Alzheimer's disease as a women's health challenge: a call for action on integrative precision medicine approaches.

Alzheimer's Disease (AD) is marked by pronounced sex differences in pathophysiology and progression. However, the field has yet to fully recognize AD as a women's health issue, delaying the development of targeted preventative strategies and treatments. This perspective explores the elements impacting AD in women, identifying sex specificity in risk factors, highlighting new diagnostic approaches with electronic health records, and reviewing key molecular studies to underscore the need for integrative precision medicine approaches. Established AD risk factors such as advancing age, the apolipoprotein E4 allele, and poorer cardiovascular health affect women differently. We also shed light on sociocultural risk factors, focusing on the gender disparities that may play a role in AD development. From a biological perspective, sex differences in AD are apparent in biomarkers and transcriptomics, further emphasizing the need for targeted diagnostics and treatments. The convergence of novel multiomics data and cutting-edge computational tools provides a unique opportunity to study the molecular underpinnings behind sex dimorphism in AD. Thus, precision medicine emerges as a promising framework for understanding AD pathogenesis through the integration of genetics, sex, environment, and lifestyle. By characterizing AD as a women's health challenge, we can catalyze a transformative shift in AD research and care, marked by improved diagnostic accuracy, targeted interventions, and ultimately, enhanced clinical outcomes.

Demographics and outcome of patients with congenital haemophilia in Sarawak, Malaysia.

INTRODUCTION: Sarawak has a population that is geographically and characteristically widely varied. This study aimed to determine the demographic profile of patients in Sarawak, Malaysia. Materials and Methods - A cross-sectional study was conducted in 2019 at four major haemophilia treatment centres in Kuching, Sibu, Bintulu and Miri Hospitals, Sarawak. Demographic and clinical data were collected with consents from patients. RESULTS AND DISCUSSION: Ninety-six haemophilia patients were identified - 79(82.3%) haemophilia A(HA) and 17(17.7%) haemophilia B(HB). Severe haemophilia patients were noted in 45.6% (36/79) of HA and 64.7% (11/17) of HB. In all 44.3% of the HA and 52.9% of the HB population had no identifiable family history of haemophilia. Two-thirds of the patients with severe HA were on prophylaxis [24/36 (66.7%)] and only onethird [4/11 (36.4%)] in severe HB. Inhibitors developed in 9/79 (11.4%) of the HA population [3/79 (3.8%) high responders]. The median inhibitor titre was not significantly different between the different treatment groups - on demand versus prophylaxis (1.0BU versus 2.0BU; z statistic -1.043, p-value 0.297, Mann-Whitney test). None of the patients developed inhibitory alloantibodies to factor IX. Four HA patients (5.1%) underwent immune tolerance induction where one case had a successful outcome. Three severe HA patients received emicizumab prophylaxis and showed remarkable reduction in bleeding events with no thromboembolic events being reported. One female moderate HA patient received PEGylated recombinant anti-haemophilic factor. Eleven patients underwent radiosynovectomy. One mild HB patient succumbed to traumatic intracranial bleeding. Our data reported a prevalence (per 100,000 males) of 5.40 cases for all severities of HA, 2.46 cases for severe HA; 1.16 cases for all severities of HB, and 0.75 cases for severe HB. The overall incidence of HA and HB was 1 in 11,500 and 1 in 46,000, respectively. CONCLUSION: This study outlines the Sarawakian haemophilia landscape and offers objective standards for forward planning. Shared responsibilities among all parties are of utmost importance to improve the care of our haemophilia population.

Ischemic Stroke in a Young Patient with Nephrotic Syndrome and Antiphospholipid Syndrome.

We report a case of a 21-year-old man with underlying nephrotic syndrome (NS) secondary to minimal change disease, who developed an ischemic stroke with left hemiparesis. He received intravenous thrombolysis followed by a mechanical thrombectomy. After mechanical thrombectomy, he developed acute kidney injury which subsequently required haemodialysis. Further workup revealed that he had concomitant antiphospholipid syndrome (APS) and NS. He was started on vitamin K antagonist anticoagulant. This case report illustrates the importance of workup in identifying causes of ischemic stroke in a young patient.

Compared to CPAP extubation to non-invasive ventilation is associated with higher risk of bronchopulmonary dysplasia in extremely low birth weight infants.

OBJECTIVE: While non-invasive ventilation (NIV) has been associated with improved extubation rates, its impact on bronchopulmonary dysplasia (BPD) remains unclear. METHOD: In this retrospective, chart review study of infants admitted to the Cleveland Clinic, we aimed to compare the incidence of BPD among extremely low birth weight (ELBW) infants extubated to continuous positive pressure (CPAP) versus those extubated to NIV via RAM cannula or biphasic CPAP. Data collected included demographics, ventilatory modes, extubation data, and presence of complications. Infants extubated to either CPAP or NIV were compared using Wilcoxon rank- sum and Chi-square tests, and data were corrected using logistic regression models. Data are presented as medians. RESULTS: A total of 120 infants were included, of whom 62% were extubated to NIV. The incidence of BPD was significantly lower in the CPAP group vs NIV (57% vs. 78%, p = 0.011). Infants in the CPAP group were heavier (birth weight (BWT) of 833 vs 724 grams, p = 0.005), more mature (gestation age (GA) 27 vs 25 weeks, p <  0.001) and were extubated significantly earlier (2 vs 8 days, p <  0.001). After adjusting for BWT and GA, NIV continued to be significantly associated with higher incidence of BPD among those extubated on the first day of life (odds ratio 5.9; 95% CI: 1.2-29.1, p = 0.029). CONCLUSION: This study concludes that, as compared to CPAP, early use of NIV is associated with higher risk of BPD in ELBW infants. Further investigation using prospective studies is recommended to validate these findings.

Subcutaneous mycosis presenting as a non- healing left calf ulcer in an immunocompromised patient.

This is a case report of subcutaneous mycosis presenting as a non-healing left calf ulcer in an immunocompromised patient. Traumatic inoculation of the causative agent is the most likely route of infection. The diagnosis requires a detailed history and high clinical suspicion, confirmed by histopathological examination. The management requires a multidisciplinary team approach involving surgeon, pathologist, physician sub-specialised in infectious disease, wound care nursing team as well as social support services. The literature review recommended that the treatment of choice for such infection is surgical debridement in addition to optimal antifungal therapy.

Ethyl carbamate in fermented foods and beverages: dietary exposure of the Hong Kong population in 2007-2008.

To evaluate the potential public health risk of ethyl carbamate (EC), EC exposure from fermented foods and beverages for Hong Kong population was estimated. In 276 samples analysed, EC was detected (limit of detection (LOD) at 0.4 µg kg(-1)) in 202 samples (73%), with higher levels in fermented red bean curd (150-650 µg kg(-1)) and yellow wine (140-390 µg kg(-1)), while low or non-detected (ND) in preserved vegetables (ND-10 µg kg(-1)) and fermented tea (ND-15 µg kg(-1)). The estimated dietary exposure from all fermented foods and beverages was 8.27 ng kg(-1) bw day(-1), while exposure excluding alcoholic beverages was 5.42 ng kg(-1) bw day(-1), with calculated margins of exposure (MOEs) at 3.6 × 10(4) and 5.5 × 10(4) respectively. The risk of adverse health effects was low for the average population but higher (MOE of 10(3)) for high consumers of alcoholic beverages especially habitual drinkers of alcoholic types with high EC contents.

Dietary exposure of secondary school students in Hong Kong to polybrominated diphenyl ethers from foods of animal origin.

This paper reports levels of polybrominated diphenyl ethers (PBDEs) in a wide range of foods of animal origin and estimates their dietary exposure for secondary school students in Hong Kong, China. Dietary exposure to PBDEs was estimated using local food consumption data obtained from secondary school students in 2000 and the concentrations of PBDEs in food samples taken from local market in 2008. The PBDE levels on a fresh weight basis for fish ranged from 13 to 6600 pg g(-1), for seafood and seafood products ranged from 15 to 1200 pg g(-1), for meat and meat products ranged from 23 to 3500 pg g(-1), for poultry ranged from 68 to 670 pg g(-1), for eggs ranged from 280 to 800 pg g(-1), and for dairy products ranged from 12 to 480 pg g(-1). The dietary exposures of secondary school students for the average and high consumers were estimated to be 2.6 and 6.4 ng kg(-1) body weight day(-1), respectively. According to the Joint FAO/WHO Expert Committee on Food Additives (JECFA), for the more toxic PBDE congeners, adverse effects would be unlikely to occur in laboratory animals at doses of less than approximately 100 microg kg(-1) body weight day(-1). The resulting margins of exposures (38,000 for average consumers and 16,000 for high consumers) showed that the estimated dietary exposures of secondary school students were far below any adverse effect dose observed in laboratory animals and were therefore of low concern for human health.

Mercury and methylmercury levels in the main traded fish species in Hong Kong.

Levels of total mercury (tHg) and mono-methylmercury (MeHg) were measured in 280 different fish, including fresh/frozen raw whole fish of 89 different species and canned tuna fish of three different species, that are traded mainly in Hong Kong, China. These samples were purchased from different commercial outlets between April and August 2007. All samples of raw whole fish were identified at species level by the Agriculture, Fisheries and Conservation Department. The range for tHg and MeHg of all samples were 3-1370 and 3-1010 µg kg(-1), respectively, with medians of 63 and 48 µg kg(-1), respectively. The results show that, according to Hong Kong legislation, the products on the market are generally 'safe'. A total of 277 samples (99?) contained tHg and MeHg below the legal limit of 500 µg kg(-1). The remaining three samples of alfonsino (species: Beryx splendens) were found to contain tHg and MeHg at levels higher than 500 µg kg(-1) (tHg: 609-1370 µg kg(-1); MeHg: 509-1010 µg kg(-1)). The ratios of MeHg to tHg in the different fish species ranged from 0.46 to 0.99.

In vivo and in vitro examination of the functional significances of novel lamin gene mutations in heart failure patients.

CONTEXT: Lamin A/C (LMNA) gene variations have been reported in more than one third of genotyped families with dilated cardiomyopathy (DCM). However, the relationship between LMNA mutation and the development of DCM is poorly understood. METHODS AND RESULTS: We found that end stage DCM patients carrying LMNA mutations displayed either dramatic ultrastructural changes of the cardiomyocyte nucleus (D192G) or nonspecific changes (R541S). Overexpression of the D192G lamin C dramatically increased the size of intranuclear speckles and reduced their number. This phenotype was only partially reversed by coexpression of the D192G and wild type lamin C. Moreover, the D192G mutation precludes insertion of lamin C into the nuclear envelope when co-transfected with the D192G lamin A. By contrast, the R541S phenotype was entirely reversed by coexpression of the R541S and wild type lamin C. As lamin speckle size is known to be correlated with regulation of transcription, we assessed the SUMO1 distribution pattern in the presence of mutated lamin C and showed that D192G lamin C expression totally disrupts the SUMO1 pattern. CONCLUSION: Our in vivo and in vitro results question the relationship of causality between LMNA mutations and the development of heart failure in some DCM patients and therefore, the reliability of genetic counselling. However, LMNA mutations producing speckles result not only in nuclear envelope structural damage, but may also lead to the dysregulation of cellular functions controlled by sumoylation, such as transcription, chromosome organisation, and nuclear trafficking.

Has implementation of the 80-hour work week made a career in surgery more appealing to medical students?

BACKGROUND: This study was conducted to determine if a surgical career became more appealing to medical students with the resident work week limited to 80 hours. METHODS: At the start and conclusion of each surgery clerkship rotation, students completed a survey addressing perception of surgeons, and surgery as a career. They were divided into the control groups (rotations before July 2003; n = 109) and the experimental group (rotations after July 2003; n = 108). RESULTS: Students in the experimental group had a significantly more favorable impression of a surgeon's lifestyle and work hours than those in the control group. This was especially true of female students post-rotation, who responded more positively to the statement that a surgical career would allow for a good balance between professional and personal life (1.87 vs 2.45, P <.01). CONCLUSION: The new Accreditation Council for Graduate Medical Education (ACGME) regulation has had a positive impact on students' perceptions of the surgeon's lifestyle, but does not necessarily increase their interest in a surgical career.

Clinical and electrophysiological features in Chinese patients with Kennedy's disease.

Kennedy's disease is a X-linked neuromuscular disorder caused by an expanded trinucleotide repeat in the androgen receptor gene. To ascertain the clinical diagnosis of Kennedy's disease in a Chinese population, we used a rapid, accurate PCR-based sizing method for the CAG repeat allelotype. The clinical and electrophysiological features of affected patients are described. The CAG repeats ranged from 43 to 53 and were inversely correlated with the age of onset (r = -0.63; P < 0.005).

Computed tomography evaluation in acute stroke: retrospective study.

OBJECTIVE: To determine the accuracy with which 'frontline' hospital doctors interpret computed tomography brain scans. DESIGN: Retrospective study. SETTING: University teaching hospital, Hong Kong. PARTICIPANTS: Medical and emergency room doctors. MAIN OUTCOME MEASURE: Accuracy in correctly identifying features of acute stroke on 18 computed tomography brain scans. RESULTS: Computed tomography brain scan images showing easily detectable haemorrhage and infarct were identified in 91% and 90% of scans, respectively; but difficult-to-interpret scans with subtle features of haemorrhage or infarct were only correctly identified in 46% and 45% of readings, respectively. More experienced doctors did not perform better than junior doctors (P=0.69; 95% confidence interval, -1.84 to 2.73) and the mean total score for doctors from the emergency department did not differ significantly from that of doctors from the medical department (P=0.57; 95% confidence interval, -2.98 to 1.67). CONCLUSION: Early signs of infarct and small bleeds on computed tomography brain scans are not well recognised by doctors, regardless of clinical exposure or seniority. Ineligible patients may be treated with thrombolytic therapy as a result of such computed tomography scan misinterpretation.

Lack of clinical utility of the Siriraj Stroke Score.

BACKGROUND: The ability to distinguish between infarct and haemorrhage is essential to the management of acute cerebrovascular disease. In hospitals where emergency neuroimaging is not available, the use of stroke scores has been proposed to distinguish ischaemic from haemorrhagic stroke. AIMS: To determine the accuracy of the Siriraj Stroke Score in distinguishing ischaemic from haemorrhagic stroke in a cohort of Chinese patients. METHODS: We prospectively assessed and calculated the Siriraj Stroke Score from 253 patients with acute stroke. The sensitivity, specificity, positive and negative predictive values of this score were determined. RESULTS: For cerebral haemorrhage, the sensitivity and specificity were both 90% or above, but the positive predictive value was not greater than 70%. For cerebral infarct, the sensitivity and specificity were around 80%, while the positive predictive value exceeded 90%. Analysis by plotting receiver operating characteristic curves failed to find other cut-off points that would improve the performance of the Siriraj Stroke Score. CONCLUSIONS: Considering the inconsistent results from this study and previous studies of the Siriraj Stroke Score, we suggest that scoring systems that only require a small number of variables are unlikely to achieve the level of accuracy needed for clinical decision-making.

Vasopressin versus epinephrine for inhospital cardiac arrest: a randomised controlled trial.

BACKGROUND: Survival rates for cardiac arrest patients, both in and out of hospital, are poor. Results of a previous study suggest better outcomes for patients treated with vasopressin than for those given epinephrine, in the out-of-hospital setting. Our aim was to compare the effectiveness and safety of these drugs for the treatment of in-patient cardiac arrest. METHODS: We did a triple-blind randomised trial in the emergency departments, critical care units, and wards of three Canadian teaching hospitals. We assigned adults who had cardiac arrest and required drug therapy to receive one dose of vasopressin 40 U or epinephrine 1 mg intravenously, as the initial vasopressor. Patients who failed to respond to the study intervention were given epinephrine as a rescue medication. The primary outcomes were survival to hospital discharge, survival to 1 h, and neurological function. Preplanned subgroup assessments included patients with myocardial ischaemia or infarction, initial cardiac rhythm, and age. FINDINGS: We assigned 104 patients to vasopressin and 96 to epinephrine. For patients receiving vasopressin or epinephrine survival did not differ for hospital discharge (12 [12%] vs 13 [14%], respectively; p50.67; 95% CI for absolute increase in survival 211.8% to 7.8%) or for 1 h survival (40 [39%] vs 34 [35%]; p50.66; 210.9% to 17.0%); survivors had closely similar median mini-mental state examination scores (36 [range 19-38] vs 35 [20-40]; p50.75) and median cerebral performance category scores (1 vs 1). INTERPRETATION: We failed to detect any survival advantage for vasopressin over epinephrine. We cannot recommend the routine use of vasopressin for inhospital cardiac arrest patients, and disagree with American Heart Association guidelines, which recommend vasopressin as alternative therapy for cardiac arrest.

Relationship between pacemaker dependency and the effect of pacing mode on cardiovascular outcomes.

BACKGROUND: A recently completed trial, the Canadian Trial of Physiological Pacing (CTOPP), showed that physiological pacing did not significantly reduce mortality, stroke, or heart failure hospitalization, but it did show that atrial fibrillation occurred less frequently in patients with physiological pacing. Many pacemaker patients experience only transient bradyarrhythmias with an adequate unpaced heart rate (UHR) and are not pacemaker-dependent. The purpose of the present analysis was to determine if pacemaker-dependent patients have an increased benefit from physiological pacing compared with non-pacemaker-dependent patients. METHODS AND RESULTS: Of 2568 patients included in the CTOPP trial, 2244 patients had a pacemaker dependency test performed at the first follow-up visit. The yearly event rate of cardiovascular death or stroke steadily increased with decreasing UHR in the ventricular pacing group, but it remained constant in the physiological pacing group. When the patients were subdivided to UHR 60 bpm, there was an interaction between pacing mode treatment and UHR subgroup. The Kaplan-Meier plot confirmed a physiological pacing advantage only in the UHR

Identification of a gene responsible for familial Wolff-Parkinson-White syndrome.

BACKGROUND: The Wolff-Parkinson-White syndrome, with a prevalence in Western countries of 1.5 to 3.1 per 1000 persons, causes considerable morbidity and may cause sudden death. We identified two families in which the Wolff-Parkinson-White syndrome segregated as an autosomal dominant disorder. METHODS: We studied 70 members of the two families (57 in Family 1 and 13 in Family 2). The subjects underwent 12-lead electrocardiography and two-dimensional echocardiography. Genotyping mapped the gene responsible to 7q34-q36, a locus previously identified to be responsible for an inherited form of Wolff-Parkinson-White syndrome. Candidate genes were identified, sequenced, and analyzed in normal and affected family members to identify the disease-causing gene. RESULTS: A total of 31 members (23 from Family 1 and 8 from Family 2) had the Wolff-Parkinson-White syndrome. Affected members of both families had ventricular preexcitation with conduction abnormalities and cardiac hypertrophy. The maximal combined two-point lod score was 9.82 at a distance of 5 cM from marker D7S636, which confirmed the linkage of the gene in both families to 7q34-q36. Haplotype analysis indicated that there were no alleles in common in the two families at this locus, suggesting that the two families do not have a common founder. We identified a missense mutation in the gene that encodes the gamma2 regulatory subunit of AMP-activated protein kinase (PRKAG2). The mutation results in the substitution of glutamine for arginine at residue 302 in the protein. CONCLUSIONS: The identification of this genetic defect has important implications for elucidating the pathogenesis of ventricular preexcitation. Further understanding of how this molecular defect leads to supraventricular arrhythmias could influence the development of specific therapies for other forms of supraventricular arrhythmia.