Phosphoregulation of DSB-1 mediates control of meiotic double-strand break activity.

In the first meiotic cell division, proper segregation of chromosomes in most organisms depends on chiasmata, exchanges of continuity between homologous chromosomes that originate from the repair of programmed double-strand breaks (DSBs) catalyzed by the Spo11 endonuclease. Since DSBs can lead to irreparable damage in germ cells, while chromosomes lacking DSBs also lack chiasmata, the number of DSBs must be carefully regulated to be neither too high nor too low. Here, we show that in Caenorhabditis elegans, meiotic DSB levels are controlled by the phosphoregulation of DSB-1, a homolog of the yeast Spo11 cofactor Rec114, by the opposing activities of PP4PPH-4.1 phosphatase and ATRATL-1 kinase. Increased DSB-1 phosphorylation in pph-4.1 mutants correlates with reduction in DSB formation, while prevention of DSB-1 phosphorylation drastically increases the number of meiotic DSBs both in pph-4.1 mutants and in the wild-type background. C. elegans and its close relatives also possess a diverged paralog of DSB-1, called DSB-2, and loss of dsb-2 is known to reduce DSB formation in oocytes with increasing age. We show that the proportion of the phosphorylated, and thus inactivated, form of DSB-1 increases with age and upon loss of DSB-2, while non-phosphorylatable DSB-1 rescues the age-dependent decrease in DSBs in dsb-2 mutants. These results suggest that DSB-2 evolved in part to compensate for the inactivation of DSB-1 through phosphorylation, to maintain levels of DSBs in older animals. Our work shows that PP4PPH-4.1, ATRATL-1, and DSB-2 act in concert with DSB-1 to promote optimal DSB levels throughout the reproductive lifespan.

Treatment of male breast cancer: meta-analysis of real-world evidence.

BACKGROUND: Breast cancer is rare in men and managed by extrapolating from breast cancer in women. The clinicopathological features of male breast cancer, however, differ from those of female breast cancer. Because clinical trials are rare, the synthesis of real-world data is one method of integrating sufficient evidence on the optimal treatment for this patient population. METHODS: PubMed, Embase, and Cochrane Library databases were searched. Clinical studies were included if they evaluated the treatments of interest in male breast cancer; these evaluations included breast-conserving surgery (BCS) versus mastectomy, postmastectomy radiation therapy versus no radiation, the accuracy of sentinel lymph node biopsy (SLNB), and a comparison of various endocrine therapies. RESULTS: Forty studies were retrieved. The pooled estimate of overall survival (OS) revealed no difference between BCS and mastectomy groups. Postmastectomy radiation to the chest wall significantly increased OS relative to no postmastectomy radiation (hazard ratio (HR) 0.67, 95 per cent confidence interval 0.54 to 0.84). The pooled estimates of identification and false-negative rates of SLNB were 97.4 and 7.4 per cent respectively. Tamoxifen treatment was associated with significantly increased OS compared with no tamoxifen intake (HR 0.62, 0.41 to 0.95). CONCLUSION: Identification and false-negative rates for SLNB were comparable to those in female breast cancer. Breast-conserving surgery can be effective and safe; postmastectomy radiation to the chest wall and 5-year tamoxifen treatment improves survival.

Consensus statements on the clinical usage and characteristics of aripiprazole for Hong Kong.

Aripiprazole, a dopamine partial agonist, is a second-generation anti-psychotic that is widely used for the treatment of schizophrenia and other psychotic disorders. A group of psychiatric experts in Hong Kong developed a set of consensus statements, aiming to facilitate the understanding of clinical properties and usages of aripiprazole among local physicians. Of note, because aripiprazole long-acting injectable has been available locally not long before the establishment of the consensus panel, which limited the discussion on its use in the local context, the consensus statements were focused primarily on oral aripiprazole. To draft the consensus statements, the panellists discussed the published evidence and their clinical experience regarding aripiprazole in a series of meetings based on several areas. At the final meeting, each drafted statement was voted on anonymously by all panellists based on its practicability of recommendation in Hong Kong. A set of consensus statements on the characteristics and clinical use of aripiprazole was established and accepted by the panel. These statements serve to provide a practical reference for physicians in Hong Kong, and possibly other parts of the Asia-Pacific region, on the use of aripiprazole in people with schizophrenia spectrum disorders and other psychotic problems.

Exploiting species specificity to understand the tropism of a human-specific toxin.

Many pathogens produce virulence factors that are specific toward their natural host. Clinically relevant methicillin-resistant Staphylococcus aureus (MRSA) isolates are highly adapted to humans and produce an array of human-specific virulence factors. One such factor is LukAB, a recently identified pore-forming toxin that targets human phagocytes by binding to the integrin component CD11b. LukAB exhibits strong tropism toward human, but not murine, CD11b. Here, phylogenetics and biochemical studies lead to the identification of an 11-residue domain required for the specificity of LukAB toward human CD11b, which is sufficient to render murine CD11b compatible with toxin binding. CRISPR-mediated gene editing was used to replace this domain, resulting in a "humanized" mouse. In vivo studies revealed that the humanized mice exhibit enhanced susceptibility to MRSA bloodstream infection, a phenotype mediated by LukAB. Thus, these studies establish LukAB as an important toxin for MRSA bacteremia and describe a new mouse model to study MRSA pathobiology.

Efficacy and safety of high-dose vs low-dose leucovorin in patients with colorectal cancer: systematic review and meta-analysis.

AIM: The clinical benefits of a combination of leucovorin and fluorouracil have been established in the treatment of colorectal cancer. Due to a leucovorin shortage in 2008, many institutions revised their protocols to reduce the dose of leucovorin. After the shortage was resolved, some hospitals still maintained their modified protocols. Thus, we conducted a systematic review to evaluate the efficacy and safety of low- vs high-dose leucovorin in the treatment of colorectal cancer. METHOD: The PubMed, Embase and Cochrane databases were searched for studies published before May 2019. The meta-analysis was performed to estimate the pooled effect sizes by using a random effect model. The primary outcomes were median survival time and tumour response rate. Secondary outcomes were haematological and nonhaematological toxicities. RESULTS: Eight randomized controlled trials and four retrospective studies were reviewed. The pooled median survival time was similar between the two dose levels (standard mean difference -0.06, 95% CI -0.19 to 0.08). The pooled tumour response rate was comparatively higher in the high-dose leucovorin regimen (OR 0.81; 95% CI 0.55-1.18). No statistically significant difference was found between the haematological and nonhaematological toxicities of the two groups. However, there were fewer diarrhoea events in the low-dose leucovorin regimen. CONCLUSION: Low-dose leucovorin regimens seemed feasible approaches for colorectal cancer treatment when the shortage happened, because both regimens manifested comparable outcomes in survival time and tumour response rate.

A new chemical approach for proximity labelling of chromatin-associated RNAs and proteins with visible light irradiation.

A new nucleus-localized singlet oxygen generator was designed and synthesized. Its capability to label nucleus-localized biomolecules through spatially-restricted oxidation under visible light was validated using fluorescence confocal microscopy. Western blot and RT-qPCR were performed to verify the desirable spatial resolution through enriching chromatin-associated RNAs and proteins.

Wound Closure after Thyroid and Parathyroid Surgery: A Meta-Analysis of Randomized Controlled Trials.

AIMS: Wound closure after thyroidectomy and parathyroidectomy is associated with patients' satisfaction, perception of cosmetic appearance, and experience of postoperative pain. Subcutaneous sutures, clips, and tissue adhesive are the three major methods of wound closure. In this study, we conducted a meta-analysis of randomized controlled trials to evaluate the outcomes of these methods. METHODS: Relevant studies published before December 2017 were identified from PubMed, Embase, Cochrane Library, Scopus, and the ClinicalTrials.gov registry. Individual effect sizes were standardized, and a meta-analysis was conducted to calculate the pooled effect size by using random-effect models. The primary outcome was the cosmetic appearance, which was evaluated 4 weeks, 6 weeks, and 6 months after surgery. The secondary outcomes were patient satisfaction, postoperative pain, and complications. RESULTS: A total of nine trials with 612 patients were reviewed. No significant difference was observed in patient satisfaction, postoperative pain, and complications among the wound closure methods. However, according to surgeon assessment, the subcutaneous suture method resulted in a significantly more favorable cosmetic appearance than the clip method (mean difference: -1.47, 95% confidence interval: -2.72 to -0.23). CONCLUSION: In the current study, no differences were found in patient satisfaction and postoperative pain among the subcutaneous suture, clip, and tissue adhesive wound closure methods. However, surgeons provided a more favorable appraisal for the subcutaneous suture method because of the improved cosmetic appearance. The choice of the closure method should be based on surgeon's preference and cost.

Antiseptic efficacies of waterless hand rub, chlorhexidine scrub, and povidone-iodine scrub in surgical settings: a meta-analysis of randomized controlled trials.

BACKGROUND: Presurgical hand washing is crucial for preventing surgical site infections (SSIs). Chlorhexidine gluconate (CHG) and povidone-iodine (PI) products have been conventionally used as hand scrubs for presurgical hand preparation. However, waterless hand rub (WHR) products have been developed for operating room staff. AIM: The aim of this study was to conduct a systematic review and meta-analysis to compare the antiseptic efficacies of WHR, CHG, and PI in surgical settings. METHODS: PubMed, Embase, and Cochrane Library databases as well as the ClinicalTrials.gov registry were searched for studies published before October 2018. Randomized controlled trials (RCTs) comparing the clinical outcomes of the use of WHRs, CHG, or PI for presurgical hand washing were included. A random effects model was used for meta-analysis. Colony-forming unit (cfu) counts, SSI rates, and preference and compliance were determined to measure efficacies. FINDINGS: Eleven RCTs involving 5135 participants were included. Residual cfu counts were significantly lower in the WHR and CHG groups than in the PI group. The differences in cfu counts between the WHR and CHG groups were non-significant. No significant differences were observed in the SSI rates between the WHR and traditional hand scrub groups. Moreover, WHRs were considered most favourable and were associated with higher compliance rates than the other products. CONCLUSION: WHRs and CHG exhibited higher antiseptic efficacies than PI. However, additional studies with consistent outcome measurements and accurate grouping are required to obtain comprehensive results. Moreover, preference, compliance, and the cost determine the selection of hand wash products.

Educating Medical Students in Counselling Older Adults about Exercise: The Impact of a Physical Activity Module.

BACKGROUND: Exercise courses during medical school contribute to medical students' confidence in promoting physical activity to their patients. However, there is still a lack of uniform physical activity education across medical school curricula to equip medical students with the necessary skills and knowledge to counsel their patients about exercise. OBJECTIVE: To determine the effects of a 1.5-hour physical activity module including a one-hour exercise tutorial combined with a 30-minute practical counselling session on senior medical students' perceptions of the importance of exercise and their perceived competence in advising older people about exercise. DESIGN: Pre-post survey. SETTING: University campus. PARTICIPANTS: 161 senior medical students taking part in the Queen Elizabeth Hospital Geriatric Medicine course in 2015 (control group) and 2016 (intervention group). MEASUREMENT: The modified Exercise and Physical Activity Competence Questionnaire (EPACQ) was administered before and after a 4.5-week Geriatric Medicine Course. Scores ranged from 1 (not important or competent) to 6 (very important or competent). The independent T-Test and repeated-measures ANOVA was used to determine differences between intervention and control group. RESULTS: Medical students perceived exercise-related skills to be highly important (score ≥4) in both the intervention (4.85 ± 0.37) and control group (4.78 ± 0.67), pre-course. The overall perceived importance could not be significantly increased by the physical activity module (P=0.082). The physical activity module, however, improved medical students' perceived competence in six out of ten exercise-related skills, and increased their overall perceived competence in counselling older people about exercise (P<0.001). CONCLUSION: A 1.5-hour physical activity module improves senior medical students' perceived competence in counselling older people about exercise. This research proves that little teaching space is needed to impact positively on medical students' exercise counselling abilities.

Cellulose nanocrystal (CNC)-inorganic hybrid systems: synthesis, properties and applications.

Cellulose nanocrystal (CNC), a class of sustainable nanomaterial derived from forest and agro-biomass can serve as nature's storage for carbon dioxide. It has many attractive features, such as large specific surface area, high tensile strength and stiffness, abundance of surface hydroxyl groups, and they are also biocompatible, biodegradable and renewable. When dispersed in a polar solvent, they assemble to form multiphase or higher order structures yielding desirable optical and structural properties. They are being explored as templates for the design of a wide range of new functional nanomaterials. CNCs are excellent support for the loading of inorganic nanoparticles (e.g. Ag, Au, Pt, Pd etc.) yielding stable nano-hybrids in aqueous media. Additional surface functionalization of CNCs impart new and attractive physicochemical properties that are being exploited for application in sensors, catalysts, drug delivery vehicles, anti-microbial agents, scaffold for tissue engineering, biomarkers etc. This review provides an overview and future perspective on recent advances in the development on functional CNC-inorganic hybrids with potential applications in biomedical and chemical systems.

A study of human neutrophil antigen genotype frequencies in Hong Kong.

BACKGROUND: Alloantibodies against human neutrophil antigens (HNA) are associated with a variety of clinical conditions. Over the past decade, the allelic and genotypic frequencies of the five HNA systems have been evaluated. Although the HNA system is less polymorphic than human leukocyte antigens (HLA), significant differences in the genotypic and allele frequencies still exist in different populations, even those living in close proximity. OBJECTIVES: To delineate HNA genotypic and allele frequencies to provide vital information on estimating the risk of HNA-associated diseases for our local population. METHODS: Using a validated, in-house-developed assay, genotyping for HNA-1, HNA-3, HLA-4 and HNA-5 was performed on 300 samples from Chinese blood donors from Hong Kong. In addition, the frequency of the HNA-2 c.843A > T allele was also determined. RESULTS: The allele frequencies of HNA-1a, -1b and -1c alleles were 67·8, 31·5 and 0%, respectively, whereas the frequencies of HNA-3a and HNA-3b were 71·0 and 29·0%, respectively. The frequencies of HNA-4a and -4b alleles were 99·5 and 0·5%, respectively, and for HNA-5a and -5b, alleles were 85·2 and 14·8%, respectively. Homozygotes for the HNA-2 c.843 TT variant were absent in our population, whereas only <4% of the population were c.843AT heterozygote carriers. CONCLUSIONS: This is the first study to define HNA genotype and allele frequencies using a validated modified in-house PCR-SSP method in the Hong Kong Chinese blood donor population. Our approach provides a cost-effective assay for conducting routine HNA typing and facilitates the incorporation of these assays into routine clinical service. Our results are comparable with those reported in the Guangzhou Chinese population, but the allele frequencies in our Hong Kong Chinese population are significantly different from the reported European frequencies, confirming that a geographical difference exists for HNA allele frequencies.

Diabetes in older people: position statement of The Hong Kong Geriatrics Society and the Hong Kong Society of Endocrinology, Metabolism and Reproduction.

Following a survey on the clinical practice of geriatricians in the management of older people with diabetes and a study of hypoglycaemia in diabetic patients, a round-table discussion with geriatricians and endocrinologists was held in January 2015. Consensus was reached for six domains specifically related to older diabetic people: (1) the considerations when setting an individualised diabetic management; (2) inclusion of geriatric syndrome screening in assessment; (3) glycaemic and blood pressure targets; (4) pharmacotherapy; (5) restrictive diabetic diet; and (6) management goals for nursing home residents.

Geniposide improves insulin production and reduces apoptosis in high glucose-induced glucotoxic insulinoma cells.

Our previous work revealed that in the pancreatic ß cell line, geniposide modulated ATP production and glucose-stimulated insulin secretion (GSIS) induced by the acute stimulation of high glucose concentration. However, the effects of geniposide on functional impairment and the mass of ß-cells exposed to elevated levels of glucose remains unknown. In the present study, impaired GSIS and restrained proliferation were observed in the prolonged culture of insulinoma INS-1 cells with 33mM of glucose (high glucose). Our results indicate that the glucose-induced impairment of insulin release was significantly reverted by the inclusion of 1 or 10µM of geniposide. Moreover, induction of the phosphorylation of AMP-activated protein kinase (AMPK) was observed, which promoted the utilization of nutrient stores for energy production. AMPK phosphorylation was enhanced by an increased number of INS-1 cells, and the increased expression of AMPK downstream target heme oxygenase 1 (HO-1), under high glucose concentration. Furthermore, geniposide protected rat insulinoma cells from apoptosis in high-glucose concentrations. We have shown that these effects were associated with an increased apoptosis-related Bcl-2/BAX protein ratio. In conclusion, geniposide dose dependently improves ß-cell function and increases the proliferation of ß-cells exposed to prolonged hyperglycemia.

Awake whole-brain functional connectivity alterations in the adolescent spontaneously hypertensive rat feature visual streams and striatal networks.

Brain mechanisms underpinning attention deficit/hyperactivity disorder (ADHD) are incompletely understood. The adolescent spontaneously hypertensive rat (SHR) is a widely studied preclinical model that expresses several of the key behavioral features associated with ADHD. Yet, little is known about large-scale functional connectivity patterns in the SHR, and their potential similarity to those of humans with ADHD. Using an approach comparable to human studies, magnetic resonance imaging in the awake animal was performed to identify whole-brain intrinsic neural connectivity patterns. An independent components analysis of resting-state functional connectivity demonstrated many common components between the SHR and both Wistar Kyoto and Sprague-Dawley control strains, but there was a divergence in other networks. In the SHR, three functional networks involving the striatum had only weak correlations with networks in the two control strains. Conversely, networks involving the visual cortex that was present in both control strains had only weak correlations with networks in the SHR. The implication is that the patterns of brain activity differ between the SHR and the other strains, suggesting that brain connectivity patterns in this animal model of ADHD may provide insights into the neural basis of ADHD. Brain connectivity patterns might also serve to identify brain circuits that could be targeted for the manipulation and evaluation of potential therapeutic options.

Use of CdS quantum dot-functionalized cellulose nanocrystal films for anti-counterfeiting applications.

Structural colors and photoluminescence have been widely used for anti-counterfeiting and security applications. We report for the first time the use of CdS quantum dot (QD)-functionalized cellulose nanocrystals (CNCs) as building blocks to fabricate nanothin films via layer-by-layer (LBL) self-assembly for anti-counterfeiting applications. Both negatively- and positively-charged CNC/QD nanohybrids with a high colloidal stability and a narrow particle size distribution were prepared. The controllable LBL coating process was characterized by scanning electron microscopy and ellipsometry. The rigid structure of CNCs leads to nanoporous structured films on poly(ethylene terephthalate) (PET) substrates with high transmittance (above 70%) over the entire range of visible light and also resulted in increased hydrophilicity (contact angles of ∼40 degrees). Nanothin films on PET substrates showed good flexibility and enhanced stability in both water and ethanol. The modified PET films with structural colors from thin-film interference and photoluminescence from QDs can be used in anti-counterfeiting applications.

Ventilator-Related Adverse Events: A Taxonomy and Findings From 3 Incident Reporting Systems.

BACKGROUND: In 2009, researchers from Johns Hopkins University's Armstrong Institute for Patient Safety and Quality; public agencies, including the FDA; and private partners, including the Emergency Care Research Institute and the University HealthSystem Consortium (UHC) Safety Intelligence Patient Safety Organization, sought to form a public-private partnership for the promotion of patient safety (P5S) to advance patient safety through voluntary partnerships. The study objective was to test the concept of the P5S to advance our understanding of safety issues related to ventilator events, to develop a common classification system for categorizing adverse events related to mechanical ventilators, and to perform a comparison of adverse events across different adverse event reporting systems. METHODS: We performed a cross-sectional analysis of ventilator-related adverse events reported in 2012 from the following incident reporting systems: the Pennsylvania Patient Safety Authority's Patient Safety Reporting System, UHC's Safety Intelligence Patient Safety Organization database, and the FDA's Manufacturer and User Facility Device Experience database. Once each organization had its dataset of ventilator-related adverse events, reviewers read the narrative descriptions of each event and classified it according to the developed common taxonomy. RESULTS: A Pennsylvania Patient Safety Authority, FDA, and UHC search provided 252, 274, and 700 relevant reports, respectively. The 3 event types most commonly reported to the UHC and the Pennsylvania Patient Safety Authority's Patient Safety Reporting System databases were airway/breathing circuit issue, human factor issues, and ventilator malfunction events. The top 3 event types reported to the FDA were ventilator malfunction, power source issue, and alarm failure. CONCLUSIONS: Overall, we found that (1) through the development of a common taxonomy, adverse events from 3 reporting systems can be evaluated, (2) the types of events reported in each database were related to the purpose of the database and the source of the reports, resulting in significant differences in reported event categories across the 3 systems, and (3) a public-private collaboration for investigating ventilator-related adverse events under the P5S model is feasible.

Reliability and Validity of the Vietnamese Depression Interview (VDI).

Current instruments used to aid in the diagnosis of psychological disorders have limited effectiveness with clients from Asian backgrounds. The Vietnamese Depression Interview (VDI) is a diagnostic instrument created to assess the presence of current and lifetime history of major depressive disorder specifically among Vietnamese refugees and immigrants. The purpose of the present study is to provide a description of the VDI, while also noting it as a reliable and valid means by which to assess depression in Vietnamese individuals. Using the Longitudinal, Expert, and All Data (LEAD; Spitzer in Compr Psychiatry 24:399-411, 1983) standard and the VDI, experienced clinicians conducted the diagnosis process with 127 Vietnamese refugees and immigrants. Assessment of the reliability and validity of the VDI yielded good to excellent AUC and kappa values, indicating the reliability of the VDI and the agreement between the LEAD procedure and the VDI. These study results imply that the VDI performs successfully as a diagnostic instrument specifically created for Vietnamese refugees and immigrants in their native language. Current and future contributions of the VDI with Vietnamese individuals are discussed.