The incremental yield of prenatal exome sequencing over chromosome microarray for congenital heart abnormalities: A systematic review and meta-analysis.

OBJECTIVES: To determine the incremental yield of prenatal exome sequencing (PES) over standard testing in fetuses with an isolated congenital heart abnormality (CHA), CHA associated with extra-cardiac malformations (ECMs) and CHA dependent upon anatomical subclassification. METHODS: A systematic review of the literature was performed using MEDLINE, EMBASE, Web of Science and grey literature January 2010-February 2023. Studies were selected if they included greater than 20 cases of prenatally diagnosed CHA when standard testing (QF-PCR/chromosome microarray/karyotype) was negative. Pooled incremental yield was determined. PROSPERO CRD 42022364747. RESULTS: Overall, 21 studies, incorporating 1957 cases were included. The incremental yield of PES (causative pathogenic and likely pathogenic variants) over standard testing was 17.4% (95% CI, 13.5%-21.6%), 9.3% (95% CI, 6.6%-12.3%) and 35.9% (95% CI, 21.0%-52.3%) for all CHAs, isolated CHAs and CHAs associated with ECMs. The subgroup with the greatest yield was complex lesions/heterotaxy; 35.2% (95% CI 9.7%-65.3%). The most common syndrome was Kabuki syndrome (31/256, 12.1%) and most pathogenic variants occurred de novo and in autosomal dominant (monoallelic) disease causing genes (114/224, 50.9%). CONCLUSION: The likelihood of a monogenic aetiology in fetuses with multi-system CHAs is high. Clinicians must consider the clinical utility of offering PES in selected isolated cardiac lesions.

Deep, rapid, and durable prostate-specific antigen decline with apalutamide plus androgen deprivation therapy is associated with longer survival and improved clinical outcomes in TITAN patients with metastatic castration-sensitive prostate cancer.

BACKGROUND: The first interim analysis of the phase III, randomized, double-blind, placebo-controlled, multinational TITAN study demonstrated improved overall survival (OS) and radiographic progression-free survival (rPFS) with apalutamide added to ongoing androgen deprivation therapy (ADT) in patients with metastatic castration-sensitive prostate cancer. The final analysis confirmed improvement in OS and other long-term outcomes. We evaluated prostate-specific antigen (PSA) kinetics and the association between PSA decline and outcomes in patients with metastatic castration-sensitive prostate cancer from TITAN. PATIENTS AND METHODS: Patients received apalutamide (240 mg/day) or placebo plus ADT (1 : 1). This post hoc exploratory analysis evaluated PSA kinetics and decline in relation to rPFS (22.7 months' follow-up) and OS, time to PSA progression, and time to castration resistance (44.0 months' follow-up) in patients with or without confirmed PSA decline using a landmark analysis, the Kaplan-Meier method, and Cox proportional hazards model. RESULTS: One thousand and fifty-two patients (apalutamide, 525; placebo, 527) were enrolled. Best confirmed PSA declines (≥50% or ≥90% from baseline or to ≤0.2 ng/ml) were achieved at any time during the study in 90%, 73%, and 68% of apalutamide-treated versus 55%, 29%, and 32% of placebo-treated patients, respectively. By 3 months of apalutamide treatment, best deep PSA decline of ≥90% or to ≤0.2 ng/ml occurred in 59% and 51% of apalutamide- and in 13% and 18% of placebo-treated patients, respectively. Achievement of deep PSA decline at landmark 3 months of apalutamide treatment was associated with longer OS [hazard ratio (HR) 0.35; 95% confidence interval (CI) 0.25-0.48), rPFS (HR 0.44; 95% CI 0.30-0.65), time to PSA progression (HR 0.31; 95% CI 0.22-0.44), and time to castration resistance (HR 0.38; 95% CI 0.27-0.52) compared with no decline (P < 0.0001 for all). Similar results were observed at landmark 6 and 12 months of apalutamide treatment. CONCLUSIONS: Apalutamide plus ADT demonstrated a robust (rapid, deep, and durable) PSA decline that was associated with improved clinical outcomes, including long-term survival.

Erythema annulare centrifugum induced by COVID-19 vaccination.

With the expansion of the COVID-19 vaccination drive, an increasing number of adverse effects are surfacing. A 74-year-old woman presented with multiple erythematous and itchy patches on several sites. She had no relevant medical history, apart from the first AZD1222 vaccination 1 month previously. Microscopically, epidermal changes, including mild spongiosis and parakeratosis, were observed. Tight perivascular lymphocytic infiltration (coat-sleeve pattern) was also observed in the dermis. The final diagnosis was erythema annulare centrifugum (EAC) induced by SARS-CoV-2 vaccination. Based on this report, dermatologists should be aware of the possibility of EAC from the AZD1222 vaccination.

Overcoming existential loneliness: a cross-cultural study.

BACKGROUND: Moving into a long-term care facility (LTCF) can reduce the ability for older adults to engage in meaningful roles and activities and the size of their social network. These changes and losses can lead them to experience existential loneliness (EL)-the intolerable emptiness and lack of meaningful existence resulted from the losses they have experienced. While EL has often been understood as a universal human experience, it has primarily been studied in people from Western cultures; little is known about how EL may be experienced by and manifested in people from Eastern cultures. Hence, this qualitative study aimed to describe the experience and coping of EL in Hong Kong Chinese and Swedish older adults living in LTCFs. METHODS: A qualitative study using Thorne's (2004) interpretive description was conducted. Thirteen Chinese and 9 Swedes living in LTCFs in Hong Kong, China and Malmo, Sweden, respectively were interviewed about their experience of EL in two series of semi-structured interviews. Data were analyzed using thematic analysis. RESULTS: The core theme of "overcoming EL" described the participants' experience of EL, which came about through the combined process of "Feeling EL" and "Self-Regulating". Both Chinese and Swedish participants had similar experience with EL. Realizing that they did not want to living with EL anymore, they coped by reframing their experience and identifying new meaning in their life. CONCLUSIONS: The study findings suggested that early and clear counselling support that help older adults to define new meaning in life may help them cope. In addition, more opportunities should be available at the LTCFs to promote quality relationships, enable older adults to reflect on their lives with pride, and support their ability to do the things they enjoy.

[Pilot study on subjectively and objectively measurable stress reduction in the daily routine of a university anesthesia department by an intervention program according to mindfulness-based stress reduction]. / Pilotstudie zu subjektiv und objektiv messbarer Stressreduktion im Alltag einer universitären Anästhesieabteilung durch ein Interventionsprogramm nach Mindfulness-Based Stress Reduction (MBSR).

BACKGROUND: Chronic stress and high workload in physicians can lead to loss of interest, emotional exhaustion and finally in burnout syndrome. This can cause serious consequences not only for the physicians personally and their own health by developing extensive health impairments, e.g. depression, suicide, substance abuse and poor self-care but also for patient care, reflected in an increase of medical errors, longer recovery times, lower care quality and consequently lower patient satisfaction. Additionally, it can also have negative effects on the healthcare system by reduced productivity, increased physician turnover and thereby higher costs. OBJECTIVE: This pilot study investigated brief interventions inspired by mindfulness-based stress reduction (MBSR) combined with short daily meditation exercises in the everyday work of anesthetists at a university hospital. Secondly, whether this program increases the development of coping mechanisms for stress and improves participants' resilience and health status. MATERIAL AND METHODS: The pilot study was designed as a monocenter prospective interventional study with four different points of measurement. Subjective and objective stress parameters were measured directly before (t0) and after (t1) the intervention as well as 3 (t2) and 6 (t3) months after end of the intervention. Measurements took place during work time and at the workplace. The intervention was based on the classical MBSR including short daily exercises and lasted for 6 weeks with sessions lasting 1- 1.5 h and an additional 20 min of daily mediation exercises. The subjective parameters were based on validated questionnaires, such as the World Health Organization (WHO) well-being index (WHO-5), resilience scale (RS-11), Maslach burnout inventory (MBI-22) and perceived stress scale (PSS-10). For objective parameters heart rate variability (HRV) was evaluated during rest and after exposure to physical exercise and hair cortisol concentrations (HCC) in a 1.5 cm length of a hair, which represents the equivalent of a 6-week period. RESULTS: Data from 27 subjects could be analyzed. Between t3 and t0 a significant improvement of resilience was detected as a positive personality trait measured by RS-11 with a large effect size (p = 0.013; r = 0.59) as well as a significant reduction of burnout symptoms (MBI-22) also with a large effect size (p = 0.019; r = 0.57). Furthermore, a significant decrease was found in well-being (WHO-5) between t2 and t0 (p = 0.003, r = 0.67) and between t1 and t0 (p = 0.001, r = 0.71). The objective parameters did not show any significant differences between the examinations. CONCLUSION: An MBSR-based intervention in combination with short exercises during and after work can be implemented in daily work of anesthetists at a university hospital. Furthermore, there was clear evidence that the intervention program increased resilience and reduced burnout symptoms for up to 6 months. These findings are in line with the literature that MBSR reduces risk of burnout symptoms. The decrease in well-being might be biased by a high amount of socially accepted answers at the beginning of the study (t0).

CONSORT 2010 statement: extension checklist for reporting within person randomised trials.

Evidence shows that the quality of reporting of randomised controlled trials (RCTs) is not optimal. The lack of transparent reporting impedes readers from judging the reliability and validity of trial findings and researchers from extracting information for systematic reviews and results in research waste. The Consolidated Standards of Reporting Trials (CONSORT) statement was developed to improve the reporting of RCTs. Within person trials are used for conditions that can affect two or more body sites, and are a useful and efficient tool because the comparisons between interventions are within people. Such trials are most commonly conducted in ophthalmology, dentistry, and dermatology. The reporting of within person trials has, however, been variable and incomplete, hindering their use in clinical decision making and by future researchers. This document presents the CONSORT extension to within person trials. It aims to facilitate the reporting of these trials. It extends 16 items of the CONSORT 2010 checklist and introduces a modified flowchart and baseline table to enhance transparency. Examples of good reporting and evidence based rationale for CONSORT within person checklist items are provided.

Causal somatic mutations in urine DNA from persons with the CLOVES subgroup of the PIK3CA-related overgrowth spectrum.

Congenital lipomatous overgrowth with vascular, epidermal, and skeletal (CLOVES) anomalies and Klippel-Trenaunay (KTS) syndromes are caused by somatic gain-of-function mutations in PIK3CA, encoding a catalytic subunit of phosphoinositide 3-kinase. Affected tissue is needed to find mutations, as mutant alleles are not detectable in blood. Because some patients with CLOVES develop Wilms tumor, we tested urine as a source of DNA for mutation detection. We extracted DNA from the urine of 17 and 24 individuals with CLOVES and KTS, respectively, and screened 5 common PIK3CA mutation hotspots using droplet digital polymerase chain reaction. Six of 17 CLOVES participants (35%) had mutant PIK3CA alleles in urine. Among 8 individuals in whom a mutation had been previously identified in affected tissue, 4 had the same mutant allele in the urine. One study participant with CLOVES had been treated for Wilms tumor. We detected the same PIK3CA mutation in her affected tissue, urine, and tumor, indicating Wilms tumors probably arise from PIK3CA mutant cells in patients with CLOVES. No urine sample from a participant with KTS had detectable PIK3CA mutations. We suggest that urine, which has the advantage of being collected non-invasively, is useful when searching for mutations in individuals with CLOVES syndrome.

Okur-Chung neurodevelopmental syndrome: Eight additional cases with implications on phenotype and genotype expansion.

Okur-Chung syndrome is a neurodevelopmental condition attributed to germline CSNK2A1 pathogenic missense variants. We present 8 unreported subjects with the above syndrome, who have recognizable dysmorphism, varying degrees of developmental delay and multisystem involvement. Together with 6 previously reported cases, we present a case series of 7 female and 7 male subjects, highlighting the recognizable facial features of the syndrome (microcephaly, hypertelorism, epicanthic fold, ptosis, arched eyebrows, low set ears, ear fold abnormality, broad nasal bridge and round face) as well as frequently occurring clinical features including neurodevelopmental delay (93%), gastrointestinal (57%), musculoskeletal (57%) and immunological (43%) abnormalities. The variants reported in this study are evolutionary conserved and absent in the normal population. We observed that the CSNK2A1 gene is relatively intolerant to missense genetic changes, and most variants are within the protein kinase domain. All except 1 variant reported in this cohort are spatially located on the binding pocket of the holoenzyme. We further provide key recommendations on the management of Okur-Chung syndrome. To conclude, this is the second case series on Okur-Chung syndrome, and an in-depth review of the phenotypic features and genomic findings of the condition with suggestions on clinical management.

Arbuscular mycorrhizal fungi spore propagation using single spore as starter inoculum and a plant host.

AIMS: The propagation of pure cultures of arbuscular mycorrhizal fungal (AMF) is an essential requirement for their large-scale agricultural application and commercialization as biofertilizers. The present study aimed to propagate AMF using the single-spore inoculation technique and compare their propagation ability with the known reference spores. METHODS AND RESULTS: Arbuscular mycorrhizal fungal spores were collected from salt-affected Saemangeum reclaimed soil in South Korea. The technique involved inoculation of sorghum-sudangrass (Sorghum bicolor L.) seedlings with single, healthy spores on filter paper followed by the transfer of successfully colonized seedlings to 1-kg capacity pots containing sterilized soil. After the first plant cycle, the contents were transferred to 2·5-kg capacity pots containing sterilized soil. Among the 150 inoculated seedlings, only 27 seedlings were colonized by AMF spores. After 240 days, among the 27 seedlings, five inoculants resulted in the production of over 500 spores. The 18S rDNA sequencing of spores revealed that the spores produced through single-spore inoculation method belonged to Gigaspora margarita, Claroideoglomus lamellosum and Funneliformis mosseae. Furthermore, indigenous spore F. mosseae M-1 reported a higher spore count than the reference spores. CONCLUSIONS: The AMF spores produced using the single-spore inoculation technique may serve as potential bio-inoculants with an advantage of being more readily adopted by farmers due to the lack of requirement of a skilled technique in spore propagation. SIGNIFICANCE AND IMPACT OF THE STUDY: The results of the current study describe the feasible and cost-effective method to mass produce AMF spores for large-scale application. The AMF spores obtained from this method can effectively colonize plant roots and may be easily introduced to the new environment.

Beyond death and dying: how Chinese spouses navigate the final days with their loved ones suffering from terminal cancer.

While advances in biomedicine exist for cancer, its diagnosis and treatment still bring the threat of mortality to the forefront of spouses' lives. Family conflict is largely due to unmet expectations that generate a lot of physical and emotional distress for spouses, as the primary surrogates. Moreover, older individuals in Hong Kong tend to lack control of where they die and who is present at the end of their lives. Deeper understanding of Chinese spouses' perspectives is needed to generate new insights, particularly in how spouses cope with caregiving. The aim of the study was to explore the Chinese spousal experience with their dying loved ones suffering from terminal cancer. A qualitative study using interpretive description was conducted. Spousal caregivers were purposively recruited through a hospice unit of two regional hospitals in Hong Kong, China. Documentary sources were used as secondary data. Fifteen individuals, consisting of seven men and eight women, participated in individual interviews. The overarching theme was a socially constructed "we" experience of confronting mortality, characterized by five subthemes: (a) balancing end-of-life tension between cure and comfort, (b) prioritizing the family goals and concerns, (c) de-medicalizing caregiving, (d) working for mutuality, and (e) creating a legacy of love. The study suggests that clinicians might consider harnessing the capacity of spouses to help work through confronting experiences of mortality and transforming events for goals that go beyond death. This places a major emphasis on salutary strategies surrounding transitions from curative to palliative care.

Clinical and genetic profile of congenital long QT syndrome in Hong Kong: a 20-year experience in paediatrics.

INTRODUCTION: Congenital long QT syndrome (LQTS) is a genetically transmitted cardiac channelopathy that can lead to sudden cardiac death. This study aimed to report the clinical and genetic characteristics of all young patients diagnosed with LQTS in the only tertiary paediatric cardiology centre in Hong Kong. METHODS: This is a retrospective review of all paediatric and young adult patients diagnosed at our centre with LQTS from January 1997 to December 2016. The diagnosis of LQTS was established with a corrected QT interval (QTc) ≥480 ms, Schwartz score of >3 points, or the presence of a pathogenic mutation. RESULTS: Fifty-nine patients (33 males) from 52 families were included, with a mean age of 8.17 years (range, 0.00-16.95 years) at presentation. Five patients had concomitant congenital heart diseases. The mean follow-up duration was 5.33 ± 4.65 years. The mean QTc in the cohort was 504 ± 47 ms. They presented with syncope and convulsion (49%), cardiac arrest (10%), bradycardia and neonatal atrioventricular block (12%). Fifteen (25%) patients were asymptomatic at diagnosis. Thirty-eight (64.4%) patients were confirmed to have a pathogenic mutation for LQTS genes. Forty-five (76.3%) patients received beta blocker therapy. Thirteen (22.0%) patients required implantable cardioverter defibrillator. There was no mortality in the study period. The 1-, 5-, and 10-year breakthrough cardiac event-free rates were 93.0%, 80.7%, and 72.6%, respectively. CONCLUSION: Identification of the disorder, administration of beta blockers, and lifestyle modification can prevent subsequent cardiac events in LQTS. Genotyping in patients with LQTS is essential in guiding medical therapy and improving prognosis.

Effect of Empagliflozin on Tacrolimus-Induced Pancreas Islet Dysfunction and Renal Injury.

An inhibitor of sodium glucose co-transporter type 2 (SGLT-2) is recommended in type 2 diabetes mellitus (DM) but its use is still undetermined in tacrolimus (TAC)-induced DM. We evaluated the effect of empagliflozin (Em) on TAC-induced pancreatic islet dysfunction and renal injury in an experimental model of TAC-induced DM and in vitro. TAC induced a twofold increase in SGLT-2 expression, while Em decreased SGLT-2 expression and further increased urinary glucose excretion compared to the TAC group. Em reduced hyperglycemia and increased plasma insulin level, pancreatic islet size, and glucose-stimulated insulin secretion compared to the TAC group. In kidney, Em alleviated TAC-induced renal dysfunction and decreased albumin excretion and histological injury compared with the TAC group. Increased oxidative stress and apoptotic cell death by TAC was remarkably decreased with Em in serum and pancreatic and renal tissues. In in vitro study, TAC decreased cell viability and increased reactive oxygen species (ROS) production in both insulin-secreting beta-cell derived (INS-1) and human kidney-2 (HK-2) cell lines. Addition of Em increased cell viability and decreased ROS production in HK-2 but not in INS-1 cell lines. This suggests that Em is effective in controlling TAC-induced hyperglycemia and has direct protective effect on TAC-induced renal injury.