geographic variation in the initiation of newer GLDs and the geographic variation in the disparities in initiating these medications.MethodsUsing 2017-2018 claims data from a 15% random nationwide sample of Medicare Part D beneficiaries, we identified individuals diagnosed with type 2 diabetes (T2D), who had ≥1 GLD prescriptions, and did not use SGLT2i or GLP1a in the year prior to the index date,1/1/2018. Patients were followed up for a year. The cohort was spatiotemporally linked to Dartmouth hospital-referral regions (HRRs), with each patient assigned to 1 of 306 HRRs. We performed multivariable Poisson regression to estimate adjusted initiation rates, and multivariable logistic regression to assess racial disparities in each HRR.ResultsAmong 795,469 individuals with T2D included in the analyses, the mean (SD) age was 73 (10) y, 53.3% were women, 12.2% were non-Hispanic Black, and 7.2% initiated a newer GLD in the follow-up year. In the adjusted model including clinical factors, compared to non-Hispanic White patients, non-Hispanic Black (initiation rate ratio, IRR [95% CI]: 0.66 [0.64-0.68]), American Indian/Alaska Native (0.74 [0.66-0.82]), Hispanic (0.85 [0.82-0.87]), and Asian/Pacific islander (0.94 [0.89-0.98]) patients were less likely to initiate newer GLDs. Significant geographic variation was observed across HRRs, with an initiation rate spanning 2.7%-13.6%.ConclusionsThis study uncovered substantial geographic variation and the racial disparities in initiating newer GLDs.

Category: Ankle; Basic Sciences/Biologics Introduction/Purpose: Next-generation DNA sequencing (NGS) technologies have increased the sensitivity of bacterial cultures and has been used in other areas of orthopaedics to better understand the native microbiome of various joints. This study uses NGS to determine whether (1) a unique microbiome exists in human ankle tissues, (2) if components of the ankle microbiome impact patient outcomes, and (3) whether microbes found on the skin are a normal part of the ankle microbiome. Methods: A prospective study recruited 32 patients undergoing total ankle arthroplasty (TAA, n=23) or ankle arthrodesis via an anterior approach (n=9) during 2020-2021 with one of two fellowship-trained foot and ankle surgeons at an academic medical center. During the operation, the surgeon would swab five layers of the ankle for analysis at a CLIA-licensed molecular diagnostic laboratory: skin (n=32), retinaculum (n=31), tibialis anterior tendon (n=31), joint capsule (n=31), and distal tibia (n=32). Demographics, medical comorbidities, surgical indication, postoperative complications, and readmission and reoperation rates were collected from patient records. Results: Of the 157 swabs sent for NGS, 19 (12.1%) indicated 27 bacteria were present (positive), while the remaining 138 (87.9%) had no bacteria present (negative). The most common organisms were Cutibacterium acnes, present in 11 ankles (34.4%), and Staphylococcus epidermidis, present in 3 ankles (9.4%). The most bacteria were found in the retinaculum (29.6%). No PROM nor follow-up duration was associated with the presence of bacteria, or the number of bacteria or affected layers. Similarly, complication (positive=18.2%, negative=23.8%; p=1.000), nonunion (positive=0.0%, negative=28.6%; p=1.000), infection (positive=0.0%, negative=4.8%; p=1.000), 90-day readmission (positive=0.0%, negative=4.8%; p=1.000), and reoperation (positive=0.0%, negative=4.8%; p=1.000) rates did not differ if a subject’s NGS profile was positive or negative. Conclusion: This study found that C. acnes and S. epidermidis were most commonly found in the ankle microbiome, with C. acnes being present in 34% of ankles. There was no difference in complication rates between patient with and without positive bacterial cultures following TAA or ankle arthrodesis.

Category: Ankle; Other Introduction/Purpose: Chronic ankle instability (CAI) is one of the most commonly encountered clinical problems by orthopaedic foot and ankle surgeons, however, little research exists on the impact of insurance status on the incidence and outcomes of CAI. This study aims to investigate the association between psychiatric diagnosis and insurance status in CAI patients to determine if insurance subgroups differ in rate of surgery and postoperative success, as well as identify if psychiatric diagnoses are more common within certain insurance types. Methods: A retrospective review was conducted of 276 patients (280 ankles) treated between 2005 and 2021 at an academic medical center by one of three fellowship-trained foot and ankle orthopaedic surgeons, of which 56 (20.0%) underwent surgery, seven (2.5%) underwent reoperation, and 130 (46.4%) had a concomitant psychiatric diagnosis (i.e., anxiety=111, depression=105, post-traumatic stress disorder [PTSD]=19, obsessive-compulsive disorder [OCD]=6, bipolar disorder [BPD]=5). Insurance type was categorized as privately- (n=147) or government-funded (n=121). For further analysis, the government-funded cohort was broken into the following groups: Medicare (n=77), Veterans Affairs (n=20), Worker’s Compensation (n=18), and Medicaid (n=6). Eleven patients (12 feet) were uninsured. Data collected included demographics, conservative and operative treatments, patient- reported outcome measures (PROMs) (e.g., Foot and Ankle Ability Measure [FAAM]), and reoperation rate. Results: When examining binomial insurance groups, rate of surgery (private=15.6%, government=24.8%; p=.061) approached, but did not reach, significance and reoperation rate (private=17.4%, government=10.0%; p=.451) did not differ. Postoperatively, PROMs did not differ between private and government insurance types, but FAAM Physical Function (p=.046) and Total (p=.035) scores were best with Medicare insurance when analyzing all insurance groups. Instance of mental illness (p=.111) or certain psychiatric diagnoses did not differ between privately- and government-insured patients, but depression (p=.013) and PTSD (p=.050) were significantly less common among patients with Veterans Affairs insurance. Conclusion: CAI patients were not found to have differing need for surgery between insurance types. This was similar for postoperative success, aside from Medicare patients having better reported FAAM scores. Furthermore, patients with a psychiatric diagnosis were not more common to an insurance group, but specific depression and PTSD diagnoses were least common for Veterans Affairs patients.

Bioremediation by in situ biostimulation is an attractive alternative to excavation of contaminated soil. Many in situ remediation methods have been tested with some success; however, due to highly variable results in realistic field conditions, they have not been implemented as widely as they might deserve. To ensure success, methods should be validated under site-analogous conditions before full scale use, which requires expertise and local knowledge by the implementers. The focus here is on indigenous microbial degraders and evaluation of their performance. Identifying and removing biodegradation bottlenecks for degradation of organic pollutants is essential. Limiting factors commonly include: lack of oxygen or alternative electron acceptors, low temperature, and lack of essential nutrients. Additional factors: the bioavailability of the contaminating compound, pH, distribution of the contaminant, and soil structure and moisture, and in some cases, lack of degradation potential which may be amended with bioaugmentation. Methods to remove these bottlenecks are discussed. Implementers should also be prepared to combine methods or use them in sequence. Chemical/physical means may be used to enhance biostimulation. The review also suggests tools for assessing sustainability, life cycle assessment, and risk assessment. To help entrepreneurs, decision makers, and methods developers in the future, we suggest founding a database for otherwise seldom reported unsuccessful interventions, as well as the potential for artificial intelligence (AI) to assist in site evaluation and decision-making.

Abstract We aim to determine whether combined thermal and ultrasound (CTUS) imaging can identify rheumatoid arthritis (RA) patients with at least moderate disease activity (DAS28 > 3.2). Temperature differences of maximum (Tmax), average (Tavg) and minimum (Tmin) temperatures from a control temperature at 22 joints (bilateral hands) were summed up to derive the respective MAX, AVG and MIN per patient. MAX (PD), AVG (PD) and MIN (PD) are CTUS results derived by multiplying MAX, AVG and MIN by a factor of 2 when a patient’s total ultrasound power Doppler (PD) joint inflammation score > median score, which otherwise remained unchanged. Receiver operating characteristic (ROC) analysis was used to determine whether CTUS imaging can identify patients with DAS28 > 3.2. In this cross-sectional study, 814 joints were imaged among 37 RA patients (mean disease duration, 31 months). CTUS (but not single modality) imaging parameters were all significantly greater comparing patients with DAS28 > 3.2 versus those with DAS28 ≤ 3.2 (all P 3.2 were 0.73 , 0.76 and 0.76 for MAX (PD), AVG (PD) and MIN (PD), respectively (with sensitivity ranging from 58 to 61% and specificity all 100%). The use of CTUS in detecting a greater severity of joint inflammation among patients with at least moderate disease activity (DAS28 > 3.2) appears promising and will require further validation in independent RA cohorts.

Droplet rebound on superhydrophobic surfaces usually occurs during the retraction phase after reaching a maximum spread diameter, even in binary impacts. The authors report a rebound phenomenon in which a sessile droplet on a hydrophobic surface lifts off in its spreading phase following the impact from a soft hydrogel bead.

Abstract Background Cardiovascular magnetic resonance (CMR) offers comprehensive right ventricular (RV) evaluation in pulmonary arterial hypertension (PAH). Emerging four-dimensional (4D) flow CMR allows visualization and quantification of intracardiac flow components and calculation of phasic blood kinetic energy (KE) parameters but it is unknown whether these parameters are associated with cardiopulmonary exercise test (CPET)-assessed exercise capacity, which is a surrogate measure of survival in PAH. We compared 4D flow CMR parameters in PAH with healthy controls, and investigated the association of these parameters with RV remodelling, RV functional and CPET outcomes. Methods PAH patients and healthy controls from two centers were prospectively enrolled to undergo on-site cine and 4D flow CMR, and CPET within one week. RV remodelling index was calculated as the ratio of RV to left ventricular (LV) end-diastolic volumes (EDV). Phasic (peak systolic, average systolic, and peak E-wave) LV and RV blood flow KE indexed to EDV (KEIEDV) and ventricular LV and RV flow components (direct flow, retained inflow, delayed ejection flow, and residual volume) were calculated. Oxygen uptake (VO2), carbon dioxide production (VCO2) and minute ventilation (VE) were measured and recorded. Results 45 PAH patients (46 ± 11 years; 7 M) and 51 healthy subjects (46 ± 14 years; 17 M) with no significant differences in age and gender were analyzed. Compared with healthy controls, PAH had significantly lower median RV direct flow, RV delayed ejection flow, RV peak E-wave KEIEDV, peak VO2, and percentage (%) predicted peak VO2, while significantly higher median RV residual volume and VE/VCO2 slope. RV direct flow and RV residual volume were significantly associated with RV remodelling, function, peak VO2, % predicted peak VO2 and VE/VCO2 slope (all P

Background: Studies had compared single-embryo transfer to double-embryo transfer with cleavage stage embryos and found that while single-embryo transfer was less costly, it was also associated with a lower live birth rate than double-embryo transfer. A single blastocyst transfer has been shown to improve the live birth rate per cycle compared to single-embryo transfer at cleavage stage. Objectives: To compare live birth rates and real costs of elective single-embryo transfer to double-embryo transfer and to determine the incremental cost-effectiveness ratio of these two strategies in an unselected pool of women in a single center. Design: Retrospective study. Methods: We analyzed data of 4232 women who underwent their first fresh in vitro fertilization/intra-cytoplasmic sperm injection cycles with at least two embryos available for transfer in KK Women’s and Children’s Hospital from 2010 to 2017. Results: Five hundred and sixty-four women underwent elective single-embryo transfer and 3668 women underwent double-embryo transfer. One hundred and fifty-six women who failed to achieve a live birth in their fresh elective single-embryo transfer cycle underwent a sequential thaw single-embryo transfer cycle. Live birth rate of fresh elective single-embryo transfer was significantly higher at 41.3% than that of double-embryo transfer at 32.6%. Cumulative live birth rate for sequential elective single-embryo transfer (fresh elective single-embryo transfer + thaw single-embryo transfer) was 47.9%. After accounting for variables which may affect live birth rates such as age and stage of embryo transfer, the odds of achieving a live birth from double-embryo transfer was 24% lower than that from sequential single-embryo transfer, although not statistically significant. For every live birth gained from an elective single-embryo transfer compared to double-embryo transfer, cost savings were S$20,172 per woman. If a woman had to have a sequential single-embryo transfer after a failed single-embryo transfer in her fresh cycle, cost savings were reduced to S$1476 per woman. Conclusion: Single-embryo transfer is a dominant strategy in an unselected population and adopting it in assisted reproductive treatments (ART) can produce cost savings without compromising on live birth rates.

Introduction The Florida-California Cancer Research, Education, and Engagement (CaRE 2 ) Health Equity Center is a triad partnership committed to increasing institutional capacity for cancer disparity research, the diversity of the cancer workforce, and community empowerment. This article provides an overview of the structure, process innovations, and initial outcomes from the first 4 years of the CaRE 2 triad partnership. Methods CaRE 2 serves diverse populations in Florida and California using a “molecule to the community and back” model. We prioritize research on the complex intersection of biological, environmental, and social determinants health, working together with scientific and health disparities communities, sharing expertise across institutions, bidirectional training, and community outreach. Partnership progress and outcomes were assessed using mixed methods and four Program Steering Committee meetings. Results Research capacity was increased through development of a Living Repository of 81 cancer model systems from minority patients for novel cancer drug development. CaRE 2 funded 15 scientific projects resulting in 38 publications. Workforce diversity entailed supporting 94 cancer trainees (92 URM) and 34 ESIs (32 URM) who coauthored 313 CaRE 2 -related publications and received 48 grants. Community empowerment was promoted via outreaching to more than 3000 individuals, training 145 community cancer advocates (including 28 Community Scientist Advocates), and publishing 10 community reports. CaRE 2 members and trainees together have published 639 articles, received 61 grants, and 57 awards. Conclusion The CaRE 2 partnership has achieved its initial aims. Infrastructure for translational cancer research was expanded at one partner institution, and cancer disparities research was expanded at the two cancer centers.

Abstract The prediction utility of Framingham Risk Score in populations with low conventional cardiovascular risk burden is limited, particularly among women. Gender-specific markers to predict cardiovascular risk in overtly healthy people are lacking. In this study we hypothesize that postprandial responses triggered by a high-calorie meal test differ by gender in their ability to triage asymptomatic subjects into those with and without subclinical atherosclerosis. A total of 101 healthy Chinese subjects (46 females, 55 males) at low risk of coronary heart disease completed the study. Subjects underwent cardiovascular imaging and postprandial blood phenotyping after consuming a standardized macronutrient meal. Prediction models were developed using logistic regression and subsequently subjected to cross-validation to obtain a de-optimized receiver operating characteristic (ROC) curve. Distinctive gender differences in postprandial trajectories of glucose, lipids and inflammatory markers were observed. We used gender-specific association with different combinations of postprandial predictors to develop 2 models for predicting risk of subclinical atherosclerosis in males (ROC AUC = 0.7867, 95% CI 0.6567, 0.9166) and females (ROC AUC = 0.9161, 95% CI 0.8340, 0.9982) respectively. We report novel postprandial models for predicting subclinical atherosclerosis in apparently healthy Asian subjects using a gender-specific approach, complementing the conventional Framingham Risk Score. Clinical Trial Registration: The trial was registered at clinicaltrials.gov as NCT03531879.

Abstract The biological underpinnings of the PD clusters remain unknown as the existing PD clusters lacks biomarker characterization. We try to identify clinical subtypes of Parkinson Disease (PD) in an Asian cohort and characterize them by comparing clinical assessments, genetic status and blood biochemical markers. A total of 206 PD patients were included from a multi-centre Asian cohort. Hierarchical clustering was performed to generate PD subtypes. Clinical and biological characterization of the subtypes were performed by comparing clinical assessments, allelic distributions of Asian related PD gene (SNCA, LRRK2, Park16, ITPKB, SV2C) and blood biochemical markers. Hierarchical clustering method identified three clusters: cluster A (severe subtype in motor, non-motor and cognitive domains), cluster B (intermediate subtype with cognitive impairment and mild non-motor symptoms) and cluster C (mild subtype and young age of onset). The three clusters had significantly different allele frequencies in two SNPs (Park16 rs6679073 A allele carriers in cluster A B C: 67%, 74%, 89%, p = 0.015; SV2C rs246814 T allele distribution: 7%, 12%, 25%, p = 0.026). Serum homocysteine (Hcy) and C-reactive protein (CRP) levels were also significantly different among three clusters (Mean levels of Hcy and CRP among cluster A B C were: 19.4 ± 4.2, 18.4 ± 5.7, 15.6 ± 5.6, adjusted p = 0.005; 2.5 ± 5.0, 1.5 ± 2.4, 0.9 ± 2.1, adjusted p

BackgroundDeep gray nuclear pathology relates to motor deterioration in idiopathic Parkinson’s disease (PD). Inconsistent deep nuclear diffusion tensor imaging (DTI) findings in cross-sectional or short-term longitudinal studies have been reported. Long-term studies in PD are clinically challenging; decade-long deep nuclear DTI data are nonexistent. We investigated serial DTI changes and clinical utility in a case-control PD cohort of 149 subjects (72 patients/77 controls) over 12 years.MethodsParticipating subjects underwent brain MRI at 1.5T; DTI metrics from segmented masks of caudate, putamen, globus pallidus and thalamus were extracted from three timepoints with 6-year gaps. Patients underwent clinical assessment, including Unified Parkinson Disease Rating Scale Part 3 (UPDRS-III) and Hoehn and Yahr (H&Y) staging. A multivariate linear mixed-effects regression model with adjustments for age and gender was used to assess between-group differences in DTI metrics at each timepoint. Partial Pearson correlation analysis was used to correlate clinical motor scores with DTI metrics over time.ResultsMD progressively increased over time and was higher in the putamen (p < 0.001) and globus pallidus (p = 0.002). FA increased (p < 0.05) in the thalamus at year six, and decreased in the putamen and globus pallidus at year 12. Putaminal (p = 0.0210), pallidal (p = 0.0066) and caudate MD (p < 0.0001) correlated with disease duration. Caudate MD (p < 0.05) also correlated with UPDRS-III and H&Y scores.ConclusionPallido-putaminal MD showed differential neurodegeneration in PD over 12 years on longitudinal DTI; putaminal and thalamic FA changes were complex. Caudate MD could serve as a surrogate marker to track late PD progression.

Background: Blood sample hemolysis continues to be a significant problem in clinical practice. In vitro hemolysis rates up to 77% have been reported in literature. The use of manual aspiration techniques for blood sampling has previously been shown to reduce the burden of erythrocyte injury in the pre-analytical phase compared to the vacuum collection technique. This study compares the hemolysis rates between two blood sampling methods: 5.0 ml BD Vacutainer® SST™ (BDV) and 4.9 ml S-Monovette® serum gel tubes in aspiration mode (SMA). Methods: This was a prospective randomised controlled study conducted in an Emergency department (ED). A convenience sample of 191 adult patients, aged 18–90 years old, presenting at the ED and requiring blood samples for serum electrolyte was included in the study. Paired blood samples were obtained through an intravenous cannula from each patient with randomised order of blood draw using SMA or BDV. Patient data was obtained and hemolysis index (HI), serum lactate dehydrogenase (LDH), and serum potassium (K) levels measured. Results: The adjusted mean HI (35.2 vs 21.5 mg/dL, p 150 mg/dL) samples was also higher in blood collected using BDV (16.2%) compared to SMA (0%). Conclusions: The burden of hemolysis in blood samples taken from IV cannulae can be effectively reduced with the use of manual aspiration using the S-Monovette® blood collection system as compared to BD-Vacutainer.

In this paper we illustrate how novel AI methods can improve the performance of intelligence analysts. These analysts aim to make sense of — often conflicting or incomplete — information, weighing up competing hypotheses which serve to explain an observed situation. Analysts have access to numerous visual analytic tools which support the temporal and/or conceptual structuring of information and collection, and support the evaluation of alternative hypotheses. We believe, however, that there are currently no tools or methods which allow analysts to combine the recording and interpretation of information, and that there is little understanding about how software tools can facilitate the hypothesis formation process. Following the identification of these requirements, we developed the CISpaces (Collaborative Intelligence Spaces) decision support tool in collaboration with professional intelligence analysts. CISpaces combines multiple AI-based methods including argumentation theory, crowdsourced Bayesian analysis, and provenance recording. We show that CISpaces is able to provide support to analysts by facilitating the interpretation of different types of evidence through argumentation-based reasoning, provenance analysis and crowdsourcing. We undertook an experimental analysis with intelligence analysts which highlights three key points. (1) The novel, principled AI methods implemented in CISpaces advance performance in intelligence analysis. (2) While designed as a research prototype, analysts benchmarked it against their existing software tools, and we provide results suggesting intention to adopt CISpaces in analysts’ daily activities. (3) Finally, the evaluation highlights some drawbacks in CISpaces. However, these are not due to the technologies underpinning the tool, but rather in its lack of integration with existing organisational standards regarding input and output formats. Our evaluation with intelligence analysts therefore demonstrates the potential impact that an integrated tool building on state-of-the-art AI techniques can have on the process of understanding complex situations, and on how such a tool can help focus human effort on identifying more credible interpretations of evidence.

Introduction: End-of-life (EOL) conditions are commonly encountered by emergency physicians (EP). We aim to explore EPs' experience and perspectives toward EOL discussions in acute settings. Methods: A qualitative survey was conducted among EPs in three tertiary institutions. Data on demographics, EOL knowledge, conflict management strategies, comfort level, and perceived barriers to EOL discussions were collected. Data analysis was performed using SPSS and SAS. Results: Of 63 respondents, 40 (63.5%) were male. Respondents comprised 22 senior residents/registrars, 9 associate consultants, 22 consultants, and 10 senior consultants. The median duration of emergency department practice was 8 (interquartile range: 6–10) years. A majority (79.3%) reported conducting EOL discussions daily to weekly, with most (90.5%) able to obtain general agreement with families and patients regarding goals of care. Top barriers were communications with family/clinicians, lack of understanding of palliative care, and lack of rapport with patients. 38 (60.3%) deferred discussions to other colleagues (e.g., intensivists), 10 (15.9%) involved more family members, and 13 (20.6%) employed a combination of approaches. Physician's comfort level in discussing EOL issues also differed with physician seniority and patient type. There was a positive correlation between the mean general comfort level when discussing EOL and the seniority of the EPs up till consultancy. However, the comfort level dropped among senior consultants as compared to consultants. EPs were most comfortable discussing EOL of patients with a known terminal illness and least comfortable in cases of sudden death. Conclusions: Formal training and standardized framework would be useful to enhance the competency of EPs in conducting EOL discussions.

Abstract Background Four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) allows quantification of biventricular blood flow by flow components and kinetic energy (KE) analyses. However, it remains unclear whether 4D flow parameters can predict cardiopulmonary exercise testing (CPET) as a clinical outcome in repaired tetralogy of Fallot (rTOF). Current study aimed to (1) compare 4D flow CMR parameters in rTOF with age- and gender-matched healthy controls, (2) investigate associations of 4D flow parameters with functional and volumetric right ventricular (RV) remodelling markers, and CPET outcome. Methods Sixty-three rTOF patients (14 paediatric, 49 adult; 30 ± 15 years; 29 M) and 63 age- and gender-matched healthy controls (14 paediatric, 49 adult; 31 ± 15 years) were prospectively recruited at four centers. All underwent cine and 4D flow CMR, and all adults performed standardized CPET same day or within one week of CMR. RV remodelling index was calculated as the ratio of RV to left ventricular (LV) end-diastolic volumes. Four flow components were analyzed: direct flow, retained inflow, delayed ejection flow and residual volume. Additionally, three phasic KE parameters normalized to end-diastolic volume (KEiEDV), were analyzed for both LV and RV: peak systolic, average systolic and peak E-wave. Results In comparisons of rTOF vs. healthy controls, median LV retained inflow (18% vs. 16%, P = 0.005) and median peak E-wave KEiEDV (34.9 µJ/ml vs. 29.2 µJ/ml, P = 0.006) were higher in rTOF; median RV direct flow was lower in rTOF (25% vs. 35%, P

Background and Study Aim. Exercise and Recreation play major role in promotion of health and fitness. Recreational exercise or sports can be useful in physically inactive population. The aim of study was to investigate the effect of recreational handball on body fat percent, VO2max, blood pressure and resting heart rate. Another purpose to find relationship between VO2max and body fat percentage. Material and Methods. Twenty-four students were randomized into intervention (n=14) and control group (n=10). The intervention group was asked to play recreational handball for 12 weeks. Handball training was held twice a week for 30 minutes duration. The Control group performed their normal routine. Aerobic capacity measured using single-stage treadmill test. Body fat was measured with Omron Body Fat Analyzer. T-test was employed to find a significant difference in the two groups. For the relationship in aerobic capacity and body fat, Pearson Product Moment Correlation was used. Results. We found significant difference in body percent (t22 = 2.031, P = 0.054). No significant difference was seen in aerobic capacity (t22 = 1.578, P = 0.129), systolic blood pressure (t22 = -1.637, P = 0.116), diastolic blood pressure (t22 = -1.562, P = 0.133) and resting heart rate (t22 = 1.620, P = 0.120). Significant relationship was established between body percent and aerobic capacity (r= -5.23, n=14, p= 0.055) in the intervention group. Conclusions. It can be concluded that recreational handball was useful in eliciting good response with respect to reduction of body fat in intervention group. However, recreation handball sessions were not effective in reducing blood pressure, resting heart and aerobic capacity among untrained males. A significant relationship was observed in VO2max and percent body fat.

Introduction: Diabetes mellitus (DM) is known to influence outcomes in the short-term following stroke. However, the impact of DM on long-term functional outcomes after stroke is unclear. We compared functional outcomes periodically over 7 years between diabetic and non-diabetic ischemic stroke patients and investigated the impact of DM on the long-term trajectory of post-stroke functional outcomes. We also studied the influence of age on the diabetes-functional outcome association. Methods: This is a longitudinal observational cohort study of 802 acute ischemic stroke patients admitted to the Singapore General Hospital from 2005 to 2007. Functional outcomes were assessed using the modified Rankin Scale (mRS) with poor functional outcome defined as mRS≥3. Follow-up data was determined at 6 months and at median follow-up durations of 29 and 86 months. Results: Among the 802 ischemic stroke patients studied (mean age 64 ± 12 years, male 63%), 42% had DM. In regression analyses adjusting for covariates, diabetic patients were more likely to have poor functional outcomes at 6 months (OR=2.12, 95% CI: 1.23–3.67) and at median follow-up durations of 29 months (OR=1.96, 95% CI: 1.37–2.81) and 86 months (OR=2.27, 95% CI: 1.58–3.25). In addition, age modulated the effect of DM, with younger stroke patients (≤65 years) more likely to have long term poor functional outcome at the 29-month (p=0.0179) and 86-month (p=0.0144) time points. Conclusions: DM was associated with poor functional outcomes following ischemic stroke in the long term with the effect remaining consistent throughout the 7-year follow-up period. Age modified the effect of DM in the long term, with an observed increase in risk in the ≤65 age group but not in the >65 age group.

Abstract Background Autistic adolescents have greater predisposition to depression and suicidality than neurotypical adolescents. Early detection is essential for timely treatment. The Patient Health Questionnaire 9-item (PHQ-9) is a brief screen for depression. The study examines the validity of the PHQ-9 for detecting major depressive disorder (MDD) in autistic youths. Methods English speaking youths aged 10–18 years, with DSM-IV/DSM-5/ICD-10 diagnosis of Autism Spectrum Disorder (ASD), and their parents presenting to a child psychiatric service were invited to participate between May 2018 to August 2020. Participants completed the respective self- and parent-rated PHQ-9 independently. MDD was verified using the MINI-Kid (Mini-International Neuropsychiatric Interview, Kid version). Results One hundred one youth, mean (SD) age 14.6 (2.3), were enrolled. 27 (27%) met criteria for current MDD. Mean total PHQ-9 scores, percentage ratings for severity of symptoms of depression, functional impairment, dysthymia and suicidality were compared. Areas under the ROC curve and statistically optimal cutoffs were determined. Parents rated depressive symptoms severity lower than their children. The PHQ-9 displayed low sensitivity with high false negative rates at conventional, adjusted and proposed cutoffs. Conclusions Future studies should improve on the validity and reliability of existing depression screening tools, or develop more appropriate screening methods of depression, for autistic youths.

BackgroundConjugation of transferrin (Tf) to imaging or nanotherapeutic agents is a promising strategy to target breast cancer. Since the efficacy of these biomaterials often depends on the overexpression of the targeted receptor, we set out to survey expression of transferrin receptor (TfR) in primary and metastatic breast cancer samples, including metastases and relapse, and investigate its modulation in experimental models.MethodsGene expression was investigated by datamining in twelve publicly-available datasets. Dedicated Tissue microarrays (TMAs) were generated to evaluate matched primary and bone metastases as well as and pre and post chemotherapy tumors from the same patient. TMA were stained with the FDA-approved MRQ-48 antibody against TfR and graded by staining intensity (H-score). Patient-derived xenografts (PDX) and isogenic metastatic mouse models were used to study in vivo TfR expression and uptake of transferrin.ResultsTFRC gene and protein expression were high in breast cancer of all subtypes and stages, and in 60-85% of bone metastases. TfR was detectable after neoadjuvant chemotherapy, albeit with some variability. Fluorophore-conjugated transferrin iron chelator deferoxamine (DFO) enhanced TfR uptake in human breast cancer cells in vitro and proved transferrin localization at metastatic sites and correlation of tumor burden relative to untreated tumor mice.ConclusionsTfR is expressed in breast cancer, primary, metastatic, and after neoadjuvant chemotherapy. Variability in expression of TfR suggests that evaluation of the expression of TfR in individual patients could identify the best candidates for targeting. Further, systemic iron chelation with DFO may upregulate receptor expression and improve uptake of therapeutics or tracers that use transferrin as a homing ligand.

Category: Ankle; Trauma Introduction/Purpose: Ankle fracture open reduction and internal fixation (ORIF) is one of the most commonly performed orthopaedic surgeries, which can be performed at a variety of surgical locations. However, there is very little data exploring the cost and efficiency of ankle fracture ORIF in different operative settings. Time-Driven Activity Based Costing (TDABC) is a novel accounting method used to accurately assign costs for various procedures by creating a process map of all personnel interactions as a patient moves through a care event. Further, it has been shown to more accurately allocate costs, as compared to traditional accounting systems. Our purpose is to evaluate cost and efficiency differences in ankle fracture ORIF at an outpatient ambulatory surgery center (ASC) versus a hospital setting. Methods: A prospective cohort study was performed at a single academic medical center involving four orthopaedic surgeons. Patients were enrolled with uni-, bi-, or tri-malleolar displaced ankle fractures undergoing ORIF. According to TD-ABC methodology, a process map was created for each peri-operative platform and hand-timed data was collected at each location (ASC=5, hospital=5) by a single observer. In addition, retrospective cost data was obtained from 181 surgical cases using our institution's existing cost accounting system (ASC=34, hospital=147). Average event times and care costs were calculated for both locations, and a process map outlining the steps of care was created for each surgical site, according to TDABC methodology. Data were analyzed to investigate the effects of surgical site on labor cost, efficiency, and provider time. Results: Overall, total direct cost was similar between locations (ASC=$10,837.43, hospital=$9,377.80; p=.114), although there were significantly higher direct costs in the hospital: perioperative/anesthesia (ASC=$2,532.61, hospital=$4,594.20; p

Category: Ankle; Other Introduction/Purpose: Ankle instability is an extremely common clinical entity. Chronic ankle instability (CAI) can develop in some patients, leading to continued pain and dysfunction. However, there is very limited data to date on what impact common psychiatric pathology may have on patients' experience with CAI. This study aimed to investigate the association between psychiatric diagnosis and CAI, and whether having a diagnosed psychiatric illness impacts the outcome of CAI. We hypothesized that a concomitant diagnosis of psychiatric pathology with CAI would be significantly associated with lower postoperative patient- reported outcome measures (PROMs). Methods: A retrospective review was conducted of 276 patients (280 ankles) treated between 2005 and 2021 at an academic medical center by one of three fellowship-trained foot and ankle orthopaedic surgeons, of which 56 underwent surgery and 130 had a concomitant psychiatric diagnosis (i.e., anxiety=111, depression=105, post-traumatic stress disorder [PTSD]=19, obsessive- compulsive disorder [OCD]=6, bipolar disorder [BPD]=5). Data collected included demographics, conservative treatment history, and patient-reported outcome measures (PROMs), such as Visual Analogue Scale (VAS), Brief Resiliency Scale (BRS), 12-Item Short-Form Survey (SF-12), Somatic Symptom Scale (SSS-8), Pain Catastrophizing Scale (PCS), Pain Disability Index (PDI), Foot and Ankle Outcome Score (FAOS), and Foot and Ankle Ability Measure (FAAM). Results: Preoperatively, patients with these concomitant psychiatric diagnoses had worse preoperative PROMs. However, the overall cohort improved postoperatively across all PROMs. In particular, the FAOS Total score relatively increased by 35.28% (preop=57.29%, postop=77.50%, p=.011) and the FAAM Total by 49.86% (preop=45.87%, postop=68.74%, p=.027). Both improvements were significant. Of note, the relative change of pre- to postoperative FAOS and FAAM scores was greater among the mental illness group in all scores but FAOS Sports and Recreation. (Table 1) However, no postoperative PROM among the mental illness group, aside from the FAOS Symptoms and Stiffness score, was as high as the postoperative score of those without mental illness. Although patients with these psychiatric illnesses more often failed conservative measures and subsequently received surgical treatment, this was not significant. Conclusion: CAI patients with a concomitant psychiatric diagnosis improved more following surgery than those without mental illness, as measured by FAOS and FAAM scores. However, the mental illness group did not report postoperative FAOS and FAAM scores as high as those without mental illness. Furthermore, CAI patients with a concomitant mental illness more often failed conservative treatment and went on to receive surgery. Physicians should be aware of this information when counseling CAI patients with a concomitant mental illness.

BackgroundSubclinical atherosclerosis can be present in individuals with an optimal cardiovascular risk factor profile. Traditional risk scores such as the Framingham risk score do not adequately capture risk stratification in low-risk individuals. The aim of this study was to determine if markers of metabolic syndrome and insulin resistance can better stratify low-risk individuals.MethodsA cross-sectional study of 101 healthy participants with a low Framingham risk score and no prior morbidities was performed to assess prevalence of subclinical atherosclerosis using computed tomography (CT) and ultrasound. Participants were compared between groups based on Metabolic Syndrome (MetS) and Insulin-Sensitivity Index (ISI-cal) scores.ResultsTwenty three individuals (23%) had subclinical atherosclerosis with elevated CT Agatston score ≥1. Presence of both insulin resistance (ISI-cal

Abstract Globally, thunderstorms are responsible for a significant fraction of rainfall, and in the mid-latitudes often produce extreme weather, including large hail, tornadoes and damaging winds. Despite this importance, how the global frequency of thunderstorms and their accompanying hazards has changed over the past 4 decades remains unclear. Large-scale diagnostics applied to global climate models have suggested that the frequency of thunderstorms and their intensity is likely to increase in the future. Here, we show that according to ERA5 convective available potential energy (CAPE) and convective precipitation (CP) have decreased over the tropics and subtropics with simultaneous increases in 0–6 km wind shear (BS06). Conversely, rawinsonde observations paint a different picture across the mid-latitudes with increasing CAPE and significant decreases to BS06. Differing trends and disagreement between ERA5 and rawinsondes observed over some regions suggest that results should be interpreted with caution, especially for CAPE and CP across tropics where uncertainty is the highest and reliable long-term rawinsonde observations are missing.

Abstract Background Parameters of myocardial deformation may provide improved insights into right ventricular (RV) dysfunction. We quantified RV longitudinal myocardial function using a fast, semi-automated method and investigated its diagnostic and prognostic values in patients with repaired tetralogy of Fallot (rTOF) and pulmonary arterial hypertension (PAH), who respectively exemplify patients with RV volume and pressure overload conditions. Methods The study enrolled 150 patients (rTOF, n = 75; PAH, n = 75) and 75 healthy controls. RV parameters of interest were fast global longitudinal strain (GLS) and strain rates during systole (GLSRs), early diastole (GLSRe) and late diastole (GLSRa), obtained by tracking the distance from the medial and lateral tricuspid valve insertions to the RV epicardial apex on cine cardiovascular magnetic resonance (CMR). Results The RV fast GLS exhibited good agreement with strain values obtained by conventional feature tracking approach (bias − 4.9%, error limits (± 2·standard deviation) ± 4.3%) with fast GLS achieving greater reproducibility and requiring reduced analysis time. Mean RV fast GLS was reduced in PAH and rTOF groups compared to healthy controls (PAH

Introduction: The creatinine-based Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate (eGFR) equation was calibrated for the general Pakistan population (eGFRcr-PK) to eliminate bias and improve accuracy. Cystatin C–based CKD-EPI equations (eGFRcys and eGFRcr-cys) have not been assessed in this population, and non-GFR determinants of cystatin C are unknown. Methods: We assessed eGFRcys, eGFRcr-cys, and non-GFR determinants of cystatin C in a cross-sectional study of 557 participants (≥40 years of age) from Pakistan. We compared bias (median difference in measured GFR [mGFR] and eGFR), precision (interquartile range [IQR] of differences), accuracy (percentage of eGFR within 30% of mGFR), root mean square error (RMSE), and classification of mGFR

Abstract Progesterone is a steroid hormone that is critical for implantation and maintenance of pregnancy, and low levels are associated with higher miscarriage risk. However, little is known about its trajectory during early pregnancy. We sought to determine the gestational age-specific normative values of serum progesterone on a week-by-week basis, and its associated maternal and fetal factors, during the first trimester of a viable low-risk pregnancy. A cross-sectional study was conducted at KK Women’s and Children’s Hospital from 2013 to 2018. 590 women with a single viable intrauterine low-risk pregnancy, between gestational weeks 5 and 12, were recruited. Serum progesterone showed an increasing trend during the first trimester, with a transient decline between gestational weeks 6–8, corresponding to the luteal–placental shift. Lowest levels were seen at week 7. Maternal age, BMI, parity, gestational age and outcome of pregnancy at 16 weeks’ gestation were found to be associated with progesterone levels. Normative values of serum progesterone for low-risk pregnancies would form the basis for future work on pathological levels of serum progesterone that may increase risk of miscarriage. Larger studies are required to validate these normative values, and personalize them to account for maternal age, BMI, parity and gestational age.

BackgroundDespite availability of clinical practice guidelines for hypertension management, blood pressure (BP) control remains sub-optimal (Methods and findingsA cluster-randomized controlled trial was conducted in 8 government clinics in Singapore. The trial enrolled 916 patients aged ≥40 years with uncontrolled hypertension (systolic BP (SBP) ≥140 mmHg or diastolic BP (DBP) ≥90 mmHg). Multicomponent intervention consisted of physician training in risk-based treatment of hypertension, subsidized losartan-HCTZ single-pill combination (SPC) medications, nurse training in motivational conversations (MCs), and telephone follow-ups. Usual care (controls) comprised of routine care in the clinics, no MC or telephone follow-ups, and no subsidy on SPCs. The primary outcome was mean SBP at 24 months' post-baseline. Four clinics (447 patients) were randomized to intervention and 4 (469) to usual care. Patient enrolment commenced in January 2017, and follow-up was during December 2018 to September 2020. Analysis used intention-to-treat principles. The primary outcome was SBP at 24 months. BP at baseline, 12 and 24 months was modeled at the patient level in a likelihood-based, linear mixed model repeated measures analysis with treatment group, follow-up, treatment group × follow-up interaction as fixed effects, and random cluster (clinic) effects. A total of 766 (83.6%) patients completed 2-year follow-up. A total of 63 (14.1%) and 87 (18.6%) patients in intervention and in usual care, respectively, were lost to follow-up. At 24 months, the adjusted mean SBP was significantly lower in the intervention group compared to usual care (-3.3 mmHg; 95% CI: -6.34, -0.32; p = 0.03). The intervention led to higher BP control (odds ratio 1.51; 95% CI: 1.10, 2.09; p = 0.01), lower odds of high (>20%) 10-year cardiovascular risk score (OR 0.67; 95% CI: 0.47, 0.97; p = 0.03), and lower mean log albuminuria (-0.22; 95% CI: -0.41, -0.02; p = 0.03). Mean DBP, mortality rates, and serious adverse events including hospitalizations were not different between groups. The main limitation was no masking in the trial.ConclusionsA multicomponent intervention consisting of physicians trained in risk-based treatment, subsidized SPC medications, nurse-delivered motivational conversation, and telephone follow-ups improved BP control and lowered cardiovascular risk. Wide-scale implementation of a multicomponent intervention such as the one in our trial is likely to reduce hypertension-related morbidity and mortality globally.Trial registrationTrial Registration: Clinicaltrials.gov NCT02972619.

Abstract Introduction Cardiovascular disease (O'Lone E, Viecelli AK, Craig JC, Tong A, Sautenet B, Herrington WG, et al., Am J Kidney Dis 76(1):109–20, 2020) remains the leading cause of death in Singapore. Uncontrolled hypertension confers the highest attributable risk of CVD and remains a significant public health issue with sub-optimal blood pressure (BP) control rates. The aim of the trial is to evaluate the effectiveness and cost-effectiveness of a multicomponent intervention (MCI) versus usual care on lowering BP among adults with uncontrolled hypertension visiting primary care clinics in Singapore. This article describes the statistical analysis plan for the primary and secondary objectives related to intervention effectiveness. Methods The study is a cluster randomized trial enrolling 1000 participants with uncontrolled hypertension aged ≥ 40 years from eight primary care clinics in Singapore. The unit of randomization is the clinic, with eight clusters (clinics) randomized in a 1:1 ratio to either MCI or usual care. All participants will be assessed at baseline, 12 months, and 24 months with measurements of systolic and diastolic BP, antihypertensive and statin medication use, medication adherence, physical activity level, anthropometric parameters, smoking status, and dietary habits. The primary objective of this study is to assess the effectiveness of MCI versus usual care on mean SBP at the 2-year follow-up. The primary outcome is SBP at 24 months. SBP at baseline, 12, and 24 months will be modeled at the subject level using a likelihood-based, linear mixed-effects model repeated measures (MMRM) analysis with treatment group and follow-up as fixed effects, random cluster (clinic) effects, Gaussian error distribution, and adjustment to degrees of freedom using the Satterthwaite approximation. Secondary outcomes will be analyzed using a similar modeling approach incorporating generalized techniques appropriate for the type of outcome. Discussion The trial will allow us to determine whether the MCI has an impact on BP and cardiovascular risk factors over a 2-year follow-up period and inform recommendations for health planners in scaling up these strategies for the benefit of society at large. A pre-specified and pre-published statistical analysis plan mitigates reporting bias and data driven approaches. Trial registration ClinicalTrials.gov NCT02972619 . Registered on 23 November 2016.

Abstract Background Coronavirus disease 2019 (COVID-19) has impacted the provision of health services in all specialties. We aim to study the impact of COVID-19 on the utilization of pediatric hospital services including emergency department (ED) attendances, hospitalizations, diagnostic categories and resource utilization in Singapore. Methods We performed a retrospective review of ED attendances and hospital admissions among children

Abstract Background Burnout is a serious issue plaguing the medical profession with potential negative consequences on patient care. Burnout symptoms are observed as early as medical school. Based on a Job Demands-Resources model, this study aims to assess associations between specific job resources measured at the beginning of the first year of medical school with burnout symptoms occurring later in the first year. Methods The specific job resources of grit, tolerance for ambiguity, social support and gender were measured in Duke-NUS Medical School students at the start of Year 1. Students were then surveyed for burnout symptoms at approximately quarterly intervals throughout the year. Using high ratings of cynicism and exhaustion as the definition of burnout, we investigated the associations of the occurrence of burnout with student job resources using multivariable logistic regression analysis. Results Out of 59 students, 19 (32.2%) indicated evidence of burnout at some point across the first year of medical school. Stepwise multivariable logistic regression analysis identified grit as having a significant protective effect against experiencing burnout (Odds Ratio, 0.84; 95%CI 0.74 to 0.96). Using grit as a single predictor of burnout, area under the ROC curve was 0.76 (95%CI: 0.62 to 0.89). Conclusions Grit was identified as a protective factor against later burnout, suggesting that less gritty students are more susceptible to burnout. The results indicate that grit is a robust character trait which can prognosticate burnout in medical students. These students would potentially benefit from enhanced efforts to develop grit as a personal job resource.

Abstract Background Knowledge and skills decline within months post simulation-based training in neonatal resuscitation. To empower ‘Millennial’ learners to take control of their own learning, a single-player, unguided web-based Neonatal Resuscitation Game was designed. The present study investigates the effectiveness of the game on retention of resuscitation knowledge and skills. Methods The study evaluated 162 healthcare professionals who attended simulation-based training in neonatal resuscitation. Following standard simulation-based training, participants were assigned to either a gaming group (Gamers) with access to the web-based Neonatal Resuscitation Game or a control group (Controls) with no access to the game. Although Gamers were given access, game utilization was completely voluntary and at will. Some Gamers chose to utilize the web-based game (Players) and others did not (Non-players). Knowledge and skills in neonatal resuscitation were assessed upon completion of training and 6 months post-training using a multiple-choice question test and a manikin-based skills test. Changes in scores were compared statistically between Gamers vs Controls, Players vs Controls, and Players vs Controls + Non-players using two-sample t-tests. Results At the final assessment, declines in knowledge scores were seen in all groups. Mean change from baseline in knowledge and skill performance scores at 6 months, adjusted for baseline skill performance and MCQ test scores, did not differ significantly between Players vs Controls and Players vs Controls + Non-players. Conclusion The web-based game in its current format may not be effective in facilitating retention of knowledge and technical skills in neonatal resuscitation.

Abstract Purpose Removal of clipped nodes can improve sentinel node biopsy accuracy in breast cancer patients post neoadjuvant chemotherapy (NACT). However, the current methods of clipped node localization have limitations. We evaluated the feasibility of a novel clipped node localization and removal technique by preoperative skin marking of clipped nodes and removal by the Skin Mark clipped Axillary nodes Removal Technique (SMART), with the secondary aim of assessing the ultrasound visibility of the various clips in the axillary nodes after NACT. Methods Invasive breast cancer patients with histologically metastatic axillary nodes, going for NACT, and ≤3 sonographically abnormal axillary nodes were recruited. All abnormal nodes had clips inserted. Patients with M1 disease were excluded. Post‐NACT, patients underwent SMART and axillary lymph node dissection. Specimen radiography and pathological analyses were performed to confirm the clipped node presence. Success, complication rates of SMART, and ultrasound visibility of the various clips were assessed. Results Twenty‐five clipped nodes in 14 patients underwent SMART without complications. The UltraCor Twirl, hydroMARK, UltraClip Dual Trigger, and UltraClip were removed in 13/13 (100%), 7/9 (77.8%), 1/2 (50.0%), and 0/1 (0%), respectively (P = .0103) with UltraCor Twirl having the best ultrasound visibility and removal rate. Removal of three clipped nodes in the same patient (P = .0010) and deeply seated clipped nodes (P = .0167) were associated with SMART failure. Conclusion Skin Mark clipped Axillary nodes Removal Technique is feasible for removing clipped nodes post‐NACT, with 100% observed success rate, using the UltraCor Twirl marker in patients with

IntroductionFear of missed serious bacterial infections (SBIs) results in many febrile young infants receiving antibiotics. We aimed to compare the time to antibiotics between infants with SBIs and those without.Materials and MethodsWe recruited febrile infants ≤ 90 days old seen in the emergency department (ED) between December 2017 and April 2021. SBI was defined as (1) urinary tract infection, (2) bacteremia or (3) bacterial meningitis. We compared the total time (median with interquartile range, IQR) from ED arrival to infusion of antibiotics, divided into (i) time from triage to decision for antibiotics and (ii) time from decision for antibiotics to administration of antibiotics.ResultsWe analyzed 81 and 266 infants with and without SBIs. Median age of those with and without SBIs were 44 (IQR 19–72) and 29 (IQR 7–56) days, respectively (p = 0.002). All infants with SBIs and 168/266 (63.2%) infants without SBIs received antibiotics. Among 249 infants who received antibiotics, the median total time from ED arrival to infusion of antibiotics was 277.0 (IQR 236.0–385.0) mins for infants with SBIs and 304.5 (IQR 238.5–404.0) mins for those without (p = 0.561). The median time to decision for antibiotics was 156.0 (IQR 115.0–255.0) mins and 144.0 (IQR 105.5–211.0) mins, respectively (p = 0.175). Following decision for antibiotics, infants with SBIs received antibiotics much faster compared to those without [107.0 (IQR 83.0–168.0) vs. 141.0 (94.0–209.5) mins, p = 0.017].ConclusionThere was no difference in total time taken to antibiotics between infants with SBIs and without SBIs. Both recognition and administration delays were observed. While all infants with SBIs were adequately treated, more than half of the infants without SBIs received unnecessary antibiotics. This highlights the challenge in managing young febrile infants at initial presentation, and demonstrates the need to examine various aspects of care to improve the overall timeliness to antibiotics.

IntroductionCognition generally declines gradually over time due to progressive degeneration of the brain, leading to dementia and eventual loss of independent functions. The rate of regression varies among the six cognitive domains (perceptual motor, executive function, complex attention, learning and memory, social cognition and language). Current modality of cognitive assessment using neuropsychological paper-and-pencil screening tools for cognitive impairment such as the Montreal Cognitive Assessment (MoCA) has limitations and is influenced by age. Virtual reality (VR) is considered as a potential alternative tool to assess cognition. A novel, fully immersive automated VR system (Cognitive Assessment using Virtual Reality, CAVIRE) has been developed to assess the six cognitive domains. As cognition is associated with age, VR performance is postulated to vary with age using this system.AimsThis is a feasibility study to evaluate the VR performance of cognitively healthy adults aged between 35 and 74 years old, based on the performance score and completion time using the CAVIRE system.MethodsConducted in a public primary care clinic in Singapore, 25 multi-ethnic Asian adults were recruited in each of the four age groups in years: (1) 35–44; (2) 45–54; (3) 55–64, and (4) 65–74. The eligibility criteria included a MoCA score of 26 or higher to reflect normal cognition and understanding English instructions. They completed common daily activities ranging from brushing teething to shopping, across 13 VR segments. Their performances scores and completion time were automatically computed by the CAVIRE system. These VR performance indices were compared across the four age groups using one-way ANOVA, F-test of the hypothesis, followed by pair-wise comparisons in the event of a significant F-test (p < 0.05).ResultsOne participant dropped out from Group 1. The demographic characteristics of 99 participants were similar across the 4 age groups. Overall, younger participants in Groups 1 and 2 attained higher VR performance scores and shorter completion time, compared to those in Groups 3 and 4, in all six cognitive domains (all p < 0.05).ConclusionThe CAVIRE VR performance scores and completion time significantly differ between the younger and older Asian participants with normal cognition. Enhancements to the system are needed to establish the age-group specific normal performance indices.

Regenerative processes depend on the interpretation of signals to coordinate cell behaviors. The role of ubiquitin-mediated signaling is known to be important in many cellular and biological contexts, but its role in regeneration is not well understood. To investigate how ubiquitylation impacts tissue regeneration in vivo, we are studying planarians that are capable of regenerating after nearly any injury using a population of stem cells. Here we used RNAi to screen RING/U-box E3 ubiquitin ligases that are highly expressed in planarian stem cells and stem cell progeny. RNAi screening identified nine genes with functions in regeneration, including the spliceosomal factor prpf19 and histone modifier rnf2; based on their known roles in developmental processes, we further investigated these two genes. We found that prpf19 was required for animal survival but not for stem cell maintenance, suggesting a role in promoting cell differentiation. Because RNF2 is the catalytic subunit of the Polycomb Repressive Complex 1 (PRC1), we also examined other putative members of this complex (CBX and PHC). We observed a striking phenotype of regional tissue misspecification in cbx and phc RNAi planarians. To identify genes regulated by PRC1, we performed RNA-seq after knocking down rnf2 or phc. Although these proteins are predicted to function in the same complex, we found that the set of genes differentially expressed in rnf2 versus phc RNAi were largely non-overlapping. Using in situ hybridization, we showed that rnf2 regulates gene expression levels within a tissue type, whereas phc is necessary for the spatial restriction of gene expression, findings consistent with their respective in vivo phenotypes. This work not only uncovered roles for RING/U-box E3 ligases in stem cell regulation and regeneration, but also identified differential gene targets for two putative PRC1 factors required for maintaining cell-type-specific gene expression in planarians.

Abstract The response of severe convective storms to a warming climate is poorly understood outside of a few well studied regions. Here, projections from seven global climate models from the CMIP6 archive, for both historical and future scenarios, are used to explore the global response in variables that describe favorability of conditions for the development of severe storms. The variables include convective available potential energy (CAPE), convection inhibition (CIN), 0–6 km vertical wind shear (S06), storm relative helicity (SRH), and covariate indices (i.e., severe weather proxies) that combine them. To better quantify uncertainty, understand variable sensitivity to increasing temperature, and present results independent from a specific scenario, we consider changes in convective variables as a function of global average temperature increase across each ensemble member. Increases to favorable convective environments show an overall frequency increases on the order of 5%–20% per °C of global temperature increase, but are not regionally uniform, with higher latitudes, particularly in the Northern Hemisphere, showing much larger relative changes. The driving mechanism of these changes is a strong increase in CAPE that is not offset by factors that either resist convection (CIN), or modify the likelihood of storm organization (S06, SRH). Severe weather proxies are not the same as severe weather events. Hence, their projected increases will not necessarily translate to severe weather occurrences, but they allow us to quantify how increases in global temperature will affect the occurrence of conditions favorable to severe weather.

Introduction: Dementia is increasingly prevalent globally. Existing questionnaire-based cognitive assessment tools may not comprehensively assess cognitive function and real-time task-performance across all cognitive domains. CAVIRE (Cognitive Assessment by VIrtual REality), a fully immersive virtual reality system incorporating automated audio-visual instructions and a scoring matrix was developed to assess the six cognitive domains, with potential to maintain consistency in execution of the testing environment and possibly time-saving in busy primary care practice.Aims: This is a feasibility study to compare the completion times of the questionnaire-based Montreal Cognitive Assessment (MoCA) and the CAVIRE in cognitively-healthy Asian adults aged between 35 and 74 years, overall, and in and across each 10-year age group (35–44; 45–54; 55–64; 65–74).Methods: A total of 100 participants with a MoCA score of 26 or more were recruited equally into the four 10-year age groups at a primary care clinic in Singapore. Completion time for the MoCA assessment for each participant was recorded. They were assessed using the CAVIRE, comprising 13 segments featuring common everyday activities assessing all six cognitive domains, and the completion time was also recorded through the embedded automated scoring and timing framework.Results: Completion time for CAVIRE as compared to MoCA was significantly (p < 0.01) shorter, overall (mean difference: 74.9 (SD) seconds) and in each age group. Younger, vs. older, participants completed both the MoCA and CAVIRE tasks in a shorter time. There was a greater variability in the completion time for the MoCA, most markedly in the oldest group, whereas completion time was less variable for the CAVIRE tasks in all age groups, with most consistency in the 45–54 year-age group.Conclusion: We demonstrate almost equivalent completion times for a VR and a questionnaire-based cognition assessment, with inter-age group variation in VR completion time synonymous to that in conventional screening methods. The CAVIRE has the potential to be an alternative screening modality for cognition in the primary care setting.

Early identification of developmental delays with timely intervention, especially before the age of 3 years, can improve child development. In Singapore, however, diagnosis and intervention for developmental delays occur at a median age of 44 months. As early detection and intervention depends on an effective developmental screening programme, we aimed to improve the detection of developmental delays before the age of 3 years in a primary care setting. We did this by implementing a novel two-tiered screening programme which uses three standardised screening tools (Parents’ Evaluation of Developmental Status, PEDS-Developmental Milestones and Ages and Stages Questionnaire-3). We used quality improvement methods to integrate and optimise this two-tiered programme into the existing 9-month and 18-month screening schedule, with an additional screening at 30 months to replace the pre-existing 36-month screening of the National Child Health Surveillance Programme. A total of three Plan–Do–Study–Act cycles were performed to ensure programme feasibility and sustainability. They focused on adequately training the primary care nurses, targeting an 80% screening rate and aiming for 20 min screening tool administration time per child. We assessed the proportion of children referred to the child development units after positive screening for developmental concerns under the new programme, with a pre–post and with–without intervention comparison, and reviewed the screening rates and screening tool administration time. The proportion of 18-month old children referred for developmental concerns improved from 3.5%–7.1% over a 6-month period. For those who received further assessment by developmental specialists after the two-tiered screening, 100% received a definitive diagnosis of developmental delays, similar to the situation before programme introduction. Our quality improvement efforts facilitated successful integration of the two-tiered programme into the pre-existing screening schedule with minimal impact to the clinic workflow. While we highlight challenges in implementation that need to be addressed, our findings support a potential nationwide adoption of the two-tiered programme.

Objective Young febrile infants represent a vulnerable population at risk for serious bacterial infections (SBI). We aimed to evaluate the diagnostic accuracy of components of the complete blood count in comparison with C-reactive protein (CRP) to predict SBI among febrile infants.Design and setting Prospective cohort study conducted in a tertiary emergency department between December 2018 and November 2019.Patients We included febrile infants ≤3 months old with complete blood count results. We analysed their white blood cell count (WBC), absolute neutrophil ratio (ANC), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio, mean platelet volume to platelet count ratio, and compared these to the performance of CRP.Main outcome measures SBIs were defined as urinary tract infection, bacteraemia, bacterial meningitis, sepsis, pneumonia, skin and soft tissue infection, bacterial enteritis, septic arthritis or osteomyelitis.Results Of the 187 infants analysed, 54 (28.9%) were diagnosed with SBI. Median values of WBC, ANC, NLR and CRP were significantly higher in infants with SBI: WBC (13.8 vs 11.4×109/L, p=0.004), ANC (6.7 vs 4.1×109/L, p

The aim of this study was to evaluate a new analytical method for calculating non-invasive fractional flow reserve (FFRAM) to diagnose ischemic coronary lesions. Patients with suspected or known coronary artery disease (CAD) who underwent computed tomography coronary angiography (CTCA) and invasive coronary angiography (ICA) with FFR measurements from two sites were prospectively recruited. Obstructive CAD was defined as diameter stenosis (DS) ≥50% on CTCA or ICA. FFRAM was derived from CTCA images and anatomical features using analytical method and was compared with computational fluid dynamics (CFD)-based FFR (FFRB) and invasive ICA-based FFR. FFRAM, FFRB, and invasive FFR ≤ 0.80 defined ischemia. A total of 108 participants (mean age 60, range: 30–83 years, 75% men) with 169 stenosed coronary arteries were analyzed. The per-vessel accuracy, sensitivity, specificity, and positive predictive and negative predictive values were, respectively, 81, 75, 86, 81, and 82% for FFRAM and 87, 88, 86, 83, and 90% for FFRB. The area under the receiver operating characteristics curve for FFRAM (0.89 and 0.87) and FFRB (0.90 and 0.86) were higher than both CTCA- and ICA-derived DS (all p < 0.0001) on per-vessel and per-patient bases for discriminating ischemic lesions. The computational time for FFRAM was much shorter than FFRB (2.2 ± 0.9 min vs. 48 ± 36 min, excluding image acquisition and segmentation). FFRAM calculated from a novel and expeditious non-CFD approach possesses a comparable diagnostic performance to CFD-derived FFRB, with a significantly shorter computational time.