Molybdenum oxide/nickel molybdenum oxide heterostructures hybridized active platinum co-catalyst toward superb-efficiency water splitting catalysis.

A new catalyst has been developed that utilizes molybdenum oxide (MoO3)/nickel molybdenum oxide (NiMoO4) heterostructured nanorods coupled with Pt ultrafine nanoparticles for the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) toward industrial-grade water splitting. This catalyst has been synthesized using a versatile approach and has shown to perform better than noble-metals catalysts, such as Pt/C and RuO2, at industrial-grade current level (≥1000 mA·cm-2). When used simultaneously as a cathode and anode, the proposed material yields 10 mA·cm-2 at a remarkably small cell voltage of 1.55 V and has shown extraordinary durability for over 50 h. Density functional theory (DFT) calculations have proved that the combination of MoO3 and NiMoO4 creates a metallic heterostructure with outstanding charge transfer ability. The DFT calculations have also shown that the excellent chemical coupling effect between the MoO3/NiMoO4 and Pt synergistically optimize the charge transfer capability and Gibbs free energies of intermediate species, leading to remarkably speeding up the reaction kinetics of water electrolysis.

Comparison of Pre-eclampsia Screening Algorithms in the First Trimester of Pregnancy Being Used in Thai Nguyen Province.

Objective To compare the rates of pregnancies in high-risk groups for preeclampsia recommended for aspirin prophylactic when screened using various common algorithms. Methods This cross-sectional study was conducted on 1726 pregnant women from 11 to 13 weeks six days of gestation receiving antenatal care at two hospitals: Thai Nguyen National Hospital and a hospital in Thai Nguyen Province from October 2022 to October 2023. All participants provided consent for the study. We collected maternal characteristics, obstetric history, mean arterial pressure (MAP), mean uterine artery-PI (UtA-PI), and placental growth factor serum (PLGF). Screening performance estimates were calculated using the Fetal Medicine Foundation (FMF) and National Institute for Health and Care Excellence (NICE) guidelines. All pregnant women in the study had their preeclampsia risk assessed using all three algorithms with two cut-off points. Our data was collected, entered and analyzed using SPSS software 20.0 (IBM Corp., Armonk, NY). Categorical data was reported as frequency and percentage. McNemar's test was used for analyzing differences in the sizes of individual groups. Results In our study, the most common high-risk factor identified was the history of preeclampsia, 132 cases (7.6%). According to the NICE guideline, BMI ≥ 35 (kg/m²) is considered a moderate risk factor for preeclampsia. Several risk factors, such as BMI ≥ 35 kg/m² and history of diabetes mellitus type 1, were not present in any participants. Only one pregnant woman had chronic kidney disease (0.06%). Out of the 1726 pregnant women surveyed, the rates of high-risk preeclampsia were as follows: 9.9% (171 cases) based on algorithm 1; 10.8% (187 cases) based on algorithm 2 with a cut-off point > 1/100, 11.8% (203 cases) with a cut-off point > 1/150; 10.3 % (178 cases) based on algorithm 3 with a cut-off point > 1/100, and 11.6% (201 cases) with a cut-off point > 1/150. Among these algorithms, pregnant women in the high-risk preeclampsia group were advised to consider taking low-dose aspirin. Conclusion Screening for pre-eclampsia based on NICE recommendations resulted in a lower number of high-risk pregnant women requiring prophylactic aspirin use compared to other algorithms. This means that some pregnant women at risk of developing preeclampsia are not recommended to use aspirin as a preventive measure. Adding PLGF to the screening strategy will help us get closer to pregnant women who are truly at risk of progressing to preterm preeclampsia.

Engagement of a community advisory group to shape and build up participation in TB research.

It is essential that communities at risk from TB are involved in TB research. Community advisory groups (CAGs) are one mechanism for involving communities in research and creating platforms for discussions between researchers and community members. We organised a CAG meeting with community members and people with lived experience in Ho Chi Minh City, Vietnam, to explore the community's knowledge about TB and their perspectives on different diagnostic tests in Vietnam, a low-middle-income country with a high TB burden. Researchers shared basic information and addressed questions about TB. CAG members commented on preference of TB screening tests, and suggested that chest X-rays and blood tests were more acceptable than sputum tests because of the difficulty in sputum expectoration. In addition, clinical studies that required fewer visits to the hospitals would be preferred, even if this meant a greater reliance on blood sampling.

Il est essentiel que les communautés exposées au risque de TB soient impliquées dans la recherche sur la TB. Les groupes consultatifs communautaires (CAG, pour l'anglais « community advisory groups ¼) constituent un mécanisme permettant d'impliquer les communautés dans la recherche et de créer des plateformes de discussion entre les chercheurs et les membres de la communauté. Nous avons organisé une réunion du CAG avec des membres de la communauté et des personnes ayant une expérience vécue à Ho Chi Minh Ville, au Viêt Nam, afin d'explorer les connaissances de la communauté sur la TB et leurs perspectives sur les différents tests de diagnostic au Viêt Nam, un pays à revenu faible et moyen où la charge de la TB est élevée. Les chercheurs ont partagé des informations de base et répondu à des questions sur la TB. Les membres du CAG ont fait part de leur préférence pour les tests de dépistage de la TB et ont suggéré que les radiographies pulmonaires et les analyses de sang étaient plus acceptables que les tests d'expectoration en raison de la difficulté d'expectoration des crachats. En outre, les études cliniques qui nécessitent moins de visites dans les hôpitaux seraient préférées, même si cela implique une plus grande dépendance à l'égard des prélèvements sanguins.

Unexpected and delayed fragmentation dynamics of the organometallic ferrocene induced by ion-collision.

We have investigated the fragmentation dynamics of the organometallic ferrocene molecule after interaction with multiply charged ions using multicoincidence mass spectrometry and quantum chemistry calculations. We observed unexpected fragmentation dynamics of the two-body breakup channels from ferrocene dications revealing a charge screening effect from the iron atom and delayed fragmentation dynamics. These observations are rationalized through the population of a specific long-lived excited state, where one positive charge is located on each cyclopentadienyl ring.

Genetic diversity of G9, G3, G8 and G1 rotavirus group A strains circulating among children with acute gastroenteritis in Vietnam from 2016 to 2021.

Rotavirus group A (RVA) is the most common cause of severe childhood diarrhea worldwide. The introduction of rotavirus vaccination programs has contributed to a reduction in hospitalizations and mortality caused by RVA. From 2016 to 2021, we conducted surveillance to monitor RVA prevalence and genotype distribution in Nam Dinh and Thua Thien Hue (TT Hue) provinces where a pilot Rotavin-M1 vaccine (Vietnam) implementation took place from 2017 to 2020. Out of 6626 stool samples, RVA was detected in 2164 (32.6%) by ELISA. RT-PCR using type-specific primers were used to determine the G and P genotypes of RVA-positive specimens. Whole genome sequences of a subset of 52 specimens randomly selected from 2016 to 2021 were mapped using next-generation sequencing. From 2016 to 2021, the G9, G3 and G8 strains dominated, with detected frequencies of 39%, 23%, and 19%, respectively; of which, the most common genotypes identified were G9P[8], G3P[8] and G8P[8]. G1 strains re-emerged in Nam Dinh and TT Hue (29.5% and 11.9%, respectively) from 2020 to 2021. G3 prevalence decreased from 74% to 20% in TT Hue and from 21% to 13% in Nam Dinh province between 2017 and 2021. The G3 strains consisted of 52% human typical G3 (hG3) and 47% equine-like G3 (eG3). Full genome analysis showed substantial diversity among the circulating G3 strains with different backgrounds relating to equine and feline viruses. G9 prevalence decreased sharply from 2016 to 2021 in both provinces. G8 strains peaked during 2019-2020 in Nam Dinh and TT Hue provinces (68% and 46%, respectively). Most G8 and G9 strains had no genetic differences over the surveillance period with very high nucleotide similarities of 99.2-99.9% and 99.1-99.7%, respectively. The G1 strains were not derived from the RVA vaccine. Changes in the genotype distribution and substantial diversity among circulating strains were detected throughout the surveillance period and differed between the two provinces. Determining vaccine effectiveness against circulating strains over time will be important to ensure that observed changes are due to natural secular variation and not from vaccine pressure.

Enhancing classical swine fever virus identification: the advantages of Field-LAMP testing.

Classical swine fever virus (CSFV) identification has witnessed significant advancements with the development of rapid reverse-transcription loop-mediated isothermal amplification (RT-LAMP) assays. However, conventional RT-LAMP assays for CSFV diagnosis are hindered by a laborious RNA extraction step. Moreover, the need for thermal incubators and expensive micropipettes has limited their application in field settings. Addressing these challenges, our study presents a groundbreaking solution-an electro-free and point-of-care (POC) tool known as the field-LAMP assay-for the rapid clinical detection of CSFV. By eliminating the RNA extraction requirement, advancing the colorimetric read-out and lyophilized reaction reagents, our field-LAMP assay streamlines the diagnostic process, saving valuable time and effort. This novel approach also overcomes the dependency on electric-dependent thermal incubators and expensive micropipettes, making it practical and accessible for use in the field. The successful development of the field-LAMP assay marks a significant milestone in CSFV detection. This electro-free and POC tool offers several advantages, including its ability to deliver rapid results without compromising accuracy, facilitating prompt response and containment measures.

Mothers' Breast Milk Composition and Their Respective Infant's Gut Microbiota Differ between Five Distinct Rural and Urban Regions in Vietnam.

Microbiota colonization and development in early life is impacted by various host intrinsic (genetic) factors, but also diet, lifestyle, as well as environmental and residential factors upon and after birth. To characterize the impact of maternal nutrition and environmental factors on vaginally born infant gut microbiota composition, we performed an observational study in five distinct geographical areas in Vietnam. Fecal samples of infants (around 39 days old) and fecal and breast milk samples of their mothers (around 28 years) were collected. The microbiota composition of all samples was analyzed by 16S rRNA gene Illumina sequencing and a bioinformatics workflow based on QIIME. In addition, various breast milk components were determined. Strong associations between the geographically determined maternal diet and breast milk composition as well as infant fecal microbiota were revealed. Most notable was the association of urban Ha Noi with relatively high abundances of taxa considered pathobionts, such as Klebsiella and Citrobacter, at the expense of Bifidobacterium. Breast milk composition was most distinct in rural Ha Long Bay, characterized by higher concentrations of, e.g., docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), selenium, and vitamin B12, while it was characterized by, e.g., iron, zinc, and α-linolenic acid (ALA) in Ha Noi. Breast milk iron levels were positively associated with infant fecal Klebsiella and negatively with Bifidobacterium, while the EPA and DHA levels were positively associated with Bifidobacterium. In conclusion, differences between five regions in Vietnam with respect to both maternal breast milk and infant gut microbiota composition were revealed, most likely in part due to maternal nutrition. Thus, there could be opportunities to beneficially steer infant microbiota development in a more desired (rural instead of urban) direction through the mother's diet.

Population structure of Vietnamese pigs using mitochondrial DNA.

The D-loop region on mitochondrial DNA (mtDNA) is frequently used for analyses of maternal lineages within domestic animal species. There are many native pig breeds in Vietnam, but their origins remain unclear. This study investigated maternal lineages using the D-loop region on mtDNA of 260 samples collected from native pigs in 20 provinces across Vietnam. The D-loop region of all samples was amplified and sequenced. We obtained 713 bp sequences of the D-loop region for each sample excluding the repeat region, and variants on this region were used to construct a phylogenetic tree. We detected 50 haplotypes from Vietnamese native pigs, with 27 novel haplotypes. Phylogenetic tree analysis showed two haplotype groups: one for the MTSEA group, frequently found in domestic pigs in the mountainous areas of Cambodia and Laos; and the D2 group, found in pigs originating from Chinese pigs. No European haplotype was found. Haplotypes in northeast Vietnam comprised only haplotypes of the D2 group, whereas in areas from the northwest mountains to the south, we found haplotypes belonging to both the D2 and MTSEA groups. This study suggested that both origins contributed to maternal lineages of current populations of Vietnamese native pigs.

Adjunctive Dexamethasone for Tuberculous Meningitis in HIV-Positive Adults.

BACKGROUND: Adjunctive glucocorticoids are widely used to treat human immunodeficiency virus (HIV)-associated tuberculous meningitis despite limited data supporting their safety and efficacy. METHODS: We conducted a double-blind, randomized, placebo-controlled trial involving HIV-positive adults (≥18 years of age) with tuberculous meningitis in Vietnam and Indonesia. Participants were randomly assigned to receive a 6-to-8-week tapering course of either dexamethasone or placebo in addition to 12 months of antituberculosis chemotherapy. The primary end point was death from any cause during the 12 months after randomization. RESULTS: A total of 520 adults were randomly assigned to receive either dexamethasone (263 participants) or placebo (257 participants). The median age was 36 years; 255 of 520 participants (49.0%) had never received antiretroviral therapy, and 251 of 484 participants (51.9%) with available data had a baseline CD4 count of 50 cells per cubic millimeter or less. Six participants withdrew from the trial, and five were lost to follow-up. During the 12 months of follow-up, death occurred in 116 of 263 participants (44.1%) in the dexamethasone group and in 126 of 257 participants (49.0%) in the placebo group (hazard ratio, 0.85; 95% confidence interval, 0.66 to 1.10; P = 0.22). Prespecified analyses did not reveal a subgroup that clearly benefited from dexamethasone. The incidence of secondary end-point events, including cases of immune reconstitution inflammatory syndrome during the first 6 months, was similar in the two trial groups. The numbers of participants with at least one serious adverse event were similar in the dexamethasone group (192 of 263 participants [73.0%]) and the placebo group (194 of 257 participants [75.5%]) (P = 0.52). CONCLUSIONS: Among HIV-positive adults with tuberculous meningitis, adjunctive dexamethasone, as compared with placebo, did not confer a benefit with respect to survival or any secondary end point. (Funded by the Wellcome Trust; ACT HIV ClinicalTrials.gov number, NCT03092817.).

Biomedical doctoral students' research practices when facing dilemmas: two vignette-based randomized control trials.

Our aim was to describe the research practices of doctoral students facing a dilemma to research integrity and to assess the impact of inappropriate research environments, i.e. exposure to (a) a post-doctoral researcher who committed a Detrimental Research Practice (DRP) in a similar situation and (b) a supervisor who did not oppose the DRP. We conducted two 2-arm, parallel-group randomized controlled trials. We created 10 vignettes describing a realistic dilemma with two alternative courses of action (good practice versus DRP). 630 PhD students were randomized through an online system to a vignette (a) with (n = 151) or without (n = 164) exposure to a post-doctoral researcher; (b) with (n = 155) or without (n = 160) exposure to a supervisor. The primary outcome was a score from - 5 to + 5, where positive scores indicated the choice of DRP and negative scores indicated good practice. Overall, 37% of unexposed participants chose to commit DRP with important variation across vignettes (minimum 10%; maximum 66%). The mean difference [95%CI] was 0.17 [- 0.65 to 0.99;], p = 0.65 when exposed to the post-doctoral researcher, and 0.79 [- 0.38; 1.94], p = 0.16, when exposed to the supervisor. In conclusion, we did not find evidence of an impact of postdoctoral researchers and supervisors on student research practices.Trial registration: NCT04263805, NCT04263506 (registration date 11 February 2020).

Tuberculin skin testing and QuantiFERON™-TB Gold Plus positivity among household contacts in Vietnam.

SETTING: TB infection (TBI) is diagnosed using the technique-dependent tuberculin skin test (TST) or costly, more accurate interferon-gamma release assays. The TST (⩾10 mm) threshold was indicated by previous research among household contacts in Vietnam, but routine implementation with a different tuberculin reagent showed unexpectedly low TST positivity. OBJECTIVE: TST (⩾5 mm and ⩾10 mm) results were compared to QuantiFERON™-TB Gold Plus (QFT) results in household contacts during community campaigns in 2020 and 2021. DESIGN: This was a cross-sectional multi-center implementation study. RESULTS: Among 1,330 household contacts in 2020, we found a TBI prevalence of 38.6% (QFT), similar to TST ⩾5 mm (37.4%) and higher than TST ⩾10 mm (13.1%). QFT+/TST+ was higher for TST ⩾5 mm (20.7%) than TST ⩾10 mm (9.4%). QFT was not discordant with TST ⩾5 mm (McNemar's test = 0.6, P = 0.5) but was discordant with TST ⩾10 mm (McNemar's test = 263.9, P < 0.01). Older age and Southern region increased odds for positive TST ⩾5 mm and QFT with weaker associations for TST ⩾10 mm. Agreement and discordance were similar in 2021 for 1,158 household contacts. CONCLUSION: Tuberculin reagents affect TST positivity rates. High TB burden countries should monitor reliability of TBI diagnosis, including tuberculin potency, cold chain, and TST technique to optimize eligibility for TB preventive treatment.

CONTEXTE: L'infection tuberculeuse (TBI) est diagnostiquée à l'aide du test cutané à la tuberculine (TST), qui dépend de la technique, ou de tests de libération de l'interféron-gamma, coûteux et plus précis. Des recherches antérieures ont indiqué que le TST (⩾10 mm) est généralement utilisé pour diagnostiquer la TB parmi les contacts familiaux au Vietnam ; la mise en œuvre de routine avec un réactif de tuberculine différent a montré une faible positivité inattendue du TST. OBJECTIF: Les résultats du TST (⩾5 mm et ⩾10 mm) ont été comparés aux résultats de QuantiFERON™-TB Gold Plus (QFT) chez les contacts familiaux au cours des campagnes communautaires de 2020 et 2021. MÉTHODE: Il s'agissait d'une étude transversale multicentrique de mise en œuvre. RÉSULTATS: Parmi 1 330 contacts familiaux en 2020, nous avons trouvé une prévalence de TBI de 38,6% (QFT), similaire au TST ⩾5 mm (37,4%) et plus élevée que le TST ⩾10 mm (13,1%). Le QFT+/TST+ était plus élevé pour le TST ⩾5 mm (20,7%) que pour le TST ⩾10 mm (9,4%). Le QFT n'était pas discordant avec le TST ≥5 mm (test de McNemar = 0,6 ; P = 0,5) mais était discordant avec le TST ⩾10 mm (test de McNemar = 263,9 ; P < 0,01). L'âge avancé et la région méridionale augmentaient les probabilités d'un TST positif ⩾5 mm et d'un QFT, avec des associations plus faibles pour un TST ⩾10 mm. La concordance et la discordance étaient similaires en 2021 pour 1 158 contacts familiaux. CONCLUSION: Les réactifs de tuberculine affectent les taux de positivité des TST. Les pays à forte charge de TB doivent surveiller la fiabilité du diagnostic de TBI, y compris la puissance de la tuberculine, la chaîne du froid et la technique du TST afin d'optimiser l'éligibilité au traitement préventif de la TB.

Quantitative and large-format histochemistry to characterize peripheral artery compositional gradients.

The femoropopliteal artery (FPA) is a long, flexible vessel that travels down the anteromedial compartment of the thigh as the femoral artery and then behind the kneecap as the popliteal artery. This artery undergoes various degrees of flexion, extension, and torsion during normal walking movements. The FPA is also the most susceptible peripheral artery to atherosclerosis and is where peripheral artery disease manifests in 80% of cases. The connection between peripheral artery location, its mechanical flexion, and its physiological or pathological biochemistry has been investigated for decades; however, histochemical methods remain poorly leveraged in their ability to spatially correlate normal or abnormal extracellular matrix and cells with regions of mechanical flexion. This study generates new histological image processing pipelines to quantitate tissue composition across high-resolution FPA regions-of-interest or low-resolution whole-section cross-sections in relation to their anatomical locations and flexions during normal movement. Comparing healthy ovine femoral, popliteal, and cranial-tibial artery sections as a pilot, substantial arterial contortion was observed in the distal popliteal and cranial tibial regions of the FPA which correlated with increased vascular smooth muscle cells and decreased elastin content. These methods aim to aid in the quantitative characterization of the spatial distribution of extracellular matrix and cells in large heterogeneous tissue sections such as the FPA. RESEARCH HIGHLIGHTS: Large-format histology preserves artery architecture. Elastin and smooth muscle content is correlated with distance from heart and contortion during flexion. Cell and protein analyses are sensitive to sectioning plane and image magnification.

Assessment of bowel movement dysfunction following laparoscopic low anterior resection for rectal cancer: a single-center study from Vietnam.

OBJECTIVE: Postoperative bowel movement dysfunction is a challenging problem greatly affecting patients' quality of life after low anterior resection. We aimed to evaluate the bowel movement function of patients undergoing laparoscopic low anterior resection for rectal cancer. PATIENTS AND METHODS: This retrospective study recruited 82 rectal cancer patients undergoing laparoscopic low anterior resection from July 2018 to July 2020 at 108 Military Central Hospital, Hanoi, Vietnam. RESULTS: The patients' mean age was 62.3±11.6 (28-84) years, 54 (65.9%) were males, and 28 (34.1%) were females. Bowel movement function changed significantly after one year: the average score for low anterior resection syndrome (LARS) after three months, six months, and one year was 17.6, 14.0, and 10.6, respectively. The rate of patients with major LARS decreased from 26.8% after three months to 14.6% after one year. The Wexner score also decreased from 5.9 after three months to 3.4 after one year. The rate of patients with normal bowel movement increased from 28.0% after three months to 46.3% after one year. The rate of patients with complete fecal incontinence decreased from 11.0% after three months to 7.3% after one year. Preoperative chemoradiotherapy (p=0.017), tumor location (p=0.02), method of anastomosis (p=0.01), and anastomosis location (p=0.000) were risk factors associated with major LARS after surgery. CONCLUSIONS: Bowel movement dysfunction in rectal cancer patients undergoing laparoscopic low anterior resection is a common and persistent problem after surgery. However, bowel function gradually recovers over time. Therefore, patients should be monitored and supported for a better quality of life.

First-principles examination of two-dimensional Janus quintuple-layer atomic structures XCrSiN2 (X = S, Se, and Te).

In this work, we propose novel two-dimensional Janus XCrSiN2 (X = S, Se, and Te) single-layers and comprehensively investigate their crystal structure, electronic properties, and carrier mobility by using a first-principles method. These configurations are the combination of the CrSi2N4 material and a transition metal dichalcogenide. The X-Cr-SiN2 single-layers are constructed by replacing the N-Si-N atomic layer on one side with chalcogen atoms (S, Se, or Te). The structural characteristics, mechanical or thermal stabilities, and electronic properties are investigated adequately. All three examined configurations are energetically stable and are all small-bandgap semiconductors (<1 eV). Since the mirror symmetry is broken in the Janus material, there exists a remarkable built-in electric field and intrinsic dipole moment. Therefore, the spin-orbit interaction is considered intensively. However, it is observed that the spin-orbit coupling has insignificant effects on the electronic properties of XCrSiN2 (X = S, Se, and Te). Moreover, an external electric field and strain are applied to evaluate the adjustment of the electronic features of the three structures. The transport properties of the proposed configurations are calculated and analyzed systematically, indicating the highly directional isotropy. Our results suggest that the proposed Janus XCrSiN2 could be potential candidates for various applications, especially in nanoscale electronic devices.

Decadal stability in coral cover could mask hidden changes on reefs in the East Asian Seas.

Coral reefs in the Central Indo-Pacific region comprise some of the most diverse and yet threatened marine habitats. While reef monitoring has grown throughout the region in recent years, studies of coral reef benthic cover remain limited in spatial and temporal scales. Here, we analysed 24,365 reef surveys performed over 37 years at 1972 sites throughout East Asia by the Global Coral Reef Monitoring Network using Bayesian approaches. Our results show that overall coral cover at surveyed reefs has not declined as suggested in previous studies and compared to reef regions like the Caribbean. Concurrently, macroalgal cover has not increased, with no indications of phase shifts from coral to macroalgal dominance on reefs. Yet, models incorporating socio-economic and environmental variables reveal negative associations of coral cover with coastal urbanisation and sea surface temperature. The diversity of reef assemblages may have mitigated cover declines thus far, but climate change could threaten reef resilience. We recommend prioritisation of regionally coordinated, locally collaborative long-term studies for better contextualisation of monitoring data and analyses, which are essential for achieving reef conservation goals.

Nivolumab for locally advanced and metastatic cutaneous squamous cell carcinoma (NIVOSQUACS study)-Phase II data covering impact of concomitant haematological malignancies.

BACKGROUND: Monoclonal antibodies, such as cemiplimab and pembrolizumab, against the programmed death receptor (PD)-1 have become the current standard of care and first-line treatment of advanced cutaneous squamous cell carcinoma (cSCC), proving remarkable clinical benefit and acceptable safety. OBJECTIVES: To assess efficacy and safety of the anti-PD-1 antibody nivolumab in patients with locally advanced and metastatic cSCC. METHODS: Patients received open-label nivolumab 240 mg intravenously every 2 weeks for up to 24 months. Patients with concomitant haematological malignancies (CHMs), either non-progressing or stable under active therapy, were eligible for inclusion. RESULTS: Of 31 patients with a median age of 80 years, 22.6% of patients achieved an investigator assessed complete response, resulting in an objective response rate (ORR) of 61.3% and a disease control rate (DCR) of 64.5%. Progression-free survival (PFS) was 11.1 months, and the median overall survival (OS) was not reached after 24 weeks of therapy. Median follow-up was 23.82 months. Subgroup analysis of the CHM cohort (n = 11; 35%) revealed an ORR of 45.5%, a DCR of 54.5%, a median PFS of 10.9 months, and median OS of 20.7 months. Treatment related adverse events were reported in 58.1% of all patients (19.4% grade 3, the remaining grade 1 or 2). PD-L1 expression and CD-8+ T-cell infiltration did not significantly correlate with clinical response, although a trend towards a shorter PFS of 5.6 months was observed with PD-L1 negativity and low CD8+ intratumoral infiltration. CONCLUSION: This study demonstrated robust clinical efficacy of nivolumab in patients with locally advanced and metastatic cSCCs and a tolerability comparable to data of other anti-PD-1 antibodies. Favourable outcomes were obtained despite involving the oldest hitherto reported study cohort for anti-PD-1 antibodies and a significant proportion of CHM patients prone to high risk tumours and an aggressive course otherwise typically excluded from clinical trials.

Aflibercept monotherapy versus aflibercept with targeted retinal laser to peripheral retinal ischemia for diabetic macular oedema (LADAMO).

OBJECTIVE: We tested the hypothesis that targeted retinal laser photocoagulation (TPRP) to peripheral retinal ischaemia reduces the overall burden of aflibercept injections when treating diabetic macular oedema (DMO) over a 24-month period. METHODS: Prospective, double-masked, multicentre, randomised controlled trial in Australia comparing aflibercept monotherapy, following a treat-and-extend protocol, or combination therapy of aflibercept and TPRP for DMO. The aflibercept monotherapy group received placebo laser. The primary outcome measure was the mean number of intravitreal aflibercept injections for each group at 24 months. Secondary outcome included: mean change in central macular thickness (CMT) and vision at trial completion, the proportion of eyes whose DMO resolved and the mean injection treatment interval. Ocular and systemic adverse events were recorded. RESULTS: We enrolled 48 eyes of 47 patients; 27 eyes were randomised to combination therapy (aflibercept and TPRP) and 21 to aflibercept monotherapy. Thirty-two eyes (67%) completed the 2-year study. The number of intravitreal treatments given were similar for combination therapy (10.5 (SD 5.8) and monotherapy (11.8 (SD5.6)) (P = 0.44). The mean visual improvement (+4.0 (-1.8, 9.8) and +7.8 (2.6, 12.9) letters, P = 0.32), mean decrease in CMT (-154 (-222,-87) µm and -152 (-218,-86) µm, P = 0.96), proportion of eyes with CMT < 300 µm (48% and 67%; P = 0.50) and safety outcomes were similar in both the combination and monotherapy treatment groups (respectively). CONCLUSIONS: Laser to areas of ischaemic peripheral retina does not reduce the burden of intravitreal aflibercept injections when treating diabetic macular oedema.

A biophysical framework for double-drugging kinases.

Orthosteric inhibition of kinases has been challenging due to the conserved active site architecture of kinases and emergence of resistance mutants. Simultaneous inhibition of distant orthosteric and allosteric sites, which we refer to as "double-drugging", has recently been shown to be effective in overcoming drug resistance. However, detailed biophysical characterization of the cooperative nature between orthosteric and allosteric modulators has not been undertaken. Here, we provide a quantitative framework for double-drugging of kinases employing isothermal titration calorimetry, Förster resonance energy transfer, coupled-enzyme assays, and X-ray crystallography. We discern positive and negative cooperativity for Aurora A kinase (AurA) and Abelson kinase (Abl) with different combinations of orthosteric and allosteric modulators. We find that a conformational equilibrium shift is the main principle governing this cooperative effect. Notably, for both kinases, we find a synergistic decrease of the required orthosteric and allosteric drug dosages when used in combination to inhibit kinase activities to clinically relevant inhibition levels. X-ray crystal structures of the doubledrugged kinase complexes reveal the molecular principles underlying the cooperative nature of double-drugging AurA and Abl with orthosteric and allosteric inhibitors. Finally, we observe the first fully-closed conformation of Abl when bound to a pair of positively cooperative orthosteric and allosteric modulators, shedding light onto the puzzling abnormality of previously solved closed Abl structures. Collectively, our data provide mechanistic and structural insights into rational design and evaluation of doubledrugging strategies.

The critical role of ultra-low-energy vibrations in the relaxation dynamics of molecular qubits.

Improving the performance of molecular qubits is a fundamental milestone towards unleashing the power of molecular magnetism in the second quantum revolution. Taming spin relaxation and decoherence due to vibrations is crucial to reach this milestone, but this is hindered by our lack of understanding on the nature of vibrations and their coupling to spins. Here we propose a synergistic approach to study a prototypical molecular qubit. It combines inelastic X-ray scattering to measure phonon dispersions along the main symmetry directions of the crystal and spin dynamics simulations based on DFT. We show that the canonical Debye picture of lattice dynamics breaks down and that intra-molecular vibrations with very-low energies of 1-2 meV are largely responsible for spin relaxation up to ambient temperature. We identify the origin of these modes, thus providing a rationale for improving spin coherence. The power and flexibility of our approach open new avenues for the investigation of magnetic molecules with the potential of removing roadblocks toward their use in quantum devices.

Sinus arrest in familial hypokalemic periodic paralysis caused by SCN4A mutation: a case report.

BACKGROUND: Primary hypokalemic periodic paralysis (HypoPP), a rare skeletal muscle channelopathy resulting in episodic muscle weakness or paralysis under hypokalemic conditions, is caused by autosomal-dominant genetic mutations. HypoPP limits physical activity, and cardiac arrhythmias during paralytic attacks have been reported. We describe a rare familial HypoPP case complicated by sinus arrest and syncope requiring urgent temporary pacemaker implantation. CASE REPORT: A 27-year-old Vietnamese man with a family history of periodic paralysis presented with his third attack of muscle weakness triggered by intense football training the previous day. Clinical and laboratory features justified a HypoPP diagnosis. During intravenous potassium replacement, the patient experienced syncopal sinus arrest requiring urgent temporary pacemaker implantation. The patient gradually improved, responding favorably to oral potassium supplements. Genetic testing revealed an Arg1132Gln mutation in the sodium ion channel (SCN4A, chromosome 17: 63947091). At discharge, the patient received expert consultation regarding nonpharmacological preventive strategies, including avoidance of vigorous exercise and carbohydrate-rich diet. CONCLUSIONS: No evidence has established a relationship between hypokalemia and sinus arrest, and no specific treatment exists for familial HypoPP due to SCN4A mutation. Clinician awareness of this rare condition will promote appropriate diagnostic approaches and management strategies for acute paralytic attacks. Treatment should be tailored according to HypoPP phenotypes and genotypes.