Membrane Microdomain Disassembly Inhibits MRSA Antibiotic Resistance.

A number of bacterial cell processes are confined functional membrane microdomains (FMMs), structurally and functionally similar to lipid rafts of eukaryotic cells. How bacteria organize these intricate platforms and what their biological significance is remain important questions. Using the pathogen methicillin-resistant Staphylococcus aureus (MRSA), we show here that membrane-carotenoid interaction with the scaffold protein flotillin leads to FMM formation, which can be visualized using super-resolution array tomography. These membrane platforms accumulate multimeric protein complexes, for which flotillin facilitates efficient oligomerization. One of these proteins is PBP2a, responsible for penicillin resistance in MRSA. Flotillin mutants are defective in PBP2a oligomerization. Perturbation of FMM assembly using available drugs interferes with PBP2a oligomerization and disables MRSA penicillin resistance in vitro and in vivo, resulting in MRSA infections that are susceptible to penicillin treatment. Our study demonstrates that bacteria possess sophisticated cell organization programs and defines alternative therapies to fight multidrug-resistant pathogens using conventional antibiotics.

Evolution of resistance to a last-resort antibiotic in Staphylococcus aureus via bacterial competition.

Antibiotic resistance is a key medical concern, with antibiotic use likely being an important cause. However, here we describe an alternative route to clinically relevant antibiotic resistance that occurs solely due to competitive interactions among bacterial cells. We consistently observe that isolates of Methicillin-resistant Staphylococcus aureus diversify spontaneously into two distinct, sequentially arising strains. The first evolved strain outgrows the parent strain via secretion of surfactants and a toxic bacteriocin. The second is resistant to the bacteriocin. Importantly, this second strain is also resistant to intermediate levels of vancomycin. This so-called VISA (vancomycin-intermediate S. aureus) phenotype is seen in many hard-to-treat clinical isolates. This strain diversification also occurs during in vivo infection in a mouse model, which is consistent with the fact that both coevolved phenotypes resemble strains commonly found in clinic. Our study shows how competition between coevolving bacterial strains can generate antibiotic resistance and recapitulate key clinical phenotypes.

3-year invasive disease-free survival with chemotherapy de-escalation using an 18F-FDG-PET-based, pathological complete response-adapted strategy in HER2-positive early breast cancer (PHERGain): a randomised, open-label, phase 2 trial.

BACKGROUND: PHERGain was designed to assess the feasibility, safety, and efficacy of a chemotherapy-free treatment based on a dual human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab and pertuzumab in patients with HER2-positive early breast cancer (EBC). It used an 18fluorine-fluorodeoxyglucose-PET-based, pathological complete response (pCR)-adapted strategy. METHODS: PHERGain was a randomised, open-label, phase 2 trial that took place in 45 hospitals in seven European countries. It randomly allocated patients in a 1:4 ratio with centrally confirmed, HER2-positive, stage I-IIIA invasive, operable breast cancer with at least one PET-evaluable lesion to either group A, where patients received docetaxel (75 mg/m2, intravenous), carboplatin (area under the curve 6 mg/mL per min, intravenous), trastuzumab (600 mg fixed dose, subcutaneous), and pertuzumab (840 mg loading dose followed by 420 mg maintenance doses, intravenous; TCHP), or group B, where patients received trastuzumab and pertuzumab with or without endocrine therapy, every 3 weeks. Random allocation was stratified by hormone receptor status. Centrally reviewed PET was conducted at baseline and after two treatment cycles. Patients in group B were treated according to on-treatment PET results. Patients in group B who were PET-responders continued with trastuzumab and pertuzumab with or without endocrine therapy for six cycles, while PET-non-responders were switched to receive six cycles of TCHP. After surgery, patients in group B who were PET-responders who did not achieve a pCR received six cycles of TCHP, and all patients completed up to 18 cycles of trastuzumab and pertuzumab. The primary endpoints were pCR in patients who were group B PET-responders after two treatment cycles (the results for which have been reported previously) and 3-year invasive disease-free survival (iDFS) in patients in group B. The study is registered with ClinicalTrials.gov (NCT03161353) and is ongoing. FINDINGS: Between June 26, 2017, and April 24, 2019, a total of 356 patients were randomly allocated (71 patients in group A and 285 patients in group B), and 63 (89%) and 267 (94%) patients proceeded to surgery in groups A and B, respectively. At this second analysis (data cutoff: Nov 4, 2022), the median duration of follow-up was 43·3 months (range 0·0-63·0). In group B, the 3-year iDFS rate was 94·8% (95% CI 91·4-97·1; p=0·001), meeting the primary endpoint. No new safety signals were identified. Treatment-related adverse events and serious adverse events (SAEs) were numerically higher in patients allocated to group A than to group B (grade ≥3 62% vs 33%; SAEs 28% vs 14%). Group B PET-responders with pCR presented the lowest incidence of treatment-related grade 3 or higher adverse events (1%) without any SAEs. INTERPRETATION: Among HER2-positive EBC patients, a PET-based, pCR-adapted strategy was associated with an excellent 3-year iDFS. This strategy identified about a third of patients who had HER2-positive EBC who could safely omit chemotherapy. FUNDING: F Hoffmann-La Roche.

Mutational landscape of risk variants in comorbid depression and obesity: a next-generation sequencing approach.

Major depression (MD) and obesity are complex genetic disorders that are frequently comorbid. However, the study of both diseases concurrently remains poorly addressed and therefore the underlying genetic mechanisms involved in this comorbidity remain largely unknown. Here we examine the contribution of common and rare variants to this comorbidity through a next-generation sequencing (NGS) approach. Specific genomic regions of interest in MD and obesity were sequenced in a group of 654 individuals from the PISMA-ep epidemiological study. We obtained variants across the entire frequency spectrum and assessed their association with comorbid MD and obesity, both at variant and gene levels. We identified 55 independent common variants and a burden of rare variants in 4 genes (PARK2, FGF21, HIST1H3D and RSRC1) associated with the comorbid phenotype. Follow-up analyses revealed significantly enriched gene-sets associated with biological processes and pathways involved in metabolic dysregulation, hormone signaling and cell cycle regulation. Our results suggest that, while risk variants specific to the comorbid phenotype have been identified, the genes functionally impacted by the risk variants share cell biological processes and signaling pathways with MD and obesity phenotypes separately. To the best of our knowledge, this is the first study involving a targeted sequencing approach toward the study of the comorbid MD and obesity. The framework presented here allowed a deep characterization of the genetics of the co-occurring MD and obesity, revealing insights into the mutational and functional profile that underlies this comorbidity and contributing to a better understanding of the relationship between these two disabling disorders.

Shared germline genomic variants in two patients with double primary gastrointestinal stromal tumours (GISTs).

BACKGROUND: Gastrointestinal stromal tumours (GISTs) are prevalent mesenchymal tumours of the gastrointestinal tract, commonly exhibiting structural variations in KIT and PDGFRA genes. While the mutational profiling of somatic tumours is well described, the genes behind the susceptibility to develop GIST are not yet fully discovered. This study explores the genomic landscape of two primary GIST cases, aiming to identify shared germline pathogenic variants and shed light on potential key players in tumourigenesis. METHODS: Two patients with distinct genotypically and phenotypically GISTs underwent germline whole genome sequencing. CNV and single nucleotide variant (SNV) analyses were performed. RESULTS: Both patients harbouring low-risk GISTs with different mutations (PDGFRA and KIT) shared homozygous germline pathogenic deletions in both CFHR1 and CFHR3 genes. CNV analysis revealed additional shared pathogenic deletions in other genes such as SLC25A24. No particular pathogenic SNV shared by both patients was detected. CONCLUSION: Our study provides new insights into germline variants that can be associated with the development of GISTs, namely, CFHR1 and CFHR3 deep deletions. Further functional validation is warranted to elucidate the precise contributions of identified germline mutations in GIST development.

Remnant cholesterol and low-grade inflammation jointly in atherosclerotic cardiovascular disease: implications for clinical trials.

PURPOSE OF REVIEW: Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death despite the development of effective treatments. Recently, elevated remnant cholesterol and low-grade inflammation have emerged as factors explaining part of the residual ASCVD risk. Interestingly, the coexistence of both high remnant cholesterol and low-grade inflammation can further increase the risk of ASCVD. The aim of this review is to describe the role of elevated remnant cholesterol and low-grade inflammation, separately and combined, in ASCVD. RECENT FINDINGS: Results from recently published studies, including observational and genetic Mendelian randomization studies, support a causal relationship between elevated remnant cholesterol and low-grade inflammation on risk of ASCVD in both primary and secondary prevention settings. In addition, current evidence from observational studies suggests that the coexistence of elevated remnant cholesterol and low-grade inflammation further increases the risk of ASCVD. SUMMARY: Recent observational studies suggest that high remnant cholesterol combined with low-grade inflammation may confer a particular high risk for ASCVD. Attention on the dual threat from high remnant cholesterol and low-grade inflammation is necessary, and further research in this field is warranted. The effect of remnant cholesterol-lowering drugs and anti-inflammatory drugs on ASCVD risk alone and combined remains to be elucidated. VIDEO ABSTRACT: http://links.lww.com/COCN/A20.

A crowdsourcing database for the copy-number variation of the Spanish population.

BACKGROUND: Despite being a very common type of genetic variation, the distribution of copy-number variations (CNVs) in the population is still poorly understood. The knowledge of the genetic variability, especially at the level of the local population, is a critical factor for distinguishing pathogenic from non-pathogenic variation in the discovery of new disease variants. RESULTS: Here, we present the SPAnish Copy Number Alterations Collaborative Server (SPACNACS), which currently contains copy number variation profiles obtained from more than 400 genomes and exomes of unrelated Spanish individuals. By means of a collaborative crowdsourcing effort whole genome and whole exome sequencing data, produced by local genomic projects and for other purposes, is continuously collected. Once checked both, the Spanish ancestry and the lack of kinship with other individuals in the SPACNACS, the CNVs are inferred for these sequences and they are used to populate the database. A web interface allows querying the database with different filters that include ICD10 upper categories. This allows discarding samples from the disease under study and obtaining pseudo-control CNV profiles from the local population. We also show here additional studies on the local impact of CNVs in some phenotypes and on pharmacogenomic variants. SPACNACS can be accessed at: http://csvs.clinbioinfosspa.es/spacnacs/ . CONCLUSION: SPACNACS facilitates disease gene discovery by providing detailed information of the local variability of the population and exemplifies how to reuse genomic data produced for other purposes to build a local reference database.

Sociodemographic correlates of late HIV diagnosis among men who have sex with men (MSM) in Ghana.

Timely HIV diagnosis and medical engagement are crucial for effective viral load suppression and treatment as prevention. However, significant delays persist, particularly in Africa, including Ghana. This study focused on Ghanaian men whose route of exposure to HIV was through same-gender sexual contact (MSM), a group disproportionately impacted by HIV. Using structured surveys, we investigated the sociodemographic factors associated with late HIV diagnosis, a topic with limited existing research. Results indicate that older age groups were associated with an increased risk of late diagnosis compared to the 18-24 age group. Among the demographic variables studied, only age showed a consistent association with late HIV diagnosis. This study underscores the importance of targeted interventions to address HIV diagnosis disparities among MSM in Ghana, particularly for older age groups. The findings emphasize the need for tailored interventions addressing age-related disparities in timely diagnosis and engagement with medical services among this population. Such interventions can play a crucial role in reducing the burden of HIV within this community and fostering improved public health outcomes.

Deubiquitinating enzyme amino acid profiling reveals a class of ubiquitin esterases.

The reversibility of ubiquitination by the action of deubiquitinating enzymes (DUBs) serves as an important regulatory layer within the ubiquitin system. Approximately 100 DUBs are encoded by the human genome, and many have been implicated with pathologies, including neurodegeneration and cancer. Non-lysine ubiquitination is chemically distinct, and its physiological importance is emerging. Here, we couple chemically and chemoenzymatically synthesized ubiquitinated lysine and threonine model substrates to a mass spectrometry-based DUB assay. Using this platform, we profile two-thirds of known catalytically active DUBs for threonine esterase and lysine isopeptidase activity and find that most DUBs demonstrate dual selectivity. However, with two anomalous exceptions, the ovarian tumor domain DUB class demonstrates specific (iso)peptidase activity. Strikingly, we find the Machado-Joseph disease (MJD) class to be unappreciated non-lysine DUBs with highly specific ubiquitin esterase activity rivaling the efficiency of the most active isopeptidases. Esterase activity is dependent on the canonical catalytic triad, but proximal hydrophobic residues appear to be general determinants of non-lysine activity. Our findings also suggest that ubiquitin esters have appreciable cellular stability and that non-lysine ubiquitination is an integral component of the ubiquitin system. Its regulatory sophistication is likely to rival that of canonical ubiquitination.

Conservation of HLA Spike Protein Epitopes Supports T Cell Cross-Protection in SARS-CoV-2 Vaccinated Individuals against the Potentially Zoonotic Coronavirus Khosta-2.

Heterologous vaccines, which induce immunity against several related pathogens, can be a very useful and rapid way to deal with new pandemics. In this study, the potential impact of licensed COVID-19 vaccines on cytotoxic and helper cell immune responses against Khosta-2, a novel sarbecovirus that productively infects human cells, was analyzed for the 567 and 41 most common HLA class I and II alleles, respectively. Computational predictions indicated that most of these 608 alleles, covering more than 90% of the human population, contain sufficient fully conserved T-cell epitopes between the Khosta-2 and SARS-CoV-2 spike-in proteins. Ninety percent of these fully conserved peptides for class I and 93% for class II HLA molecules were verified as epitopes recognized by CD8+ or CD4+ T lymphocytes, respectively. These results show a very high correlation between bioinformatic prediction and experimental assays, which strongly validates this study. This immunoinformatics analysis allowed a broader assessment of the alleles that recognize these peptides, a global approach at the population level that is not possible with experimental assays. In summary, these findings suggest that both cytotoxic and helper cell immune protection elicited by currently licensed COVID-19 vaccines should be effective against Khosta-2 virus infection. Finally, by being rapidly adaptable to future coronavirus pandemics, this study has potential public health implications.

Endoplasmic Reticulum Stress in Gliomas: Exploiting a Dual-Effect Dysfunction through Chemical Pharmaceutical Compounds and Natural Derivatives for Therapeutical Uses.

The endoplasmic reticulum maintains proteostasis, which can be disrupted by oxidative stress, nutrient deprivation, hypoxia, lack of ATP, and toxicity caused by xenobiotic compounds, all of which can result in the accumulation of misfolded proteins. These stressors activate the unfolded protein response (UPR), which aims to restore proteostasis and avoid cell death. However, endoplasmic response-associated degradation (ERAD) is sometimes triggered to degrade the misfolded and unassembled proteins instead. If stress persists, cells activate three sensors: PERK, IRE-1, and ATF6. Glioma cells can use these sensors to remain unresponsive to chemotherapeutic treatments. In such cases, the activation of ATF4 via PERK and some proteins via IRE-1 can promote several types of cell death. The search for new antitumor compounds that can successfully and directly induce an endoplasmic reticulum stress response ranges from ligands to oxygen-dependent metabolic pathways in the cell capable of activating cell death pathways. Herein, we discuss the importance of the ER stress mechanism in glioma and likely therapeutic targets within the UPR pathway, as well as chemicals, pharmaceutical compounds, and natural derivatives of potential use against gliomas.

Short-term outcomes of dogs and cats undergoing lung lobectomy using either a self-ligating loop or a thoracoabdominal stapler.

OBJECTIVE: To assess clinical outcomes of lung lobectomies in dogs and cats using either self-ligating loops (SLLs) or thoracoabdominal (TA) staplers, aiming to inform sample size calculations for future superiority trials. STUDY DESIGN: Retrospective study. ANIMALS: A total of 72 dogs and 15 cats. METHODS: Records from January 2003 to October 2023 at a single institution were reviewed. Cases with lung lobectomy performed via TA stapler or SLL with a minimum 14-day postoperative follow-up were included. Pre-, intra-, and postoperative data were collected, with outcomes of interest including the frequency of intra- and postoperative complications. Outcome comparisons between techniques were performed to inform sample size calculations. RESULTS: A total of 101 lung lobectomies were performed. The TA stapler was used in 83 (82.2%) and the SLL in 18 (17.8%) lung lobectomies. Intraoperative complications were identified in 14/101 lung lobectomies (13.9%), including intraoperative hemorrhage in 12/101 lobectomies (11.8%) and air leakage in 2/101 lobectomies (1.9%). Postoperative complications were identified in 12/87 cases (13.8%), including 4 (4.6%) catastrophic complications and 5 (5.8%) major complications. All intra- and postoperative complications occurred in cases having undergone stapled lung lobectomy; however, no differences were identified between surgical technique and either intraoperative (p = .069) or postoperative complications (p = .112). A sample size of 103 lobectomies per technique group would be required for appropriate evaluation. CONCLUSION: Lung lobectomy using either surgical technique provided a good short-term outcome in this population. CLINICAL SIGNIFICANCE: Self-ligating loop lung lobectomy provided a comparable alternative to stapled lung lobectomy. Further studies are needed to assess technique superiority.

Impact of Lymphedema on Foot-Health-Related Quality of Life: A Case-Control Investigation.

OBJECTIVE: To evaluate the foot-health-related quality of life in individuals with versus without lower-limb lymphedema. METHODS: A case-control study was carried out in an academic clinic in Lisbon, Portugal. Eighty participants (40 controls and 40 with lymphedema) were included in the study. The researchers examined sociodemographic and clinical data and foot-health-related quality of life in both groups. In the group with lymphedema, lower-limb lymphedema was also characterized. RESULTS: Individuals with lower-limb lymphedema had significantly lower scores on all dimensions of the Foot Health Status Questionnaire in comparison with the control group. CONCLUSIONS: Individuals with lower-limb lymphedema appear to have a poorer foot-health-related quality of life than the general population.

Influence of the biomechanical evaluation of rupture using two shapes of same intramedullary implant after proximal interphalangeal joint arthrodesis to correct the claw/hammer pathology: A finite element study.

We used finite element analysis to study the mechanical stress distribution of a new intramedullary implant used for proximal interphalangeal joint (PIPJ) arthrodesis (PIPJA) to surgically correct the claw-hammer toe deformity that affects 20% of the population. After geometric reconstruction of the foot skeleton from claw toe images of a 36-year-old male patient, two implants were positioned, in the virtual model, one neutral implant (NI) and another one 10° angled (10°AI) within the PIPJ of the second through fourth HT during the toe-off phase of gait and results were compared to those derived for the non-surgical foot (NSF). A PIPJA was performed on the second toe using a NI reduced tensile stress at the proximal phalanx (PP) (45.83 MPa) compared to the NSF (59.44 MPa; p < 0.001). When using the 10°AI, the tensile stress was much higher at PP and middle phalanges (MP) of the same toe, measuring 147.58 and 160.58 MPa, respectively, versus 59.44 and 74.95 MPa at corresponding joints in the NSF (all p < 0.001). Similar results were found for compressive stresses. The NI reduced compressive stress at the second PP (-65.12 MPa) compared to the NSF (-113.23 MPa) and the 10°AI (-142 MPa) (all p < 0.001). The von Mises stresses within the implant were also significantly lower when using NI versus 10°AI (p < 0.001). Therefore, we do not recommend performing a PIPJA using the 10°AI due to the increase in stress concentration primarily at the second PP and MP, which could promote implant breakage.

Influence of quality of life related to perceived foot health between in a rural an urban population: A case-control research.

Foot problems are very common in the community. Studies indicate that between 18% and 63% of people have foot pain or stiffness and that foot problems have a large impact on people's functional decline and a significant detrimental impact on measures of quality of life related to health. The general objective of this research was to compare foot health in people from the rural population compared to people from the urban population and its relationship with quality of life. A case-control descriptive study was developed with a sample of 304 patients, 152 patients from the rural population and 152 patients from the urban population. Quality of life was measured through the SF-36 Health Questionnaire in its Spanish version. The rural population group had a mean age of 46.67 ± 13.69 and the urban population group 49.02 ± 18.29. Regarding the score of the lowest levels of quality of life related to foot problems, the rural population group compared to the urban population group showed: for body pain (52.21 ± 30.71 vs. 67.80 ± 25.28, p < 0.001); and for mental health (69.58 ± 18.98 vs. 64.60 ± 14.88, p < 0.006). Differences between groups were analysed using Student's t-test for independent samples, which showed statistical significance (p < 0.05). This research offers evidence that the rural population presents better levels of mental health and lower levels of bodily pain in the domains of the SF-36 Health Questionnaire comparing with the urban population.

Biological maturity vs. relative age: Independent impact on physical performance in male and female youth handball players.

Maturity status and relative age are two of the determining factors in talent development. The aim of the study was to analyze the influence of biological maturity status and relative age on physical performance in young male and female handball players. The sample included 48 males (14.11 ± 1.17 years) and 41 females (14.25 ± 1.64 years) players from one Spanish professional handball academy. Anthropometric data (height, sitting height, body mass and self-reported biological parent heights) and physical performance data (CMJ, DJ, 20 m speed, T-test and throwing velocity) were collected. Biological maturity status was determined as the percentage of predicted adult height, while relative age was estimated in birth quartiles based on biennial age grouping (Q1-Q8). The results showed a positive correlation between maturity status and CMJ in male players (p < 0.01). Differences in CMJ performance according to maturity status were identified (p < 0.05), with higher jump heights being recorded especially in early maturing boys (p < 0.01) and first lines and wings (p < 0.05). The variance in CMJ test scores could be explained by the maturity status by 42.90% in U-15 (p < 0.05) and 72.60% in U-16 male players (p < 0.001). By contrast, no differences were found in girls (p > 0.05). Moreover, no relationships were found between relative age and indices of physical performance (p > 0.05). Overall, maturity status had greater impacts on the tests of physical performance than relative age. Stakeholders should monitor the maturity status of young handball players to avoid physical performance biases that do not allow them to develop their sporting potential.

Spatially and Chemically Resolved Visualization of Fe Incorporation into NiO Octahedra during the Oxygen Evolution Reaction.

The activity of Ni (hydr)oxides for the electrochemical evolution of oxygen (OER), a key component of the overall water splitting reaction, is known to be greatly enhanced by the incorporation of Fe. However, a complete understanding of the role of cationic Fe species and the nature of the catalyst surface under reaction conditions remains unclear. Here, using a combination of electrochemical cell and conventional transmission electron microscopy, we show how the surface of NiO electrocatalysts, with initially well-defined surface facets, restructures under applied potential and forms an active NiFe layered double (oxy)hydroxide (NiFe-LDH) when Fe3+ ions are present in the electrolyte. Continued OER under these conditions, however, leads to the creation of additional FeOx aggregates. Electrochemically, the NiFe-LDH formation correlates with a lower onset potential toward the OER, whereas the formation of the FeOx aggregates is accompanied by a gradual decrease in the OER activity. Complementary insight into the catalyst near-surface composition, structure, and chemical state is further extracted using X-ray photoelectron spectroscopy, operando Raman spectroscopy, and operando X-ray absorption spectroscopy together with measurements of Fe uptake by the electrocatalysts using time-resolved inductively coupled plasma mass spectrometry. Notably, we identified that the catalytic deactivation under stationary conditions is linked to the degradation of in situ-created NiFe-LDH. These insights exemplify the complexity of the active state formation and show how its structural and morphological evolution under different applied potentials can be directly linked to the catalyst activation and degradation.

Liver transplantation in metastatic colorectal cancer: are we ready for it?

Colorectal cancer (CRC) is a prevalent disease worldwide, with more than 50% of patients developing metastases to the liver. Five-year overall survival remains modest among patients with metastatic CRC (mCRC) treated with conventional therapies however, liver transplantation in a highly selected population can improve clinical outcomes with an impressive 5-year overall survival of 83%. Despite liver transplantation appearing to be a promising therapeutical option for well-selected patients with mCRC with the liver-limited disease, these data come from small monocentric trials which included a heterogeneous population. Currently, several clinical trials are evaluating liver transplantation in this scenario, aiming for a more accurate patient selection by integrating liquid biopsy, tissue profiling, and nuclear medicine to the already known clinical biomarkers that eventually may lead to a survival improvement. In this paper, the clinical outcomes and inclusion criteria from the most relevant clinical trials and clinical series involving liver transplantation in patients with liver-limited disease colorectal cancer are reviewed as well as the trials currently recruiting.

Dry needling of the flexor digitorum brevis muscle reduces postural control in standing: A pre-post stabilometric study.

There are studies that show the better balance after dry needling in lumbar pain. However, the postural control effects after foot dry needling are unknown. Our objective was to check if dry needling reduces postural control. Eighteen subjects with flexor digitorum brevis (FDB) muscle Myofascial trigger point were evaluated pre- and post-deep dry needling. We measured stabilometric variables in a pre-post study. We have found significant differences in three stabilometric variables: surface with eyes closed (29.36-53.21 mm2 ) (p = 0.000), medium speed of the laterolateral displacement with eyes closed (1.42-1.64 mm/s) (p = 0.004), and medium speed of the anteroposterior displacement with eyes closed (1.30-1.53 mm/s) (p = 0.025). Dry needling therapy application in FDB muscle reduces standing postural control with eyes closed.

Predicted impact of the viral mutational landscape on the cytotoxic response against SARS-CoV-2.

The massive assessment of immune evasion due to viral mutations that increase COVID-19 susceptibility can be computationally facilitated. The adaptive cytotoxic T response is critical during primary infection and the generation of long-term protection. Here, potential HLA class I epitopes in the SARS-CoV-2 proteome were predicted for 2,915 human alleles of 71 families using the netMHCIpan EL algorithm. Allele families showed extreme epitopic differences, underscoring genetic variability of protective capacity between humans. Up to 1,222 epitopes were associated with any of the twelve supertypes, that is, allele clusters covering 90% population. Next, from all mutations identified in ~118,000 viral NCBI isolates, those causing significant epitope score reduction were considered epitope escape mutations. These mutations mainly involved non-conservative substitutions at the second and C-terminal position of the ligand core, or total ligand removal by large recurrent deletions. Escape mutations affected 47% of supertype epitopes, which in 21% of cases concerned isolates from two or more sub-continental areas. Some of these changes were coupled, but never surpassed 15% of evaded epitopes for the same supertype in the same isolate, except for B27. In contrast to most supertypes, eight allele families mostly contained alleles with few SARS-CoV-2 ligands. Isolates harboring cytotoxic escape mutations for these families co-existed geographically within sub-Saharan and Asian populations enriched in these alleles according to the Allele Frequency Net Database. Collectively, our findings indicate that escape mutation events have already occurred for half of HLA class I supertype epitopes. However, it is presently unlikely that, overall, it poses a threat to the global population. In contrast, single and double mutations for susceptible alleles may be associated with viral selective pressure and alarming local outbreaks. The integration of genomic, geographical and immunoinformatic information eases the surveillance of variants potentially affecting the global population, as well as minority subpopulations.