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The frequency and clinical impact of LRRK2 p.G2385R and p.R1628P risk variants in Parkinson’s disease (PD) remain uncertain, particularly across different Asian populations. We genotyped 3058 multi-ethnic Malaysian PD patients, performed detailed phenotyping in 185, and analyzed disease progression in 635 using longitudinal Clinical Impression of Severity Index for PD scores. p.G2385R was largely confined to Chinese (8.2%), while p.R1628P occurred in mixed ancestry (11.0%), Chinese (8.3%), Malays (7.7%), and is reported for the first time in indigenous groups (3.9%). Double-variant carriers had younger onset and more frequently had positive family history. Compared with non-carriers, p.R1628P carriers had lower rates of dementia and orthostatic hypotension, and slower progression of global PD severity. Our findings highlight ethnic differences in the distribution of LRRK2 Asian variants, and suggest that these variants influence onset age, familial occurrence, non-motor features, and disease course, with implications for personalized approaches to PD in Asian populations.

Distal acquired demyelinating symmetric neuropathy (DADS) is a variant of chronic inflammatory demyelinating polyneuropathy (CIDP) characterized by symmetrical, distal, sensory or sensorimotor involvement. DADS with M-protein (DADS-M) is less responsive to immunotherapy compared to those without M-protein (DADS-I). We report a case of DADS-I with severe clinical presentation viz. early hand involvement with marked wasting, inexcitable peripheral nerves on neurophysiology and poor response to immunotherapy. Despite the unusual presentation, ancillary tests including cerebrospinal fluid analysis, nerve biopsy and nerve ultrasound were supportive of an inflammatory demyelinating polyneuropathy. This case demonstrated the heterogeneity of the disorder and expands the clinical spectrum of DADS neuropathy.

AbstractBackgroundEstablished protocols for implementing high-quality targeted temperature management (TTM) provide guidance concerning the cooling rate, duration of maintenance, and rewarming speed. However, whether compliant to TTM protocols results in improved survival and better neurological recovery has not been examined. MethodsA retrospective cohort study enrolled 1141 survivors of non-traumatic adult cardiac arrest with a pre-arrest cerebral performance category (CPC) score of 1–2 from 2015 to 2020 at a tertiary medical center. Of the survivors, 330 patients who underwent TTM were further included. Patients with spontaneous hypothermia (<35 °C) ( n = 107) and expired during the TTM ( n = 21) were excluded. A total of 202 patients were thus enrolled. One hundred and ten patients underwent TTM that completely complied with the protocol (protocol-complaint group), but 92 patients deviated in some manner from the protocol (protocol non-compliant group). ResultsFifty patients (50%) and 46 patients (50%) in the protocol-compliant and non-compliant groups, respectively, did not survive to hospital discharge. In the protocol-compliant group, 42 patients (38.2%) had favorable neurological recovery, compared with 32 patients (34.8%) in the protocol non-compliant group. After adjusting for age, initial shockable rhythm, witnessed collapse, and cardiopulmonary resuscitation duration, protocol non-compliant was associated with the poor neurological outcomes (aOR 2.44, 95% CI = 1.13–5.25), but not with in-hospital mortality (aOR 1.31, 95% CI = 0.70–2.47). The most common reason for noncompliance was a prolonged duration reaching the target temperature ( n = 33, 58.7%). The number of phases of non-compliant was not significantly associated with in-hospital mortality or poor neurological recovery. ConclusionAmong cardiac arrest survivors undergoing TTM, those who did not receive TTM that in compliance with the protocol were more likely to experience poor neurological recovery than those whose TTM fully complied with the protocols. The most frequently identified deviation was a prolonged duration to reaching the target temperature.

Background Irritable bowel syndrome (IBS) is a debilitating disorder affecting 4–9% of the global population. It is a multifaceted disorder with complex and varied causes. This review aims to consolidate the evidence regarding IBS risk factors by examining existing systematic reviews and meta-analyses, covering potential genetic, immunological, psychological, and dietary causes. Methods Systematic literature searches were conducted in MEDLINE, Embase and Cochrane library databases. Study selection and data extraction were conducted independently by four authors, with discrepancies resolved by consensus with a senior author. Systematic reviews examining risk factors of IBS development were eligible for review. Results were narratively synthesized. Quality of reviews were analysed using AMSTAR 2, and evidence were appraised using GRADE methodology. Results A total of 69 systematic reviews were included in this study. Most reviews were of “critically low” quality, while the remaining were “low” quality. Common shortcomings included the absence of a list of excluded studies with justifications for their exclusion and inadequate consideration of the risk of bias in individual studies. Eight major categories of risk factors for IBS identified were as follows: dietary, genetic, environmental, psychological, gut microbiome, socio-economic, physiological, and pathological, albeit overlaps exist. The most frequently reported risk factors for IBS development were female gender and anxiety disorders, with overall GRADE evaluation of “low”; depression and gastroenteritis, with overall GRADE evaluation of “moderate”. Conclusions Clinical practice should prioritize recognition of these risk factors. Future reviews should improve their reporting of results based on the PRISMA guidelines, to enhance the quality of research in this field. Protocol registration PROSPERO CRD42023493739.

Background The emergence of the Coronavirus Disease 2019 (COVID-19) Pandemic threatened living kidney donor transplantation services. Data on ABO-incompatible kidney transplants (ABOi KT) performed during the COVID-19 Pandemic is scarce. Objectives This study sought to compare characteristics and outcomes of ABOi KT performed before and during the COVID-19 Pandemic at an academic medical centre in Singapore. Methods A retrospective cohort study was performed on ABOi KT from 1st December 2009 to 31st May 2023. Data was compared between patients who received ABOi KT before the COVID-19 Pandemic (1st December 2009 to 10th March 2020 or pre-COVID-19 era) and during the COVID-19 Pandemic (11th March 2020 to 31st May 2023 or COVID-19 era). Results The study population consisted of 28 ABOi KT, 19 during the pre-COVID-19 era and nine during the COVID-19 era. There were no significant differences in baseline characteristics between the two groups and notably waiting time for transplantation was not significantly increased during the COVID-19 era. The median dose of Rituximab given for desensitization was low at 135 (range 0-500) mg and 100 (range 100-200) mg for both pre-COVID-19 and COVID-19 era patients. There were no significant differences in post-operative outcomes. COVID-19 infected 57.1% (n = 16/28) of patients, among which 93.7% (n = 15/16) were adequately vaccinated. None of these patients were admitted to the intensive care unit, died, or lost their graft from COVID-19. Conclusion Despite greater complexity and immunosuppression in ABOi KT, ABOi KT can be performed safely during the Pandemic, provided patients are adequately vaccinated and healthcare system and process are in place to minimize the risks of COVID-19.

Yoon Shin Cho, Mark Seielstad and colleagues report a meta-analysis of genome-wide association studies for type 2 diabetes in individuals of east Asian ancestry. They identify eight new loci associated with type 2 diabetes. We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3 , PEPD , FITM2-R3HDML-HNF4A , KCNK16 , MAEA , GCC1-PAX4 , PSMD6 and ZFAND3 . GLIS3 , which is involved in pancreatic beta cell development and insulin gene expression 1 , 2 , is known for its association with fasting glucose levels 3 , 4 . The evidence of an association with T2D for PEPD 5 and HNF4A 6 , 7 has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings, derived from an east Asian population, provide new perspectives on the etiology of T2D.

To describe the 25-year surgical trends, long-term outcomes and risk factors affecting the outcomes of giant retinal tear-related rhegmatogenous retinal detachments (GRT-RRD). Patients’ demographics, pre-operative characteristics, risk factors, operative procedures and post-operative outcomes were collected and divided into three groups – Group A: 1991 to 2015 (overall); Group B: 1991 to 2005, and Group C: 2006 to 2015. Functional and anatomical successes were monitored over a 5-year period. Multivariate logistic regression analysis was performed to identify the risk factors related to functional and anatomical success.127 eyes of 127 patients were included in the study. At 5 th year, 69.4% patients had visual acuity (VA) < logMAR 1.0 with 87.5% primary anatomical success rate. While the functional outcome remained the same between group B and C, there was an increase in the anatomical success from 89.7% to 100%, albeit not statistically significant. Patients with worse presenting VA, 150 degrees or more of giant retina tear, macula-detached status and presence of PVR were associated with VA of> logMAR 1.0 (all p < 0.05). The types of surgery (TPPV vs combined SB/TPPV), number of breaks, lens extraction and additional cryotherapy were not associated with the functional or anatomical success. In conclusion, the GRT-RRD functional and structural outcomes were comparable between 1991–2005 and 2006–2015, albeit a statistically insignificant improvement of anatomical outcome over the past 25 years. Worse presenting VA, 150 degrees or more of giant retinal tear, detached macula and presence of PVR were associated with poorer visual outcome.

Age-related macular degeneration (AMD) is a major cause of blindness, but presents differently in Europeans and Asians. Here, we perform a genome-wide and exome-wide association study on 2,119 patients with exudative AMD and 5,691 controls, with independent replication in 4,226 patients and 10,289 controls, all of East Asian descent, as part of The Genetics of AMD in Asians (GAMA) Consortium. We find a strong association between CETP Asp442Gly (rs2303790), an East Asian-specific mutation, and increased risk of AMD (odds ratio (OR)=1.70, P =5.60 × 10 −22 ). The AMD risk allele (442Gly), known to protect from coronary heart disease, increases HDL cholesterol levels by 0.17 mmol l −1 ( P =5.82 × 10 −21 ) in East Asians ( n =7,102). We also identify three novel AMD loci: C6orf223 Ala231Ala (OR=0.78, P= 6.19 × 10 −18 ), SLC44A4 Asp47Val (OR=1.27, P =1.08 × 10 −11 ) and FGD6 Gln257Arg (OR=0.87, P= 2.85 × 10 −8 ). Our findings suggest that some of the genetic loci conferring AMD susceptibility in East Asians are shared with Europeans, yet AMD in East Asians may also have a distinct genetic signature. Age-related macular degeneration (AMD) is a major cause of blindness worldwide. Here, the authors carry out a two-stage genome-wide association study for AMD and identify three new AMD risk loci, highlighting the shared and distinct genetic basis of the disease in East Asians and Europeans.

AimsTo determine the impact of neovascular age-related macular degeneration (nAMD) on vision-related quality of life (VRQoL) in an Asian population.MethodsIn this cross-sectional study, 162 subjects with nAMD from the Asian AMD Phenotyping Study and 105 randomly sampled age-matched and gender-matched controls from the population-based Singapore Chinese Eye Study were recruited. nAMD was categorised as either polypoidal choroidal vasculopathy (PCV) or ‘typical’ AMD (tAMD). The reading, mobility and emotional well-being subscales of the impact of vision impairment (IVI) scale were validated using Rasch analysis and used as the main outcome measures and collectively referred to as VRQoL. Multivariate linear regression analyses were performed to assess the impact of nAMD overall, and PCV and tAMD subtypes, on the three IVI domains.ResultsOf the 162 with nAMD, 103 (63.6%) had PCV and 59 (36.4%) had tAMD. In multivariate models, nAMD overall was independently associated with a 21% reduction in reading (β=−1.08; CI −1.58 to −0.57); 16% reduction in mobility (β=−0.74; −1.14 to −0.33) and 44% reduction in emotional well-being (β=−2.15; −2.83 to −1.47) compared with controls. There were significant VRQoL deficits (p<0.05) associated with both PCV and tAMD; these deficits were similar and not statistically different between the two nAMD subtypes (p>0.05).ConclusionsNeovascular AMD, including both PCV and tAMD subtypes, has a detrimental impact on VRQoL in Asian subjects independent of level of vision impairment. Interventions to increase reading capacity, enhance mobility and independence and improve mental health outcomes for subjects with neovascular AMD further address the impact of the condition on VRQoL in addition to pharmacological therapies.

Norihiro Kato and colleagues perform a meta-analysis of genome-wide association studies to identify common variants associated with blood pressure variation in east Asians. They identify five new genome-wide significant signals and replicate seven loci previously discovered in populations of European ancestry. We conducted a meta-analysis of genome-wide association studies of systolic (SBP) and diastolic (DBP) blood pressure in 19,608 subjects of east Asian ancestry from the AGEN-BP consortium followed up with de novo genotyping ( n = 10,518) and further replication ( n = 20,247) in east Asian samples. We identified genome-wide significant ( P < 5 × 10 −8 ) associations with SBP or DBP, which included variants at four new loci ( ST7L - CAPZA1 , FIGN-GRB14 , ENPEP and NPR3 ) and a newly discovered variant near TBX3 . Among the five newly discovered variants, we obtained significant replication in the independent samples for all of these loci except NPR3 . We also confirmed seven loci previously identified in populations of European descent. Moreover, at 12q24.13 near ALDH2 , we observed strong association signals ( P = 7.9 × 10 −31 and P = 1.3 × 10 −35 for SBP and DBP, respectively) with ethnic specificity. These findings provide new insights into blood pressure regulation and potential targets for intervention.