Effectiveness of bespoke or customised orthotic treatment in plantar pressure reduction of the central metatarsals: A systematic review and meta-analysis.

Background: Conservative treatment is the first therapeutical option for central heads metatarsalgia, a common foot condition. However, to our best knowledge, systematic review and meta-analysis of its effectiveness in terms of plantar pressure improvement have not been yet carried out. Our aim was to answer the following research question: Is bespoke or customized orthotic treatment effective for plantar pressure reduction in patients with mechanical metatarsalgia in the central metatarsal heads? Methods: A systematic review and meta-analysis of the effectiveness of bespoke or customised orthotic treatment in terms of plantar pressure reduction beneath the central -2nd to 4th - metatarsal heads in mechanical metatarsalgia patients were carried out. Pubmed database was searched from September to November 2022. All type of related-topic studies were included. Cochrane Collaboration tool was used to assess the risk of bias of each study. Descriptive and frequency analyses were performed with SPSS 25.0 software. Review Manager v5.4.1 software was used to analyse the data using the inverse variance method for continuous outcomes according to a fixed or random effects model. Results: A total of 5 studies met our inclusion criteria, with 158 participants. Bespoke or customised orthotic treatment is effective for the improvement of plantar pressure under 2nd to 4th metatarsal heads in mechanical metatarsalgia patients (MD -37.54 [95 % CI -65.84, -9.24], p = 0.009). Customised orthotic treatment is more effective than no treatment in terms of reducing plantar pressure (MD -78.63 [95 % CI -119.70, -39.16], p = 0.0002), but its effectiveness is similar to standardised footwear, standardised foot orthoses and isolated metatarsal domes. Conclusions: We found conservative bespoke or customised orthotic treatment to be effective for the improvement of plantar pressure under the central metatarsal heads.

Unveiling Intrinsic Bulk Photovoltaic Effect in Atomically Thin ReS2.

The bulk photovoltaic effect (BPVE) offers a promising avenue to surpass the efficiency limitations of current solar cell technology. However, disentangling intrinsic and extrinsic contributions to photocurrent remains a significant challenge. Here, we fabricate high-quality, lateral devices based on atomically thin ReS2 with minimal contact resistance, providing an optimal platform for distinguishing intrinsic bulk photovoltaic signals from other extrinsic photocurrent contributions originating from interfacial effects. Our devices exhibit large bulk photovoltaic performance with intrinsic responsivities of ∼1 mA/W in the visible range, without the need for external tuning knobs such as strain engineering. Our experimental findings are supported by theoretical calculations. Furthermore, our approach can be extrapolated to investigate the intrinsic BPVE in other noncentrosymmetric van der Waals materials, paving the way for a new generation of efficient light-harvesting devices.

Effects of direct and conventional planting systems on mycorrhizal activity in wheat grown in the Cerrado.

Direct planting systems offer several benefits to the soil and plants, as reflected in soil organisms. The Arbuscular mycorrhizal fungi are extremely sensitive to environmental changes and can be used as indicators of soil quality. This study focused on the native diversity of mycorrhizae in the region. Thus, the objective of this work was to evaluate mycorrhizal colonization, spore density, soil glomalin content and species diversity in five wheat genotypes under direct and conventional planting systems. This work was carried out in the experimental area of Embrapa Cerrados, Planaltina, DF, Brazil. The rates of mycorrhizal colonization, spore density and easily extractable glomalin were evaluated, and species of arbuscular mycorrhizal fungi were identified in five wheat genotypes under direct and conventional planting. For all the genotypes under conventional planting, there was a decrease in mycorrhizal colonization, the number of spores in the rhizosphere and the amount of easily extractable glomalin. The composition of the arbuscular mycorrhizal fungal community differed among the wheat genotypes and management systems. The richness of morphospecies of AMF in the direct planting system was similar to that in the conventional system, with twelve species each, but the conventional system reduced root colonization and spore density. The most common species were A. scrobiculata, Si. tortuosum and G. macrocarpum, which were found in all the genotypes in both cultivation systems.

A non-randomized pragmatic historically controlled trial evaluating the effectiveness and safety of a bedaquiline or a linezolid-based short regimen for rifampicin-resistant tuberculosis.

BACKGROUND: Short all-oral regimens for Rifampicin-resistant tuberculosis (ShORRT) have been a turning point in the treatment of drug-resistant tuberculosis. Despite this, access to drugs, stockouts, or adverse effects may limit the use of the recommended regimens. METHODS: Pragmatic non-randomized trial evaluating the efficacy and safety of a ShORRT strategy for the treatment of rifampicin-resistant Tuberculosis (RR-TB) at the Hospital Nossa Senhora da Paz (Angola). The strategy assigned participants to receive a bedaquiline (BDQ) or a linezolid-based (LZF) regimen supplemented with levofloxacin, clofazimine, and cycloserine for up to 9 months. RESULTS: One hundred and twenty-one participants with pulmonary RR-TB were treated with the ShORRT strategy; 69 received the bedaquiline- and 52 the linezolid-based regimen. Overall, 98 (81%) participants had successful treatment outcomes, which was significantly higher compared to a 20-month historical injectable-based regimen (successful outcome rate including cure and treatment completed: 53.7%) (p < 0.001). No significant differences between treatment success rates (85.5% vs. 75.0%), treatment failure (0.0% vs. 1.9%), death (5.8% vs. 13.5%), or lost to follow-up (LTFU) (8.7% vs. 9.6%) were seen between the BDQ and the LZF-based regimen. Globally, 72 adverse events (AE) occurred in 36 (29.7%) participants. Eighteen (14.9%) of these were grade ≥3 and were more frequently observed in those receiving the LZD-based regimen (p = 0.02). CONCLUSION: The ShORRT strategy with a nine-month BDQ- or LZD-based regimen supports the efficacy of shorter all-oral regimens for the treatment of RR-TB and presents real-world data from schemes without bedaquiline, nitroimidazole, or injectables.

Toxicity of the FOLFOX-6 regimen, with or without 5-fluorouracil bolus, in metastatic colorectal cancer. / Toxicidad del esquema FOLFOX-6, asociado o no a bolo de 5-fluorouracilo, en cáncer colorrectal metastásico.

OBJECTIVE: Standard treatment of metastatic colorectal cancer includes oxaliplatin and 5-fluorouracil in continuous infusion. Although FOLFOX-6 is the reference combination, it is aggressive and has high toxicity. Variants such as the TTD regimen, which does not include folinic acid or 5-fluorouracil bolus, are used. This study evaluates the toxicity of FOLFOX-6 and TTD in first line treatment for metastatic colorectal cancer and its effectiveness. METHOD: Retrospective observational study with patients who started treatment with FOLFOX-6 and TTD, for three years. Demographic and clinical data were collected (age, sex, chronic pathologies, molecular profile, laterality, ECOG classification and stage), as well as treatment variables (previous adjuvant chemotherapy, intentionality, number of cycles, duration and pharmacogenetic aspects) and toxicity. Objective response rate and progression-free survival were calculated. RESULTS: The study included 71 patients, 35 treated with FOLFOX-6 and 36 with TTD. Both groups showed similar overall toxicity profiles. FOLFOX-6 had a higher incidence of neutropenia (46% vs. 8%; p < 0.01) and mucositis (51% vs. 22%; p < 0.013). In addition, there were more treatment delays (40% vs. 11%; p < 0.05) and 5-fluorouracil dose reductions (22% vs. 14%; p < 0.05) in the FOLFOX-6 group. Deaths due to toxicity were only recorded in the FOLFOX-6 group. Effectiveness was similar in both groups. CONCLUSIONS: The TTD regimen could be a beneficial first-line option for metastatic colorectal cancer, with lower toxicity and effectiveness comparable to FOLFOX-6. It is a safe alternative for elderly or frail patients, suitable for reduced-dose 5-fluorouracil regimen with oxaliplatin.

Assessment of nitrogen and phosphorus losses due to erosion in compost-treated and non-treated vineyard soils: effect of rainfall intensity.

Vineyards in Mediterranean areas suffer from significant soil degradation through erosion, due to rainfall and soil characteristics, as well as soil management practices. Previous studies pointed out the nutrient losses produced by erosion and the benefits that some management practices could have on reducing erosion. This research tried to evaluate the effect of events of different intensities and to assess whether the beneficial effect of compost amendment may pose a potential risk of nutrient loss and environmental pollution in particular under high-intensity events. The study compared soil and nutrient losses in compost-treated and non-treated vineyard soils after rainfall events of different intensities analyzed over 2 years in two vineyards. Runoff samples were collected by triplicate in treated and non-treated soils. Sediment and nitrogen and phosphorous concentrations in the runoff samples were analyzed. The results reveal a reduction in runoff rates and an increase in soil water content in compost-treated soils, which represents a benefit for rainfed vineyards. Both nitrogen and phosphorus losses depended on rainfall characteristics. Although for low intensities there were no significant differences in the amount of nutrient lost by runoff in both treated and non-treated soils, nitrogen and phosphorus losses were higher after high-intensity rainfall events in compost-treated soils. With the expected increase in high-intensity rainfall events associated with climate change in the Mediterranean region, organic amendments should be applied in several splits or incorporated into the soil to avoid increased nutrient loss to water bodies.

Sex-specific dietary patterns and their association with metabolic syndrome: Insights from a cross-sectional analysis.

AIMS: This study aims to identify a posteriori dietary patterns with a sex approach and to evaluate their association with metabolic syndrome criteria. METHODS: Cross-sectional study conducted in 6821 men and women between 55 and 75 years of age. Forty-two food groups were analyzed from dietary information collected with food frequency questionnaires, using principal component analysis and cluster analysis and then information from both statistical methods was compared. Prevalences were calculated foreach cluster group, based on the number and types of metabolic syndrome criteria they met. RESULTS: Following principal component analysis, two dietary patterns labeled "healthy" and "unhealthy" were identified in both men and women, due to the presence of foods that are considered more or less healthy. These same dietary patterns were found in cluster analysis plus an "intermediate" cluster consisting of both healthy and unhealthy foods. The presence of metabolic syndrome is related to the "healthy" dietary pattern in women and to the "unhealthy" dietary pattern in men. Comparison of the two statistical approaches showed a high level of correlation between them (weighted Kappa = 0.703 in women and weighted Kappa = 0.691 in men). CONCLUSIONS: Adherence to both healthy and unhealthy dietary pattern appears to be related to the development of MS. The differences found by sex make it necessary to develop interventions with a sex-specific approach.

The function of episodic memory in animals.

The best-known example of episodic memory in animals came from food-storing birds. One of the beauties of the food-storing system was that inherent in the behaviour were the elements that (at the time) made up episodic memory: what, where and when. While there were then already plenty of data on animals' ability to put together what and where, the addition of the time element in animals' memory and its testing was one that was both new and experimentally challenging. It has, however, led to an increasing variety of examples showing that animals can put together all three informational components. If episodic memories can be described as those memories that make any one of us who we are, why should non-human animals have such memories? Here, we argue that episodic memories play a significant functional role in the lives of real animals, in particular, enabling them to make decisions about how they might or should act in their future. We support our argument with data from a range of examples, focussing on data from the field.This article is part of the theme issue 'Elements of episodic memory: lessons from 40 years of research'.

Genetic variants in triglyceride metabolism genes among individuals with hypertriglyceridemia in Colombia.

BACKGROUND: The genetic substrate of severe hypertriglyceridemia (sHTG) in Latin America is insufficiently understood. OBJECTIVE: To identify genetic variants in genes related to triglyceride (TG) metabolism among adults with sHTG from Colombia. METHODS: In individuals with plasma TG≥880 mg/dL at least once in their lifetime, we amplified and sequenced all exons and intron/exon boundaries of the genes LPL, APOC2, APOA5, GPIHBP1 and LMF1. For each variant we ascertained its location, zygosity, allelic frequency and pathogenicity classification according to American College of Medical Genetics (ACMG) criteria. RESULTS: The study included 166 participants (62 % male, mean age 50), peak TG levels ranged between 894 and 11,000 mg/dL. We identified 92 variants: 19 in LPL, 7 in APOC2, 11 in GPIHBP1, 38 in LMF1, and 17 in APOA5. Eighteen of these variants had not been reported. We identified a new pathogenic variant in LMF1 (c.41C>A; p.Ser14*), a new likely pathogenic variant in LMF1 (c.1527 C > T; p.Pro509=, also expressed as c.1447C>T; p.Gln483*), and a known pathogenic variant in LMF1 (c.779G>A; p.Trp260*). Four participants were heterozygous for variant c.953A>G; p.Asn318Ser in LPL, a known risk factor for hypertriglyceridemia. Participants with variants of unknown significance (VUS) in LMF1 had significantly higher peak TG than those with VUS in other genes. Peak TG were 4317 mg/dL in participants with a history of pancreatitis, and 1769 mg/dL in those without it (p = 0.001). CONCLUSION: Our study identified variants associated with sHTG among Latinos, and showed that genetic variation in LMF1 may be frequently associated with sHTG in this population.

Metabolic changes associated with PFAS exposure in firefighters: A pilot study.

This pilot study investigated the association between occupational exposure to per- and polyfluoroalkyl substances (PFASs) and metabolic profiles among two groups of aviation firefighters (n = 37), with an average of 6 and 31 years of working experience (here referred as junior and senior firefighters) at airports across Australia, with samples collected in 2013. PFAS levels in serum were determined in a previous study to be >17 times higher in the senior firefighter group, reflecting the difference in their occupational exposure to fluorosurfactants among the groups. The aim was to examine metabolic patterns across a broad range of PFAS exposure by comparing metabolic differences and their associations with PFAS levels. In this cross-sectional study, the length of firefighting experience and PFAS levels in serum were both further associated with changes in several classes of metabolites, including free fatty acids, bile acids, amino acids, lipids and metabolites related to gut microbial metabolism. The metabolites associated with the length of firefighting experience showed similarities with the metabolites associated with PFAS levels. A non-monotonic response to PFAS concentrations, particularly in saturated fatty acids, was also observed. In the junior firefighter group, the PFAS concentrations were positively associated with saturated fatty acids, i.e., the saturated fatty acid levels increased with increased PFAS levels. In the senior firefighter group, the trend was opposite, with saturated fatty acids decreasing with increasing levels of PFAS. Accounting for potential confounding factors such as BMI and age could not explain the results. While the study population was small, our results plausibly indicate that PFAS exposure can lead to a metabolic compensation strategy that is disrupted at high, long-term exposures. Our study also suggests that serum metabolites serve as better effect-based markers of the impact of exposure than the traditional clinical measurements alone, such as total triglycerides or total cholesterol.

Cu2O Nanoparticles as Nanocarriers and Its Antibacterial Efficacy.

In this study, Cu2O nanoparticles were synthesized using the sol-gel technique and subsequently functionalized with extracts from plants of the Rauvolfioideae subfamily and citrus fruits. Comprehensive characterization techniques, including UV-Vis spectroscopy, FT-IR, XRD, BET, SEM, and TEM, were employed to evaluate the structural and surface properties of the synthesized nanoparticles. The results demonstrated that both functionalized Cu2O nanoparticles exhibit mesoporous structures, as confirmed by nitrogen adsorption-desorption isotherms and the pore size distribution analysis. The green extract functionalized nanoparticles displayed a more uniform pore size distribution compared to those functionalized with the orange extract. The study underscores the potential of these functionalized Cu2O nanoparticles for applications in drug delivery, catalysis, and adsorption processes, highlighting the influence of the functionalization method on their textural properties and performance in antibacterial efficacy.

Resistencia a la Insulina en adultos con sobrepeso y obesidad / Insulin resistance in overweight and obese adults

Resumen El objetivo de esta investigación fue analizar la relación de resistencia a la insulina, sobrepeso y obesidad. Con una población de 2574 pacientes con diagnóstico de obesidad y sobrepeso, se obtuvo una muestra de 334 pacientes. Se realizó un estudio de tipo descriptivo, documental, retrospectivo, transversal y correlacional. Para la recolección de datos se empleó las historias clínicas registradas en el sistema operativo AS400 de IBM, de atención médica del Instituto Ecuatoriano de Seguridad Social. El resultado total de los pacientes perteneció al sexo femenino con un porcentaje del 77.84 %, residencia urbana (73.65 %) e instrucción superior (60.5 %). El 52.8 % de los individuos registró un IMC >30kg/m2. Los pacientes adultos jóvenes de instrucción superior, sexo masculino y sector urbano registraron la mayor prevalencia de resistencia a la insulina, siendo ésta del 61.7 %. En el análisis bivariado los pacientes con obesidad mórbida presentaron mayor riesgo de resistencia a la insulina (RP:1.5; IC95 %:1. 29; 1.77). Se estableció una relación significativa entre el antecedente familiar de diabetes mellitus tipo 2 y el riesgo de presentar resistencia a la insulina (p<0.001; RP: 1.32; IC 95 %: 1.12: 1.56). Los valores de hiperglucemia, hiperinsulinemia e hiperuricemia, así como de AST Y ALT elevadas registraron una relación significativamente con HOMA-IR >3. Se concluye que la resistencia a la insulina es una entidad frecuente en pacientes con sobrepeso y obesidad, identificándose una mayor prevalencia en el género masculino, misma que predispone a la progresión de enfermedades crónicas.

Abstract This research aimed to analyze the relationship between insulin resistance, overweight and obesity. A population of 2,574 patients diagnosed with obesity and overweight was obtained, considering a sample of 334 patients. A descriptive, documentary, retrospective, cross-sectional, and correlational study was conducted. For data collection, the medical records recorded in the IBM AS400 operating system for the Ecuadorian Social Security Institute's medical care were used. The total result of the patients belonged to the female sex with a percentage of 77.84%, urban residence (73.65%), and higher education (60.5%). 52.8% of the individuals registered a BMI > 30kg/m2. Young adult patients with higher education, male sex, and urban sector registered the highest insulin resistance prevalence, 61.7%. In the bivariate analysis, patients with morbid obesity presented a higher risk of insulin resistance (PR: 1.5; 95% CI: 1. 29, 1.77). A significant relationship was established between family history of type 2 diabetes mellitus and the risk of developing insulin resistance (p<0.001; PR: 1.32; 95% CI: 1.12: 1.56). The values of hyperglycemia, hyperinsulinemia, hyperuricemia, and elevated AST and ALT were significantly related to HOMA-IR > 3. It was concluded that insulin resistance is a frequent entity in overweight and obese patients, with a higher prevalence identified in the male gender, which predisposes to the progression of chronic diseases.

QM/MM Study of the Reaction Mechanism of L-Tyrosine Hydroxylation Catalyzed by the Enzyme CYP76AD1.

We have studied the hydroxylation mechanism of l-Tyr by the heme-dependent enzyme CYP76AD1 from the sugar beet (Beta vulgaris). This enzyme has a promising biotechnological application in modified yeast strains to produce medicinal alkaloids, an alternative to the traditional opium poppy harvest. A generative machine learning software based on AlphaFold was used to build the structure of CYP76AD1 since there are no structural data for this specific enzyme. After model validation, l-Tyr was docked in the active site of CYP76AD1 to assemble the reactive complex, whose catalytic distances remained stable throughout the 100 ns of MD simulation. Subsequent QM/MM calculations elucidated that l-Tyr hydroxylation occurs in two steps: hydrogen abstraction from l-Tyr by CpdI, forming an l-Tyr radical, and subsequent radical rebound, corresponding to a rate-limiting step of 16.0 kcal·mol-1. Our calculations suggest that the hydrogen abstraction step should occur in the doublet state, while the radical rebound should happen in the quartet state. The clarification of the reaction mechanism of CYP76AD1 provides insights into the rational optimization of the biosynthesis of alkaloids to eliminate the use of opium poppy.

Architectural traditions in the structures built by cooperative weaver birds.

Humans cooperate to build complex structures with culture-specific architectural styles. However, they are not the only animals to build complex structures nor to have culture. We show that social groups of white-browed sparrow weavers (Plocepasser mahali) build structures (nests for breeding and multiple single-occupant roosts for sleeping) that differ architecturally among groups. Morphological differences are consistent across years and are clear even among groups with territories a few meters apart. These repeatable differences are not explained by among-group variation in local weather conditions, bird size, tree height, or patterns of genetic relatedness. Architectural styles are also robust to the immigration of birds from other groups.

Identification of novel small molecule-based strategies of COL7A1 upregulation and readthrough activity for the treatment of recessive dystrophic epidermolysis bullosa.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic disease caused by loss of function mutations in the gene coding for collagen VII (C7) due to deficient or absent C7 expression. This disrupts structural and functional skin architecture, leading to blistering, chronic wounds, inflammation, important systemic symptoms affecting the mouth, gastrointestinal tract, cornea, and kidney function, and an increased skin cancer risk. RDEB patients have an extremely poor quality of life and often die at an early age. A frequent class of mutations in RDEB is premature termination codons (PTC), which appear in homozygosity or compound heterozygosity with other mutations. RDEB has no cure and current therapies are mostly palliative. Using patient-derived keratinocytes and a library of 8273 small molecules and 20,160 microbial extracts evaluated in a phenotypic screening interrogating C7 levels, we identified three active chemical series. Two of these series had PTC readthrough activity, and one upregulated C7 mRNA, showing synergistic activity when combined with the reference readthrough molecule gentamicin. These compounds represent novel potential small molecule-based systemic strategies that could complement topical-based treatments for RDEB.

More Adult Women than Men at High Cardiometabolic Risk Reported Worse Lifestyles and Self-Reported Health Status in the COVID-19 Lockdown.

BACKGROUND: The COVID-19 lockdown represented an immense impact on human health, which was characterized by lifestyle and dietary changes, social distancing and isolation at home. Some evidence suggests that these consequences mainly affected women and altered relevant ongoing clinical trials. The aim of this study was to evaluate the status and changes in diet, physical activity (PA), sleep and self-reported health status (SRH) as perceived by older adult men and women with metabolic syndrome during the COVID-19 lockdown. METHODS: We analyzed data from 4681 Spanish adults with metabolic syndrome. We carried out a telephone survey during May and June 2020 to collect information on demographics, dietary habits, PA, sleep, SRH and anthropometric data. RESULTS: The mean age of participants was 64.9 years at recruitment, and 52% of participants were men. Most participants (64.1%) perceived a decrease in their PA during confinement. Regarding gender-specific differences, a higher proportion of women than men perceived a decrease in their PA (67.5% vs. 61.1%), Mediterranean diet adherence (20.9% vs. 16.8%), sleep hours (30.3% vs. 19.1%), sleep quality (31.6% vs. 18.2%) and SRH (25.9% vs. 11.9%) (all p < 0.001). CONCLUSIONS: The COVID-19 lockdown affected women more negatively, particularly their self-reported diet, PA, sleep and health status.

Efficacy of high-intensity interval training versus continuous training on serum myonectin and lipid outcomes in adults with metabolic syndrome: A post-hoc analysis of a clinical trial.

BACKGROUND: Myonectin is a myokine with potential effects on the lipid metabolism; however, its regulation by exercise in humans remains unclear. We aimed to compare the efficacy of high-intensity interval training low-volume (HIIT) versus moderate-intensity continuous training (MICT) on serum myonectin, serum lipids, appendicular fat and lean mass, and intramuscular lipids in humans. METHODS: Secondary analysis of a controlled, randomized, clinical trial in adults of both sexes with metabolic syndrome, who underwent a supervised, three-times/week, 12-week treadmill program. HIIT (n = 29) consisted of six intervals with one-minute, high-intensity phases at 90% of peak oxygen consumption (VO2peak) for a total of 22 min. MICT (n = 31) trained at 60% of VO2peak for 36 min. Serum myonectin was measured using a human enzyme-linked immunosorbent assay. Lipid profile was determined by enzymatic methods and free fatty acids (FFA) were measured by gas chromatography. Fat and lean mass were assessed by dual-energy X-ray absorptiometry. Intramuscular lipids were measured through proton magnetic resonance spectroscopy. RESULTS: Subjects had a mean age of 50.8±6.0 years and body mass index of 30.6±4.0 kg/m2. Compared to MICT, HIIT was not superior at increasing serum myonectin (p = 0.661) or linoleic acid (p = 0.263), reducing palmitic (p = 0.286) or stearic acid (p = 0.350), or improving lipid profile (all p>0.05), appendicular fat mass index -AFMI- (p = 0.713) or appendicular lean mass percentage -ALM- (p = 0.810). Compared to baseline, only HIIT significantly increased myonectin (p = 0.042), with a large effect size, although both interventions reduced AFMI and increased ALM with a large effect size. Lipid profile, FFA and intramuscular lipids did not change in any intervention group (p>0.05). CONCLUSIONS: Compared to MICT, HIIT low volume did not demonstrate superiority in improving serum lipids. The fact that both training types reduced AFMI without paralleled significant changes in serum myonectin suggests that this myokine may have a minor effect on short-middle-term exercise-induced fat mobilization.

Off-label use of dalbavancin in children: a case series.

INTRODUCTION: Dalbavancin is an antibiotic active against most Gram-positive bacteria approved for acute bacterial skin and skin structure infections (ABSSSI). Owing to its long half-life, it is being increasingly used for other indications. PATIENTS AND METHODS: We present a case series of children and adolescents treated with dalbavancin for osteoarticular, catheter-related and other non-ABSSSI infections. RESULTS: Dalbavancin was prescribed to 15 patients. Six (40%) were female and median age at prescription was 11.9 (IQR 1.3-18.0) years. Most of them (12/15) had significant comorbidities. Patients presented mainly with deep surgical site infections, osteoarticular infections and central-line-associated bloodstream infections. The most common isolate was Staphylococcus aureus followed by Staphylococcus epidermidis. Major reasons to prescribe dalbavancin were to ensure compliance and patients' convenience. Two patients discontinued the drug due to adverse events possibly related to it. The rest of the patients completed the treatment with dalbavancin, with a median duration of 56 days (IQR 17.5, 115.5). All achieved complete resolution and present no relapse after a median follow-up of 9.9 months (IQR 4.8, 16.6). CONCLUSIONS: Dalbavancin was a safe, effective and convenient alternative in selected paediatric patients with complicated non-ABSSSI infections caused by Gram-positive bacteria.

Repurposing the Open Global Health Library for the discovery of novel Mpro destabilizers with scope as broad-spectrum antivirals.

The SARS coronavirus 2 (SARS-CoV-2) epidemic remains globally active. The emergence of new variants of interest and variants of concern (VoCs), which are potentially more vaccine-resistant and less sensitive to existing treatments, is evident due to their high prevalence. The prospective spread of such variants and other coronaviruses with epidemic potential demands preparedness that can be met by developing fast-track workflows to find new candidates that target viral proteins with a clear in vitro and in vivo phenotype. Mpro (or 3CLpro) is directly involved in the viral replication cycle and the production and function of viral polyproteins, which makes it an ideal target. The biological relevance of Mpro is highly conserved among betacoronaviruses like HCoV-OC43 and SARS-CoV-2, which makes the identification of new chemical scaffolds targeting them a good starting point for designing broad-spectrum antivirals. We report an optimized methodology based on orthogonal cell-free assays to identify small molecules that inhibit the binding pockets of both SARS-CoV-2-Mpro and HCoV-OC43-Mpro; this blockade correlates with antiviral activities in HCoV-OC43 cellular models. By using such a fast-tracking approach against the Open Global Health Library (Merck KGaA), we have found evidence of the antiviral activity of compound OGHL98. In silico studies dissecting intermolecular interactions between OGHL98 and both proteases and comprising docking and molecular dynamics simulations (MDSs) concluded that the binding mode was primarily governed by conserved H-bonds with their C-terminal amino acids and that the rational design of OGHL98 has potential against VoCs proteases resistant to current therapeutics.