METHODS: We used individual data from a prospective, observational, multicentre, and intercontinental cohort study (Eurobact2). We included patients who were followed for ≥1 day and for whom time-to-appropriate treatment was available. We used an adjusted frailty Cox proportional-hazard model to assess the effect of time-to-treatment-adequacy on 28-day mortality. Infection- and patient-related variables identified as confounders by the Directed Acyclic Graph were used for adjustment. Adequate therapy within 24 hours was used for the primary analysis. Secondary analyses were performed for adequate therapy within 48 and 72 hours and for identified patient subgroups.

AIMS: To explore the effect of gender, stimuli type and PD status and their interactions on the O-DDK rates among Malaysian-Malay speakers.

METHODS & PROCEDURES: O-DDK performance of 62 participants (29 individuals with PD and 33 healthy elderly) using a non-word ('pataka'), a Malay real-word ('patahkan') and an English real-word ('buttercake') was audio recorded. The number of syllables produced in 8 s was counted. A hierarchical linear modelling was performed to investigate the effects of stimuli type (non-word, Malay real-word, English real-word), PD status (yes, no), gender (male, female) and their interactions on the O-DDK rate. The model accounted for participants' age as well as the nesting of repeated measurements within participants, thereby providing unbiased estimates of the effects.

OUTCOMES & RESULTS: The stimuli effect was significant (p < 0.0001). Malay real-word showed the lowest O-DDK rate (5.03 ± 0.11 syllables/s), followed by English real-word (5.25 ± 0.11 syllables/s) and non-word (5.42 ± 0.11 syllables/s). Individuals with PD showed a significantly lower O-DDK rate compared to healthy elderly (4.73 ± 0.15 syllables/s vs. 5.74 ± 0.14 syllables/s, adjusted p < 0.001). A subsequent analysis indicated that the O-DDK rate declined in a quadratic pattern. However, neither gender nor age effects were observed. Additionally, no significant two-way interactions were found between stimuli type, PD status and gender (all p > 0.05). Therefore, the choice of stimuli type has no or only limited effect considering the use of O-DDK tests in clinical practice for diagnostic purposes.

CONCLUSIONS & IMPLICATIONS: The observed slowness in O-DDK among individuals with PD can be attributed to the impact of the movement disorder, specifically bradykinesia, on the physiological aspects of speech production. Speech-language pathologists can gain insights into the impact of PD on speech production and tailor appropriate intervention strategies to address the specific needs of individuals with PD according to disease stages.

PURPOSE: We set out to describe the reproductive health issues in women being treated with either hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD).

PATIENTS AND METHODS: All adult female patients on chronic dialysis in Hospital Seremban from January 1991 to December 2001 were included in our study. Patients (or their spouses or children) were interviewed regarding the menstrual status of the patient, gynecologic screening tests administered to the patient, and the patient's use of hormone replacement therapy (HRT).

RESULTS: We recruited 137 women into the study. Of those women, 52.6% were on HD; the rest were on CAPD. Mean age at diagnosis of ESRD was 46.5 +/- 14.1 years (range: 14 - 82 years), and mean duration on dialysis was 33.3 months (range: 2 months - 18 years). Responses about menstrual status were obtained for 118 patients. Of those 118 patients, 55 (46.6%) were postmenopausal at dialysis initiation. Average age at menopause had been 48.5 +/- 4.9 years. Another 19 patients (16.1%) had still been menstruating at dialysis initiation, but subsequently entered menopause. Their average age at menopause had been 45.1 +/- 10.3 years. The remaining 44 patients (37.3%) were still menstruating at an average age of 35.7 years (range: 15 - 49 years). Only 3 of 73 responders were on HRT; 63% had undergone a Pap smear; and 54% had had a breast examination.

OBJECTIVE: To compare the efficacy of HD201 with referent trastuzumab.

DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial (TROIKA) included 502 women with ERBB2-positive early breast cancer treated with either HD201 or referent trastuzumab. It was conducted across 70 centers in 12 countries, including Western and Eastern Europe and Asian countries. Randomization was stratified by tumor hormone receptor status, clinical stage, and geographic region of recruitment. This analysis was conducted on February 12, 2021, after the completion of the adjuvant phase at a median of 31 months (IQR, 28-33 months) of follow-up.

INTERVENTIONS: Patients with ERBB2-positive early breast cancer were randomly assigned to receive HD201 or referent trastuzumab in the neoadjuvant setting for 8 cycles, concurrently with 4 cycles of docetaxel, which was followed by 4 cycles of epirubicin and cyclophosphamide. Patients then underwent surgery, which was followed by treatment with 10 cycles of adjuvant HD201 or referent trastuzumab.

MAIN OUTCOME AND MEASURES: The primary end point was the total pathological complete response (tpCR) assessed after neoadjuvant treatment. Equivalence was concluded if the 95% CI of the absolute difference in tpCR between arms in the per-protocol set was within the margin of more or less than 15%. Other objectives included the breast pathological complete response, overall response, event-free and overall survival, safety, pharmacokinetics, and immunogenicity.

RESULTS: A total of 502 female patients (mean [range] age, 53 [26-82] years) were randomized to receive either HD201 or referent trastuzumab, and 474 (94.2%) were eligible for inclusion in the per-protocol set. The baseline characteristics were well balanced between the 2 arms; 195 tumors (38.8%) were hormone receptor-negative , and 213 patients (42.4%) had clinical stage III disease. The tpCR rates were 45% and 48.7% for HD201 and referent trastuzumab, respectively. The difference between the 2 groups was not significant at -3.8% (95% CI, -12.8% to 5.4%) and fell within the predefined equivalence margins. The ratio of the tpCR rates between the 2 arms was 0.92 (95% CI, 0.76 to 1.12). A total of 433 patients (86.1%) presented with 2232 treatment-emergent adverse events of special interest for trastuzumab during the entire treatment period, with 220 (88.0%) and 213 (84.5%) patients in the HD201 and referent trastuzumab groups, respectively.

CONCLUSIONS AND RELEVANCE: The results of this randomized clinical trial found that HD201 demonstrated equivalence to referent trastuzumab in terms of efficacy for the end point of tpCR, with a similar safety profile.

METHODS: Ethnic Malay, Chinese or Indian subjects aged 45-90 years old were recruited from Selangor, Malaysia from June 2016 to August 2018. Subjects with known medical conditions (e.g., bone disorders, malnutrition, immobilisation, renal impairment, hormonal disorders) and medications (including regular calcium or vitamin D supplements) that may affect CTX and P1NP were excluded. Additionally, subjects with osteoporosis or fracture on imaging studies were excluded. The blood samples were collected between 8 a.m. and 9 a.m. in fasting state. The CTX and P1NP were measured on Roche e411 platform in batches.

RESULTS: The 2.5th-97.5th percentiles reference intervals (and bootstrapped 90%CI) for plasma CTX in men (n = 91) were 132 (94-175) - 775 (667-990) ng/L; in post-menopausal women (n = 132) 152 (134-177) - 1025 (834-1293) ng/L. The serum P1NP reference intervals in men were 23.7 (19.1-26.4) - 83.9 (74.0-105.0) µg/L, and in post-menopausal women, 25.9 (19.5-29.3) - 142.1 (104.7-229.7) µg/L.

METHODS: The surveys were done in Eastern and Sarawak administrative regions using the rapid assessment of avoidable blindness technique. It involved a multistage cluster sampling method, each cluster comprising 50 residents aged 50 years and older. The prevalence of cataract was determined through a visual acuity (VA) check and eye examination. The VA of those who had undergone cataract surgery was measured, and the findings were compared with the previous survey.

RESULTS: A total of 9709 subjects, 50 years old and older, were examined (percentages of response were 94.5% and 96.2% for Eastern and Sarawak, respectively). Comparing the current to the previous survey in 2014, the prevalence of cataract at all levels of surgical thresholds (except unilateral VA <6/60 and <6/18 in the Eastern) was reduced. The percentages of cataract surgery visual outcomes with good VA (6/12) were improved, and those with poor VA (<6/60) were reduced in both regions.

METHODS: We queried the Centers for Disease Control and Prevention's Wide-Ranging Online Data for Epidemiologic Research database among adults aged ≥25 from 1999 to 2019. Heart failure/cardiomyopathy were listed as the main causes of death, with obesity as a contributing cause. We calculated age-adjusted mortality rates (AAMR) per 100,000 individuals and estimated the average annual percent change (AAPC). We also evaluated the social vulnerability of United States counties (2014-2018).

RESULTS: There were 29,334 deaths related to heart failure/cardiomyopathy among patients with comorbid obesity. The overall AAMR increased from 0.41 in 1999 to 0.94 in 2019, with an AAPC of 3.78 (95 % CI, 3.41-4.14). The crude mortality rate increase for heart failure/cardiomyopathy was greater in individuals with comorbid obesity than in those without. Males had a higher AAMR than females (0.78 vs 0.55). African Americans also had higher AAMR than Whites (1.35 vs 0.62). The AAMR was higher in rural areas than in urban regions (0.76 vs 0.66). The overall AAMR was higher in counties with social vulnerability index-Quartile 4 (SVI-Q4) (most vulnerable) (1.08) compared to SVI-Q1 (least vulnerable) (0.63) with a risk ratio of 1.71 (95 % CI: 1.61-1.83).

PURPOSE: We aimed to examine the role of age-dependent intervention thresholds (ITs) applied to the Fracture Risk Assessment (FRAX) tool in therapeutic decision making for osteoporosis in the Malaysian population.

METHODS: Data were collated from 1380 treatment-naïve postmenopausal women aged 40-85 years who underwent bone mineral density (BMD) measurements for clinical reasons. Age-dependent ITs, for both major osteoporotic fracture (MOF) and hip fracture (HF), were calculated considering a woman with a BMI of 25 kg/m2, aged between 40 and 85years, with a prior fragility fracture, sans other clinical risk factors. Those with fracture probabilities equal to or above upper assessment thresholds (UATs) were considered to have high fracture risk. Those below the lower assessment thresholds (LATs) were considered to have low fracture risk.

RESULTS: The ITs of MOF and HF ranged from 0.7 to 18% and 0.2 to 8%, between 40 and 85years. The LATs of MOF ranged from 0.3 to 11%, while those of HF ranged from 0.1 to 5.2%. The UATs of MOF and HF were 0.8 to 21.6% and 0.2 to 9.6%, respectively. In this study, 24.8% women were in the high-risk category while 30.4% were in the low-risk category. Of the 44.8% (n=618) in the intermediate risk group, after recalculation of fracture risk with BMD input, 38.3% (237/618) were above the ITs while the rest (n=381, 61.7%) were below the ITs. Judged by the Youden Index, 11.5% MOF probability which was associated with a sensitivity of 0.62 and specificity of 0.83 and 4.0% HF probability associated with a sensitivity of 0.63 and a specificity 0.82 were found to be the most appropriate fixed ITs in this analysis.

PURPOSE: To assess the feasibility of a Fracture Liaison Service in Malaysia and to benchmark our service against the International Osteoporosis Foundation Best Practice Framework.

METHODS: This feasibility study was conducted at a tertiary hospital in Malaysia from March 2021 to March 2022. Patients aged ≥ 50 years admitted with fragility fractures were recruited. Excluded were those with poor prognosis or transferred out from the hospital during admission. Patients were screened, assessed, and followed up at months 4 and 12 post-fracture presentations. Data was collected using Microsoft Excel and the REDCap database. The feasibility of the Fracture Liaison Service was evaluated using the typology of feasibility.

RESULTS: A total of 140 patients (female (93/140, 66.4%), median age 77 (IQR 72, 83), hip fractures (100/140, 65.8%)) were recruited into the Fracture Liaison Service. The recruitment rate was (140/215, 65.1%), as some patients were "missed" due to the COVID-19 pandemic. The completion rate was high (101/114, 88.6%). Among those indicated for antiosteoporosis medication, 82/100 (82%) were initiated on treatment. Various "Best Practice Standards," such as patient evaluation (140/140, 100%), fall prevention (130/140, 92.9%), and medication review standards (15/15, 100%) were high. Complicated referral pathways, inexperienced staff, lack of resources, and communication issues were some of the barriers identified while implementing the Fracture Liaison Service. Challenges were overcome by modifying the service workflow and coordinating with different departments.

OBJECTIVE: This study aims to conduct a comprehensive analysis of machine learning (ML) methods for MRI-based biomarker selection and classification to investigate early cognitive decline in AD. The focus to discriminate between classifying healthy control (HC) participants who remained stable and those who developed mild cognitive impairment (MCI) within five years (unstable HC or uHC).

METHODS: 3-Tesla (3T) MRI data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Open Access Series of Imaging Studies 3 (OASIS-3) were used, focusing on HC and uHC groups. Freesurfer's recon-all and other tools were used to extract anatomical biomarkers from subcortical and cortical brain regions. ML techniques were applied for feature selection and classification, using the MATLAB Classification Learner (MCL) app for initial analysis, followed by advanced methods such as nested cross-validation and Bayesian optimization, which were evaluated within a Monte Carlo replication analysis as implemented in our customized pipeline. Additionally, polynomial regression-based data harmonization techniques were used to enhance ML and statistical analysis. In our study, ML classifiers were evaluated using performance metrics such as Accuracy (Acc), area under the receiver operating characteristic curve (AROC), F1-score, and a normalized Matthew's correlation coefficient (MCC').

RESULTS: Feature selection consistently identified biomarkers across ADNI and OASIS-3, with the entorhinal, hippocampus, lateral ventricle, and lateral orbitofrontal regions being the most affected. Classification results varied between balanced and imbalanced datasets and between ADNI and OASIS-3. For ADNI balanced datasets, the naíve Bayes model using z-score harmonization and ReliefF feature selection performed best (Acc = 69.17%, AROC = 77.73%, F1 = 69.21%, MCC' = 69.28%). For OASIS-3 balanced datasets, SVM with zscore-corrected data outperformed others (Acc = 66.58%, AROC = 72.01%, MCC' = 66.78%), while logistic regression had the best F1-score (66.68%). In imbalanced data, RUSBoost showed the strongest overall performance on ADNI (F1 = 50.60%, AROC = 81.54%) and OASIS-3 (MCC' = 63.31%). Support vector machine (SVM) excelled on ADNI in terms of Acc (82.93%) and MCC' (70.21%), while naïve Bayes performed best on OASIS-3 by F1 (42.54%) and AROC (70.33%).

METHOD: This study was approved by the institutional Ethics Committees. Postmortem nasal mucosa and brain tissues from patients with AD (n = 10) and normal subjects (n = 10) were collected with patient consent at the Fukushimura Brain Bank. Nasal and brain tissue homogenates were added to HEK293 cells expressing tau 3-repeat domain with the L266V and V337M mutations (3RD∗VM) or 4-repeat domain with the P301L and V337M mutations (4RD∗LM), which was fused with GFP at the C-terminus.

RESULT: GFP fluorescence was detected uniformly within the cell bodies of HEK293T cells expressing 3RD∗VM-EGFP and 4RD∗LM-EGFP. There were no changes in the fluorescence after the additions of the brain homogenates from normal subjects. In contrast, a large number of fluorescent puncta was detected both in HEK293T cells expressing 3RD∗VM-EGFP and 4RD∗LM-EGFP at 4 days after the additions of the brain homogenates from patients with AD. Furthermore, the nasal tissue homogenates from patients with AD also induce the formation of fluorescent aggregates in HEK293T cells expressing 3RD∗VM-EGFP and 4RD∗LM-EGFP. Quantitative analysis revealed that the nasal tissue homogenates from AD patients significantly induced the aggregate formation, compared with normal subjects.

METHOD: A total of 137 fecal samples of the elderly were collected, and subjected to DNA analysis, and enzyme-linked immunosorbent assays (ELISA). Plasma samples were subjected to mass spectrometry proteomic analysis. The parameters of the subjects measured include functional reach test (FRT), handgrip strength (HGS), Visual Cognitive Assessment Test (VCAT), Montreal Cognitive Assessment (MoCA), timed up and go (TUG) and UCLA three-item loneliness scale (UCLA-3).

RESULT: At the genus level, Alistipes which are potential drivers of dysbiosis, are significantly increased in CF subjects. Proteobacteria are also negatively linked to FRT, HGS, VCAT, and MoCA, but positively correlated to TUG and UCLA-3. Lactoferrin was upregulated in pre-frail subjects. The plasma apolipoprotein AI (Apo-AI) was upregulated 5 times in the CF subjects.