Computational Screening and Stabilization of Boron-Substituted Type-I and Type-II Carbon Clathrates.

Boron substitution represents a promising approach to stabilize carbon clathrate structures, but no thermodynamically stable substitution schemes have been identified for frameworks other than the type-VII (sodalite) structure type. To investigate the possibility for additional tetrahedral carbon-based clathrate networks, more than 5000 unique boron decoration schemes were investigated computationally for type-I and type-II carbon clathrates with a range of guest elements including Li, Na, K, Rb, Cs, Mg, Ca, Sr, and Ba. Density functional theory calculations were performed at 10 and 50 GPa, and the stability and impact of boron substitution were evaluated. The results indicate that the boron-substituted carbon clathrates are stabilized under high-pressure conditions. Full cage occupancies of intermediate-sized guest atoms (e.g., Na, Ca, and Sr) are the most favorable energetically. Clathrate stability is maximized when the boron atoms are substituted within the hexagonal rings of the large [51262]/[51264] cages. Several structures with favorable formation enthalpies <-200 meV/atom were predicted, and type-I Ca8B16C30 is on the convex hull at 50 GPa. This structure represents the first thermodynamically stable type-I clathrate identified and suggests that boron-substituted carbon clathrates may represent a large family of diamond-like framework materials with a range of structure types and guest/framework substitutions.

Virucidal effect of mouthwash on acyclovir-resistant herpes simplex virus.

OBJECTIVES: The symptoms of herpes simplex viruses type 1 (HSV-1) infections might be severe and persistent in immunocompromised patients in whom they reactivate at a high frequency. The development of Acyclovir (ACV) resistant strains due to long-term treatment with antiviral agents in those patients is not uncommon. The aim of the present study was to assess the virucidal effect of commercially available mouthwashes against ACV-resistant HSV-1 strains. MATERIALS AND METHODS: Two acyclovir-resistant HSV-1 strains were exposed for 30 s to essential oil-based (Listerine Fresh Burst® and Listerine Zero®), chlorhexidine gluconate 0.2% (Hexidyl®) and povidone-iodine 7.5% (Betadine Gargle®) mouthwashes. Loss of virus infectivity was determined by means of plaque reduction assays in a cell culture system. RESULTS: All 4 of the tested solutions significantly reduced virus infectivity, with the essential oil-based and povidone-iodine mouthwashes being slightly more efficacious, compared to chlorhexidine. CONCLUSION: The findings of this analysis revealed that the tested oral rinses demonstrated in-vitro antiviral activity against ACV-resistant HSV. Comparative clinical trials are required to establish the clinical effectiveness of daily use of oral rinses in reducing the appearance of oral HSV lesions in immunocompromised patients.

Antimicrobial treatment of ENT infections.

Ear, nose and throat (ENT) or upper respiratory tract infections (URTI) are the most common infections in children and the leading causes of antibiotic prescriptions. In most cases, these infections are due to (or are triggered by) viruses and even when bacterial species are implicated, recovery is usually spontaneous. The first imperative is to refrain from prescribing antibiotics in a large number of URTIs: common cold, most cases of sore throat, laryngitis, congestive otitis, and otitis media with effusion. On the contrary, a decision to treat sore throats with antibiotics is based primarily on the positivity of the Group A Streptococcus (GAS) rapid antigen diagnostic tests. For ear infections, only (a) purulent acute otitis media in children under 2 years of age and (b) complicated or symptomatic forms of purulent acute otitis media (PAOM) in older children should be treated with antibiotics. Amoxicillin is the first-line treatment in the most cases of ambulatory ENT justifying antibiotics. Severe ENT infections (mastoiditis, epiglottitis, retro- and parapharyngeal abscesses, ethmoiditis) are therapeutic emergencies necessitating hospitalization and initial intravenous antibiotic therapy.

Pediatric ambulatory pertussis epidemiology in France, recent updates.

OBJECTIVES: Following various changes in the vaccine strategy in 2013 and the mandatory vaccination in 2018, we aimed to analyze the vaccination status, age, and source of contamination of pertussis and parapertussis cases in outpatient surveillance. PATIENTS AND METHODS: Confirmed pertussis and parapertussis cases were enrolled by 35 pediatricians. RESULTS: From 2014 to 2022, 73 confirmed cases of pertussis (n = 65) and parapertussis (n = 8) were reported. For children below 6 years of age, the number of cases with a 2 + 1 schedule (n = 22) was higher than that of those with a 3 + 1 schedule (n = 7). The age of cases with a 3 + 1 or a 2 + 1 schedule was not significantly different (3.8y ± 1.4 vs 4.2y ± 1.5). The main source of contamination was either adults or adolescents. CONCLUSION: Vaccination status and source of contamination are crucial to study the impact of vaccination recommendations.

Prediction of response to immune checkpoint blockade in patients with metastatic colorectal cancer with microsatellite instability.

BACKGROUND: Mismatch repair-deficient (dMMR) tumors displaying microsatellite instability (MSI) represent a paradigm for the success of immune checkpoint inhibitor (ICI)-based immunotherapy, particularly in patients with metastatic colorectal cancer (mCRC). However, a proportion of patients with dMMR/MSI mCRC exhibit resistance to ICI. Identification of tools predicting MSI mCRC patient response to ICI is required for the design of future strategies further improving this therapy. PATIENTS AND METHODS: We combined high-throughput DNA and RNA sequencing of tumors from 116 patients with MSI mCRC treated with anti-programmed cell death protein 1 ± anti-cytotoxic T-lymphocyte-associated protein 4 of the NIPICOL phase II trial (C1, NCT03350126, discovery set) and the ImmunoMSI prospective cohort (C2, validation set). The DNA/RNA predictors whose status was significantly associated with ICI status of response in C1 were subsequently validated in C2. Primary endpoint was progression-free survival by immune RECIST (iRECIST) (iPFS). RESULTS: Analyses showed no impact of previously suggested DNA/RNA indicators of resistance to ICI, e.g. MSIsensor score, tumor mutational burden, or specific cellular and molecular tumoral contingents. By contrast, iPFS under ICI was shown in C1 and C2 to depend both on a multiplex MSI signature involving the mutations of 19 microsatellites hazard ratio cohort C2 (HRC2) = 3.63; 95% confidence interval (CI) 1.65-7.99; P = 1.4 × 10-3] and the expression of a set of 182 RNA markers with a non-epithelial transforming growth factor beta (TGFB)-related desmoplastic orientation (HRC2 = 1.75; 95% CI 1.03-2.98; P = 0.035). Both DNA and RNA signatures were independently predictive of iPFS. CONCLUSIONS: iPFS in patients with MSI mCRC can be predicted by simply analyzing the mutational status of DNA microsatellite-containing genes in epithelial tumor cells together with non-epithelial TGFB-related desmoplastic RNA markers.

Efficacy of immunotherapy in mismatch repair-deficient advanced colorectal cancer in routine clinical practice. An AGEO study.

BACKGROUND: Immunotherapy demonstrated remarkable efficacy in metastatic colorectal cancers (mCRCs) with mismatch repair deficiency (MMRd)/microsatellite instability (MSI). However, data regarding efficacy and safety of immunotherapy in the routine clinical practice are scarce. PATIENTS AND METHODS: This is a retrospective, multicenter study aiming to evaluate efficacy and safety of immunotherapy in routine clinical practice and to identify predictive markers for long-term benefit. Long-term benefit was defined as progression-free survival (PFS) exceeding 24 months. All patients who received immunotherapy for an MMRd/MSI mCRC were included. Patients who received immunotherapy in combination with another known effective therapeutic class agent (chemotherapy or tailored therapy) were excluded. RESULTS: Overall, 284 patients across 19 tertiary cancer centers were included. After a median follow-up of 26.8 months, the median overall survival (mOS) was 65.4 months [95% confidence interval (CI) 53.8 months-not reached (NR)] and the median PFS (mPFS) was 37.9 months (95% CI 30.9 months-NR). There was no difference in terms of efficacy or toxicity between patients treated in the real-world or as part of a clinical trial. Overall, 46.6% of patients had long-term benefit. Independent markers associated with long-term benefit were Eastern Cooperative Oncology Group-performance status (ECOG-PS) 0 (P = 0.025) and absence of peritoneal metastases (P = 0.009). CONCLUSIONS: Our study confirms the efficacy and safety of immunotherapy in patients with advanced MMRd/MSI CRC in the routine clinical practice. ECOG-PS score and absence of peritoneal metastases provide simple markers that could help identify patients who benefit the most from this treatment.

BRCA carriers after risk-reducing bilateral salpingo-oophorectomy: menopausal hormone therapy knowledge gaps, and the impact of physicians' recommendations.

OBJECTIVE: Female carriers of BRCA1/2 gene mutations are at an increased lifetime risk for breast and ovarian cancers. They are recommended to undergo risk-reducing surgery, including bilateral salpingo-oophorectomy (RR-BSO), upon completion of childbearing. RR-BSO surgery decreases morbidity and mortality but results in early menopause. Menopausal hormone therapy (MHT) is under-utilized despite being shown as safe for carriers. We aim to evaluate the factors associated with decision-making regarding MHT use following RR-BSO in healthy BRCA mutation carriers. METHODS: Female carriers aged <50 years who underwent RR-BSO and were followed in a multidisciplinary clinic completed online multiple-choice and free-text questionnaires. RESULTS: A total of 142 women met the inclusion criteria and filled the questionnaire: 83 were MHT users and 59 were non-users. MHT users underwent RR-BSO earlier than non-users (40.82 ± 3.91 vs. 42.88 ± 4.34; p < 0.0001). MHT usage was positively associated with MHT explanation (odds ratio 4.318, 95% confidence interval [CI] [1.341-13.902], p = 0.014), and knowledge regarding the safety of MHT and its effects on general health (odds ratio 2.001, 95% CI [1.443-2.774], p < 0.0001). MHT users and non-users retrospectively evaluated their comprehension of RR-BSO consequences as significantly lower than before surgery (p < 0.001). CONCLUSION: Post-RR-BSO outcomes, including the effects on women's quality of life and its possible mitigation through MHT use, need to be addressed pre surgery by healthcare providers.

Hemodynamic changes in patients with SARS-CoV-2 infection presenting for cesarean delivery under spinal anesthesia: a retrospective case-control study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with adverse maternal and neonatal outcomes. Early studies suggested that COVID-19 was associated with a higher incidence of hypotension following neuraxial anesthesia in parturients. We explored the hemodynamic response to spinal anesthesia for cesarean delivery in pregnant severe respiratory distress syndrome-coronavirus-2 (SARS-CoV-2) positive patients, using a retrospective case-control design. METHODS: We searched our electronic medical records for patients who received spinal anesthesia for cesarean delivery, and were SARS-CoV-2 positive or recovered at delivery, and used historical and SARS-CoV-2 negative controls from two tertiary care hospitals. We compared the demographic, clinical, and hemodynamic variables between patients who were SARS-CoV-2 positive at delivery, those who were positive during pregnancy and recovered before delivery, and controls. Analyses were stratified by normotensive versus hypertensive status of the patients at delivery. RESULTS: We identified 22 SARS-CoV-2 positive, 73 SARS-CoV-2 recovered, and 1517 controls. The SARS-CoV-2 positive, and recovered pregnant patients, had on average 5.6 and 2.2 mmHg, respectively, higher post-spinal mean arterial pressures (MAPs) than control patients, adjusting for covariates. Additionally, the lowest post-spinal MAP was negatively correlated with the number of daysbetween the onset of COVID-19 symptoms and delivery in patients with hypertension (correlation -0.55, 95% CI -0.81 to -0.09). CONCLUSIONS: Patients with SARS-CoV-2 infection during pregnancy exhibit less spinal hypotension than non-infected patients. While the clinical significance of this finding is unknown, it points to important cardiovascular effects of the virus.

Is Police Misconduct Contagious? Non-trivial Null Findings from Dallas, Texas.

Objectives: Understanding if police malfeasance might be "contagious" is vital to identifying efficacious paths to police reform. Accordingly, we investigate whether an officer's propensity to engage in misconduct is associated with her direct, routine interaction with colleagues who have themselves engaged in misbehavior in the past. Methods: Recognizing the importance of analyzing the actual social networks spanning a police force, we use data on collaborative responses to 1,165,136 "911" calls for service by 3475 Dallas Police Department (DPD) officers across 2013 and 2014 to construct daily networks of front-line interaction. And we relate these cooperative networks to reported and formally sanctioned misconduct on the part of the DPD officers during the same time period using repeated-events survival models. Results: Estimates indicate that the risk of a DPD officer engaging in misconduct is not associated with the disciplined misbehavior of her ad hoc, on-the-scene partners. Rather, a greater risk of misconduct is associated with past misbehavior, officer-specific proneness, the neighborhood context of patrol, and, in some cases, officer race, while departmental tenure is a mitigating factor. Conclusions: Our observational findings-based on data from one large police department in the United States-ultimately suggest that actor-based and ecological explanations of police deviance should not be summarily dismissed in favor of accounts emphasizing negative socialization, where our study design also raises the possibility that results are partly driven by unobserved trait-based variation in the situations that officers find themselves in. All in all, interventions focused on individual officers, including the termination of deviant police, may be fruitful for curtailing police misconduct-where early interventions focused on new offenders may be key to avoiding the escalation of deviance.

Dynamics of cooperative networks associated with gender among South Indian Tamils.

Helping behaviour is thought to play a major role in the evolution of group-living animals. Yet, it is unclear to what extent human males and human females use the same strategies to secure support. Accordingly, we investigate help-seeking over a 5-year period in relation to gender using data from virtually all adults in two Tamil villages (N = 782). Simulations of network dynamics (i.e. stochastic actor-oriented models) calibrated to these data broadly indicate that women are more inclined than men to create and maintain supportive bonds via multiple mechanisms of cooperation (e.g. reciprocity, kin bias, friend bias, generalized exchange). However, gender-related differences in the simulated dynamics of help-seeking are modest, vary based on structural position (e.g. out-degree), and do not appear to translate to divergence in the observed structure of respondents' egocentric networks. Findings ultimately suggest that men and women in the two villages are similarly social but channel their sociality differently. This article is part of the theme issue 'Cooperation among women: evolutionary and cross-cultural perspectives'.

Vaccinating children: The pros and cons.

Vaccinating children against Covid raised a debate, due to generally mild clinical presentation. The decision to vaccinate teenagers was motivated by the global public health need: to decrease transmission to other age groups. Among adolescents, the efficacy (better immunity than in young adults) and safety of vaccines was clearly demonstrated. Among 5-to-12-year-olds, due to lower contamination the collective benefit is less clear, and when the m-RNA vaccines were available for this age group, the Omicron variant was predominant and their effect on non-severe infections and transmission had yet to be determined. Individual benefit is based both on somatic criteria and on the child's schooling and mental health. Children under 5 years of age received a 3 µg dose of vaccine, which is one tenth of the adult dose, resulting in immunogenicity similar to that of 16-to-25-year-olds.

From the original SARS-CoV-2 strain to the Omicron variant: Predictors of COVID-19 in ambulatory symptomatic children.

OBJECTIVES: To determine the predictors of a positive SARS-CoV-2 test in a pediatric ambulatory setting. PATIENTS AND METHODS: We performed a cross-sectional prospective study (November 2020-February 2022) of 93 ambulatory settings in France. We included symptomatic children < 15 years old tested for SARS-CoV-2. For each period corresponding to the spread of the original strain and its variants (period 1: original strain; period 2: Alpha, period 3: Delta; period 4: Omicron), we used a multivariate analysis to estimate adjusted odds ratios (aORs) associated with COVID-19 among age, signs, symptoms or contact, and 95 % confidence intervals (95CIs). RESULTS: Of 5,336 children, 13.9 % (95CI 13.0-14.8) had a positive test. During the first three periods, the positivity rate ranged from 5.6 % (95CI 4.6-6.7) to 12.6 % (95CI 10.8-14.6). The main factors associated with a positive test were contact with an infected adult at home or outside the home (aOR 11.5 [95CI 4.9-26.9] to 38.9 [95CI 19.3-78.7]) or an infected household child (aOR 15.0 [95CI 4.8-47.1] to 28.4 [95CI 8.7-92.6]). By contrast, during period 4, aORs for these predictors were substantially lower (2.3 [95CI 1.1-4.5] to 5.5 [95CI 3.2-7.7]), but the positivity rate was 45.7 % (95CI 42.3-49.2). CONCLUSIONS: In pediatric ambulatory settings, before the Omicron period, the main predictor of a positive test was contact with an infected person. During the Omicron period, the odds of these predictors were substantially lower while the positivity rate was higher. An accurate diagnostic strategy should only rely on testing and not on age, signs, symptoms or contact.

Social Support and Network Formation in a Small-Scale Horticulturalist Population.

Evolutionary studies of cooperation in traditional human societies suggest that helping family and responding in kind when helped are the primary mechanisms for informally distributing resources vital to day-to-day survival (e.g., food, knowledge, money, childcare). However, these studies generally rely on forms of regression analysis that disregard complex interdependences between aid, resulting in the implicit assumption that kinship and reciprocity drive the emergence of entire networks of supportive social bonds. Here I evaluate this assumption using individual-oriented simulations of network formation (i.e., Stochastic Actor-Oriented Models). Specifically, I test standard predictions of cooperation derived from the evolutionary theories of kin selection and reciprocal altruism alongside well-established sociological predictions around the self-organisation of asymmetric relationships. Simulations are calibrated to exceptional public data on genetic relatedness and the provision of tangible aid amongst all 108 adult residents of a village of indigenous horticulturalists in Nicaragua (11,556 ordered dyads). Results indicate that relatedness and reciprocity are markedly less important to whom one helps compared to the supra-dyadic arrangement of the tangible aid network itself.

"Virtual patch clamp analysis" for predicting the functional significance of pathogenic variants in sodium channels.

OBJECTIVE: Opening of voltage-gated sodium channels is crucial for neuronal depolarization. Proper channel opening and influx of Na+ through the ion pore, is dependent upon binding of Na+ ion to a specific amino-acid motif (DEKA) within the pore. In this study we used molecular dynamic simulations, an advanced bioinformatic tool, to research the dysfunction caused by pathogenic variants in SCN1a, SCN2a and SCN8a genes. METHOD: Molecular dynamic simulations were performed in six patients: three patients with Dravet syndrome (p.Gly177Ala,p.Ser259Arg and p.Met1267Ile, SCN1a), two patients with early onset drug resistant epilepsy(p.Ala263Val, SCN2a and p.Ile251Arg, SCN8a), and a patient with autism (p.Thr155Ala, SCN2a). After predicting the 3D-structure of mutated proteins by homology modeling, time dependent molecular dynamic simulations were performed, using the Schrödinger algorithm. The opening of the sodium channel, including the detachment of the sodium ion to the DEKA motif and pore diameter were assessed. Results were compared to the existent patch clamp analysis in four patients, and consistency with clinical phenotype was noted. RESULTS: The Na+ ion remained attached to DEKA filter longer when compared to wild type in the p.Gly177Ala, p.Ser259Arg,SCN1a, and p.Thr155Ala, SCN2a variants, consistent with loss-of-function. In contrast, it detached quicker from DEKA than wild type in the p.Ala263Val,SCN2a variant, consistent with gain-of-function. In the p.Met1267Ile,SCN1a variant, detachment from DEKA was quicker, but pore diameter decreased, suggesting partial loss-of-function. In the p.Leu251Arg,SCN8a variant, the pore remained opened longer when compared to wild type, consistent with a gain-of-function. The molecular dynamic simulation results were consistent with the existing patch-clamp analysis studies, as well as the clinical phenotype. SIGNIFICANCE: Molecular dynamic simulation can be useful in predicting pathogenicity of variants and the disease phenotype, and selecting targeted treatment based on channel dysfunction. Further development of these bioinformatic tools may lead to "virtual patch-clamp analysis".

Ultrahigh-pressure disordered eight-coordinated phase of Mg2GeO4: Analogue for super-Earth mantles.

Mg2GeO4 is important as an analog for the ultrahigh-pressure behavior of Mg2SiO4, a major component of planetary interiors. In this study, we have investigated magnesium germanate to 275 GPa and over 2,000 K using a laser-heated diamond anvil cell combined with in situ synchrotron X-ray diffraction and density functional theory (DFT) computations. The experimental results are consistent with the formation of a phase with disordered Mg and Ge, in which germanium adopts eightfold coordination with oxygen: the cubic, Th3P4-type structure. DFT computations suggest partial Mg-Ge order, resulting in a tetragonal [Formula: see text] structure indistinguishable from [Formula: see text] Th3P4 in our experiments. If applicable to silicates, the formation of this highly coordinated and intrinsically disordered phase may have important implications for the interior mineralogy of large, rocky extrasolar planets.

Measuring the melting curve of iron at super-Earth core conditions.

The discovery of more than 4500 extrasolar planets has created a need for modeling their interior structure and dynamics. Given the prominence of iron in planetary interiors, we require accurate and precise physical properties at extreme pressure and temperature. A first-order property of iron is its melting point, which is still debated for the conditions of Earth's interior. We used high-energy lasers at the National Ignition Facility and in situ x-ray diffraction to determine the melting point of iron up to 1000 gigapascals, three times the pressure of Earth's inner core. We used this melting curve to determine the length of dynamo action during core solidification to the hexagonal close-packed (hcp) structure. We find that terrestrial exoplanets with four to six times Earth's mass have the longest dynamos, which provide important shielding against cosmic radiation.

Thermal conductivity of Fe-Si alloys and thermal stratification in Earth's core.

Light elements in Earth's core play a key role in driving convection and influencing geodynamics, both of which are crucial to the geodynamo. However, the thermal transport properties of iron alloys at high-pressure and -temperature conditions remain uncertain. Here we investigate the transport properties of solid hexagonal close-packed and liquid Fe-Si alloys with 4.3 and 9.0 wt % Si at high pressure and temperature using laser-heated diamond anvil cell experiments and first-principles molecular dynamics and dynamical mean field theory calculations. In contrast to the case of Fe, Si impurity scattering gradually dominates the total scattering in Fe-Si alloys with increasing Si concentration, leading to temperature independence of the resistivity and less electron-electron contribution to the conductivity in Fe-9Si. Our results show a thermal conductivity of ∼100 to 110 W⋅m-1⋅K-1 for liquid Fe-9Si near the topmost outer core. If Earth's core consists of a large amount of silicon (e.g., > 4.3 wt %) with such a high thermal conductivity, a subadiabatic heat flow across the core-mantle boundary is likely, leaving a 400- to 500-km-deep thermally stratified layer below the core-mantle boundary, and challenges proposed thermal convection in Fe-Si liquid outer core.

Long-term endoscopic follow-up after sleeve gastrectomy.

BACKGROUND: Endoscopic follow-up after sleeve gastrectomy (SG) sometime reveals worrisome findings as the presence of major digestive lesions such as esophagitis, Barrett's esophagus (BE), and also esophageal cancer. OBJECTIVES: The aim of this study was to investigate the frequency and severity of esophageal and gastric lesions after SG. METHODS: Our team collected the results of esogastric endoscopies performed on patients who underwent SG up to five years before in our hospital, from April 2010 to August 2014. Summons were sent by mail to all patients operated on between those dates. The results were collected from January 2018 to June 2019. RESULTS: Of the 765 patients who underwent SG up to five years before, only 78 (10.2%) agreed to undergo an upper digestive endoscopy. The average age before surgery was 51 years (range: 25-70 years). The mean preoperative body mass index (BMI) was 44.2±4.6kg/m2. For 12 out of these 78 patients (15.4%) it was revisional surgery: 9 SG after gastric banding, and 3 revisional SG (Re-SG). With an average follow-up of 6.3±0.8 years, the endoscopic results of the 78 patients were found to be normal in 31 cases (39.7%): gastritis was found in 28 patients (35.9%), severe grade C or D esophagitis was found in 15 cases (19.2%), hiatal hernia in 18 cases (23.1%), a benign gastric polyp in 2 cases (2.6%). Of the 28 patients with gastritis, HelicobacterPylori was detected in 8 cases (28.6%). No cancer was diagnosed, and BE after SG was found in only one case (1.3%) (normal before surgery). Six of 15 patients with esophagitis (40%) had reflux symptoms. Fourteen of these patients (93.3%) developed de novo esophagitis. CONCLUSION: Only 10.2% of operated patients agreed to a long-term esogastric endoscopy. The frequency and severity of endoscopic anomalies observed with an average follow-up of more than 6 years pleads for a policy of systematic upper endoscopies of long-term control after SG.