Apolipoprotein E-ε2 and Resistance to Atherosclerosis in Midlife: The PESA Observational Study.

BACKGROUND: APOE is a known genetic contributor to cardiovascular disease, but the differential role APOE alleles play in subclinical atherosclerosis remains unclear. METHODS: The PESA (Progression of Early Subclinical Atherosclerosis) is an observational cohort study that recruited 4184 middle-aged asymptomatic individuals to be screened for cardiovascular risk and multiterritorial subclinical atherosclerosis. Participants were APOE-genotyped, and omics data were additionally evaluated. RESULTS: In the PESA study, the frequencies for APOE -ε2, -ε3, and -ε4 alleles were 0.060, 0.844, and 0.096, respectively. This study included a subcohort of 3887 participants (45.8±4.3 years of age; 62% males). As expected, APOE-ε4 carriers were at the highest risk for cardiovascular disease and had significantly greater odds of having subclinical atherosclerosis compared with ε3/ε3 carriers, which was mainly explained by their higher levels of low-density lipoprotein (LDL)-cholesterol. In turn, APOE-ε2 carriers were at the lowest risk for cardiovascular disease and had significantly lower odds of having subclinical atherosclerosis in several vascular territories (carotids: 0.62 [95% CI, 0.47-0.81]; P=0.00043; femorals: 0.60 [0.47-0.78]; P=9.96×10-5; coronaries: 0.53 [0.39-0.74]; P=0.00013; and increased PESA score: 0.58 [0.48-0.71]; P=3.16×10-8). This APOE-ε2 atheroprotective effect was mostly independent of the associated lower LDL-cholesterol levels and other cardiovascular risk factors. The protection conferred by the ε2 allele was greater with age (50-54 years: 0.49 [95% CI, 0.32-0.73]; P=0.00045), and normal (<150 mg/dL) levels of triglycerides (0.54 [0.44-0.66]; P=4.70×10-9 versus 0.90 [0.57-1.43]; P=0.67 if ≥150 mg/dL). Omics analysis revealed an enrichment of several canonical pathways associated with anti-inflammatory mechanisms together with the modulation of erythrocyte homeostasis, coagulation, and complement activation in ε2 carriers that might play a relevant role in the ε2's atheroprotective effect. CONCLUSIONS: This work sheds light on the role of APOE in cardiovascular disease development with important therapeutic and prevention implications on cardiovascular health, especially in early midlife. REGISTRATION: URL: https://www.clinicaltrials.gov: NCT01410318.

The clinical and genetic landscape of developmental and epileptic encephalopathies in Egyptian children.

Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of epilepsies characterized by early-onset, refractory seizures associated with developmental regression or impairment, with a heterogeneous genetic landscape including genes implicated in various pathways and mechanisms. We retrospectively studied the clinical and genetic data of patients with genetic DEE who presented at two tertiary centers in Egypt over a 10-year period. Exome sequencing was used for genetic testing. We report 74 patients from 63 unrelated Egyptian families, with a high rate of consanguinity (58%). The most common seizure type was generalized tonic-clonic (58%) and multiple seizure types were common (55%). The most common epilepsy syndrome was early infantile DEE (50%). All patients showed variable degrees of developmental impairment. Microcephaly, hypotonia, ophthalmological involvement and neuroimaging abnormalities were common. Eighteen novel variants were identified and the phenotypes of five DEE genes were expanded with novel phenotype-genotype associations. Obtaining a genetic diagnosis had implications on epilepsy management in 17 patients with variants in 12 genes. In this study, we expand the phenotype and genotype spectrum of DEE in a large single ethnic cohort of patients. Reaching a genetic diagnosis guided precision management of epilepsy in a significant proportion of patients.

Mapping Health Technology Assessment Agency Approaches for Biosimilar Value Assessment: An ISPOR Special Interest Group Report.

OBJECTIVES: A systematic literature review undertaken by the ISPOR Biosimilar Special Interest Group highlighted that limited guidance exists on how to assess biosimilars value and on appropriate economic evaluation techniques. This study described current health technology assessment (HTA) agency approaches for biosimilar value assessment. METHODS: Semi-structured interviews (n = 16) were carried out with HTA experts in Africa, America, Asia, Australia, and Europe to investigate current HTA practices for biosimilars. Data categorization was based on a thematic analysis approach. Findings from the qualitative data analysis were interpreted in view of relevant published literature. RESULTS: Our research suggests that in systems in which frameworks for biosimilar regulatory approval are well established, HTA agencies can accept the regulators' comparability exercise, and reimbursement decisions can generally be based on price comparisons. This approach is accepted in practice and allows streamlining of biosimilars value assessment. Nevertheless, conducting HTAs for biosimilars can be relevant when (1) the originator is not reimbursed, (2) the biosimilar marketing authorization holder seeks reimbursement for indications/populations, pharmaceutical forms, methods and routes of administration that differ with respect to the originator, and (3) a price premium is sought for a biosimilar based on an added-value claim. Further, HTA agencies' role conducting class-review updates following biosimilar availability can support greater patients' access to biologics. CONCLUSIONS: Internationally, there are differences in how national competent authorities on pricing and reimbursement of pharmaceuticals perceive HTA's role for biosimilars. Therefore, HTA agencies are encouraged to issue clear guidance on when and how to conduct HTAs for biosimilars, and on which economic techniques to apply.

Long-term care facilities' response to the COVID-19 pandemic: An international, cross-sectional survey.

AIMS: To (i) assess the adherence of long-term care (LTC) facilities to the COVID-19 prevention and control recommendations, (ii) identify predictors of this adherence and (iii) examine the association between the adherence level and the impact of the pandemic on selected unfavourable conditions. DESIGN: Cross-sectional survey. METHODS: Managers (n = 212) and staff (n = 2143) of LTC facilities (n = 223) in 13 countries/regions (Brazil, Egypt, England, Hong Kong, Indonesia, Japan, Norway, Portugal, Saudi Arabia, South Korea, Spain, Thailand and Turkey) evaluated the adherence of LTC facilities to COVID-19 prevention and control recommendations and the impact of the pandemic on unfavourable conditions related to staff, residents and residents' families. The characteristics of participants and LTC facilities were also gathered. Data were collected from April to October 2021. The study was reported following the STROBE guidelines. RESULTS: The adherence was significantly higher among facilities with more pre-pandemic in-service education on infection control and easier access to information early in the pandemic. Residents' feelings of loneliness and feeling down were the most affected conditions by the pandemic. More psychological support to residents was associated with fewer residents' aggressive behaviours, and more psychological support to staff was associated with less work-life imbalance. CONCLUSIONS: Pre-pandemic preparedness significantly shaped LTC facilities' response to the pandemic. Adequate psychological support to residents and staff might help mitigate the negative impacts of infection outbreaks. IMPACT: This is the first study to comprehensively examine the adherence of LTC facilities to COVID-19 prevention and control recommendations. The results demonstrated that the adherence level was significantly related to pre-pandemic preparedness and that adequate psychological support to staff and residents was significantly associated with less negative impacts of the pandemic on LTC facilities' staff and residents. The results would help LTC facilities prepare for and respond to future infection outbreaks. PATIENT OR PUBLIC CONTRIBUTION: No Patient or Public Contribution.

Walking the talk for dementia: A unique immersive, embodied, and multi-experiential initiative.

Coping with dementia requires an integrated approach encompassing personal, health, research, and community domains. Here we describe "Walking the Talk for Dementia," an immersive initiative aimed at empowering people with dementia, enhancing dementia understanding, and inspiring collaborations. This initiative involved 300 participants from 25 nationalities, including people with dementia, care partners, clinicians, policymakers, researchers, and advocates for a 4-day, 40 km walk through the Camino de Santiago de Compostela, Spain. A 2-day symposium after the journey provided novel transdisciplinary and horizontal structures, deconstructing traditional hierarchies. The innovation of this initiative lies in its ability to merge a physical experience with knowledge exchange for diversifying individuals' understanding of dementia. It showcases the transformative potential of an immersive, embodied, and multi-experiential approach to address the complexities of dementia collaboratively. The initiative offers a scalable model to enhance understanding, decrease stigma, and promote more comprehensive and empathetic dementia care and research.

Seasonal and Geographic Dynamics in Bioproperties and Phytochemical Profile of Limonium algarvense Erben.

This study delved into the influence of ecological and seasonal dynamics on the synthesis of secondary metabolites in the medicinal halophyte Limonium algarvense Erben, commonly known as sea lavender, and examined their antioxidant and anti-inflammatory properties. Aerial parts of sea lavender were systematically collected across winter, spring, summer, and autumn seasons from distinct geographic locations in southern Portugal, specifically "Ria de Alvor" in Portimão and "Ria Formosa" in Tavira. The investigation involved determining the total polyphenolic profile through spectrophotometric methods, establishing the chemical profile via liquid chromatography electrospray ionization quadrupole time-of-flight mass spectrometry (LC-ESI-QTOF-MS/MS), and evaluating in vitro antioxidant properties using radical and metal-based methods, along with assessing anti-inflammatory capacity through a cell model. Results unveiled varying polyphenol levels and profiles across seasons, with spring and autumn samples exhibiting the highest content, accompanied by the most notable antioxidant and anti-inflammatory capacities. Geographic location emerged as an influential factor, particularly distinguishing plants from "Ria de Alvor". Seasonal fluctuations were associated with environmental factors, including temperature, which, when excessively high, can impair plant metabolism, but also with the presence of flowers and seeds in spring and autumn samples, which also seems to contribute to elevated polyphenol levels and enhanced bioproperties of these samples. Additionally, genetic factors may be related to differences observed between ecotypes (geographical location). This study underscores sea lavender's potential as a natural source of antioxidant and anti-inflammatory agents, emphasizing the significance of considering both geographic location and seasonal dynamics in the assessment of phenolic composition and bioactive properties in medicinal plant species.

Promoting workplace retention during global crises: An international survey of the preventive role of psychological support among victims of social discrimination in long-term care facilities.

This international cross-sectional survey examined the potential role of organizational psychological support in mitigating the association between experiencing social discrimination against long-term care (LTC) facilities' healthcare professionals (HCPs) and their intention to stay in the current workplace during the COVID-19 pandemic. Participants included a convenience sample of 2,143 HCPs (nurses [21.5 %], nurse aids or residential care workers [40.1 %], social workers [12.1 %], and others [26.4 %]) working at 223 LTC facilities in 13 countries/regions. About 37.5 % of the participants reported experiencing social discrimination, and the percentage ranged from 15.3 % to 77.9 % across countries/regions. Controlling for socio-demographic and work-related variables, experiencing social discrimination was significantly associated with a lower intention to stay, whereas receiving psychological support showed a statistically significant positive association (p-value=0.015 and <0.001, respectively). The interaction term between social discrimination and psychological support showed a statistically significant positive association with the intention to stay, indicating a moderating role of the psychological support.

AMFR dysfunction causes autosomal recessive spastic paraplegia in human that is amenable to statin treatment in a preclinical model.

Hereditary spastic paraplegias (HSP) are rare, inherited neurodegenerative or neurodevelopmental disorders that mainly present with lower limb spasticity and muscle weakness due to motor neuron dysfunction. Whole genome sequencing identified bi-allelic truncating variants in AMFR, encoding a RING-H2 finger E3 ubiquitin ligase anchored at the membrane of the endoplasmic reticulum (ER), in two previously genetically unexplained HSP-affected siblings. Subsequently, international collaboration recognized additional HSP-affected individuals with similar bi-allelic truncating AMFR variants, resulting in a cohort of 20 individuals from 8 unrelated, consanguineous families. Variants segregated with a phenotype of mainly pure but also complex HSP consisting of global developmental delay, mild intellectual disability, motor dysfunction, and progressive spasticity. Patient-derived fibroblasts, neural stem cells (NSCs), and in vivo zebrafish modeling were used to investigate pathomechanisms, including initial preclinical therapy assessment. The absence of AMFR disturbs lipid homeostasis, causing lipid droplet accumulation in NSCs and patient-derived fibroblasts which is rescued upon AMFR re-expression. Electron microscopy indicates ER morphology alterations in the absence of AMFR. Similar findings are seen in amfra-/- zebrafish larvae, in addition to altered touch-evoked escape response and defects in motor neuron branching, phenocopying the HSP observed in patients. Interestingly, administration of FDA-approved statins improves touch-evoked escape response and motor neuron branching defects in amfra-/- zebrafish larvae, suggesting potential therapeutic implications. Our genetic and functional studies identify bi-allelic truncating variants in AMFR as a cause of a novel autosomal recessive HSP by altering lipid metabolism, which may potentially be therapeutically modulated using precision medicine with statins.

A Systematic Literature Review of Gaps and Challenges in Value Assessment of Biosimilars: An ISPOR Special Interest Group Report.

OBJECTIVES: This study aims to provide an overview of the gaps and challenges in the value assessment of biosimilars and to identify potential approaches to address them. METHODS: A multidisciplinary, international team of biosimilar experts identified gaps and challenges. A systematic review was conducted of the peer-reviewed literature in PubMed, EMBASE, Web of Science Core Collection, EBSCOhost Business Source Complete; and of the gray literature. Preliminary results were presented at ISPOR conferences and this article benefited from 2 review rounds among ISPOR Biosimilar Special Interest Group members. RESULTS: Given that a biosimilar is highly similar to its reference biologic, health technology assessment agencies should accept the comparability exercise approved by regulatory authorities and, thus, conduct a price comparison when biosimilar reimbursement is requested for the same indication as the reference biologic. If the reference biologic is not reimbursed or is not the standard of care, a full economic evaluation of the biosimilar versus a relevant comparator needs to be conducted. To date, little consideration has been given to specific challenges, such as how biosimilar value assessment can account for the nocebo effect, potential differences between biologic-naive and biologic-experienced patients, the availability of intravenous and subcutaneous administration forms or different administration devices for the same active compound, value-added services, and the contribution of biosimilars for generating health gain at the population level. CONCLUSIONS: There is a need to gather further insights in the methodology of value assessment for biosimilars, and health technology assessment agencies need to develop more elaborate guidance on biosimilar value assessment in specific circumstances.

From Threat to Opportunity: Harnessing the Invasive Carpobrotus edulis (L.) N.E.Br for Nutritional and Phytotherapeutic Valorization Amid Seasonal and Spatial Variability.

Carpobrotus edulis (L.) N.E.Br. (Hottentot-fig) is a problematic invasive species found in coastal areas worldwide. Mechanical removal is a common control method, leaving the removed biomass available as a possible source of natural phytochemicals with prospective commercial applications. While the Hottentot-fig's vegetative organs have been studied previously, this work establishes for the first time a seasonal and spatial comparative analysis of its nutritional, chemical, and bioactivity profiles (in three locations over four seasons). Proximate and mineral contents were assessed, along with its phenolic composition and in vitro antioxidant and anti-inflammatory properties. Hottentot-fig's biomass offered a good supply of nutrients, mainly carbohydrates, proteins, and minerals, with a tendency for higher concentrations of the most relevant minerals and proteins in autumn and winter, and in plants from sites A (Ria de Alvor lagoon) and B (Ancão beach). The extracts were rich in polyphenolics, with higher levels in spring and summer, especially for luteolin-7-O-glucoside and salicylic and coumaric acids. The extracts were also effective antioxidants, with stronger radical scavenging activities in spring and summer, along with anti-inflammatory properties. Our results suggest that the usually discarded plant material of this invasive halophyte could be valuable as a source of natural products with potential biotechnological applications in the food and nutraceutical industries.

Salt-Tolerant Plants as Sources of Antiparasitic Agents for Human Use: A Comprehensive Review.

Parasitic diseases, especially those caused by protozoans and helminths, such as malaria, trypanosomiasis, leishmaniasis, Chagas disease, schistosomiasis, onchocerciasis, and lymphatic filariasis, are the cause of millions of morbidities and deaths every year, mainly in tropical regions. Nature has always provided valuable antiparasitic agents, and efforts targeting the identification of antiparasitic drugs from plants have mainly focused on glycophytes. However, salt-tolerant plants (halophytes) have lately attracted the interest of the scientific community due to their medicinal assets, which include antiparasitic properties. This review paper gathers the most relevant information on antiparasitic properties of halophyte plants, targeting human uses. It includes an introduction section containing a summary of some of the most pertinent characteristics of halophytes, followed by information regarding the ethnomedicinal uses of several species towards human parasitic diseases. Then, information is provided related to the antiprotozoal and anthelmintic properties of halophytes, determined by in vitro and in vivo methods, and with the bioactive metabolites that may be related to such properties. Finally, a conclusion section is presented, addressing perspectives for the sustainable exploitation of selected species.

Maternal height as a predictor of glucose intolerance in the postpartum and its relationship with maternal pre-gestational weight.

PURPOSE: Short stature predicts higher risk of developing type 2 diabetes. We studied the association between height and glucose intolerance in women with gestational diabetes mellitus (GDM) and whether this association differed according to body mass index (BMI). METHODS: Retrospective study of the Portuguese GDM registry. EXCLUSION CRITERIA: missing data on postpartum oral glucose tolerance test (OGTT) or BMI. ENDPOINT: postpartum glucose intolerance (diabetes mellitus or prediabetes on the 6-8 weeks postpartum OGTT). Women were divided by mean height and compared. A multivariate logistic regression was used, and the analysis was stratified by BMI (cut-off: 30 kg/m2) and interaction was tested. RESULTS: We included 7402 women; mean height was 161.9 ± 6.2 cm. Taller women had lower BMI and lower rates of glucose intolerance (6.8 vs. 8.8%, p = 0.002). Women with BMI < 30 kg/m2 were taller than those with obesity. Height associated with glucose intolerance. The multivariate adjusted OR of glucose intolerance was 0.98 (95% CI 0.96-0.99), p = 0.001, per 1 cm increase in height. This association was only observed in women with BMI < 30 kg/m2: OR 0.97 (95% CI 0.95-0.99), < 0.001. There was no such association in women with BMI ≥ 30 kg/m2: OR 0.99 (95% CI 0.97-1.02), p = 0.65. P for interaction between BMI and height was 0.09. CONCLUSIONS: In non-obese pre-gestational women, height is inversely associated with postpartum glucose intolerance. Per 1 cm increase in height, women present a 3% decrease in the risk of developing diabetes mellitus or prediabetes.

Is preoperative fat infiltration in lumbar spine muscles associated with worse clinical outcomes after lumbar interbody fusion?

PURPOSE: Lumbar musculature has a fundamental role in spine stability and spinal balance. Muscle atrophy and fat infiltration play an important role in pain pathophysiology. Accordingly, the preoperative condition of lumbar muscles may influence clinical outcomes after surgical treatment. In this context, the aim of this study was to evaluate the association between preoperative lumbar paravertebral muscle fat infiltration and clinical outcomes after lumbar interbody fusion. METHODS: A retrospective study of patients with lumbar pathology submitted to lumbar transforaminal (TLIF) or posterior interbody fusion (PLIF) was performed, with a minimum of two years of follow-up. Preoperative lumbar magnetic resonance imaging (MRI) images were classified for fat infiltration in lumbar multifidus muscle and correlated with clinical outcomes. RESULTS: Seventy-five patients were included: 24 submitted to PLIF and 51 to TLIF. Most patients underwent surgery for spondylolisthesis (67%). Higher degrees of fat infiltration were associated with more advanced age (54.8 vs. 49.1 years old, p = 0.04) and more leg pain after surgery (p = 0.04). No statistically significant differences in other clinical outcomes such as Oswestry Disability Index, visual analogue scale for back and leg pain, self-reported back pain relief, return to work and overall satisfaction were found between different groups of fat infiltration. The improvement in leg pain was associated with improvement in self-reported lumbar pain (p < 0.001). CONCLUSION: Age and preoperative degree of fat infiltration may be important to predict improvement in leg pain after lumbar interbody fusion. The absence of solid literature on this topic and universal assessment methodologies reinforce the need for further studies.

The relationship between depression and risk of violence in portuguese community-dwelling older people.

BACKGROUND: Mental disorders are highly prevalent in older people, being depression a predominant disorder. Evidence points to a possible relationship between depression and violence against older people. Nonetheless, the role of the depressive symptomology severity in the risk of violence against older people remains unclear. Thus, this study's main objective was to analyze the relationship between geriatric depressive symptomatology and the risk of violence against older people. METHODS: This exploratory study involved 502 community-dwelling older persons aged 65 to 96 years (73.3 ± 6.5). Measures were performed using the Geriatric Depression Scale and the Risk Assessment of Violence against the Non-Institutionalized Elderly scale. RESULTS: One hundred nineteen older people (23.7%) had mild/moderate depressive symptomology, and twenty-six (5.2%) had severe depressive symptomology. There were significant relationships between the severity of depressive symptomatology and the risk of violence (p < 0.05). The presence of depressive symptomatology increased the likelihood of being victims of violence, particularly among women (odds ratio: 2-8, p < 0.05). CONCLUSIONS: The severity of depressive symptomatology plays an essential role in the risk of violence against community-dwelling older people. Moreover, it was found that older persons with depression symptomatology were at higher risk of being victims of violence. Our study findings support the need for protective measures within mental health national or regional policies to prevent depression and violence against community-dwelling older people.

Creative dance associated with traditional Portuguese singing as a strategy for active aging: a comparative cross-sectional study.

BACKGROUND: Multimodal forms of exercise can influence several physical and mental factors important for successful aging. In the present study, we introduce a new type of multimodal intervention, combining movement (creative dance) with traditional singing. This study aims to compare physical fitness, functional physical independence, depressive symptoms, general cognitive status, and daytime sleepiness among older adults participating in multimodal exercise, those participating in traditional physical exercise, and those not actively engaged in physical exercise. METHODS: This cross-sectional study included 112 people aged ≥ 65 years (75.3 ± 0.7 years) living independently in the community, divided into 3 groups: multimodal exercise (n = 34), traditional exercise (n = 41), and no physical exercise (n = 37). RESULTS: The multimodal exercise group showed greater flexibility of the lower limbs and upper limbs/shoulders and better general cognitive status than the traditional exercise group (p < 0.05). The traditional exercise group had better agility and dynamic balance, aerobic endurance, and strength of the lower and upper limbs than the no-exercise group (p < 0.05). CONCLUSIONS: The results suggest that the two types of programs studied may have different impacts on some of the variables investigated and support the design of future experimental studies that include interventions based on the combination of creative dance and traditional Portuguese singing.

Can two multimodal psychomotor exercise programs improve attention, affordance perception, and balance in community dwellings at risk of falling? A randomized controlled trial.

BACKGROUND: Falls are associated with cognitive and physical function deterioration. Attention decline, inaccurate affordance perception, and balance impairment are considered to be risk factors for falls. Furthermore, few studies have reported psychomotor intervention as a fall prevention program. This study aimed to investigate the effects of two multimodal programs on attention, perceptual and stepping-forward boundaries, and balance in community-dwelling older adults at risk of falling. METHODS: Fifty-one community-dwelling older adults were recruited to participate in a 24-week randomized controlled trial. Participants (75.4 ± 5.6 years) were randomly assigned to one of three groups: the 1) multimodal psychomotor program [EG1], 2) combined program (multimodal psychomotor program + whole-body vibration program) [EG2], and 3) control group. Participants were assessed at baseline, at post-intervention, and after a 12-week no-intervention follow-up period. RESULTS: The within-group comparisons showed significant improvements in attention and balance in EG1 and EG2 after the intervention (p <  0.05). The magnitudes of the treatment effects were similar in both EGs, ranging from medium to large. Decreases in the fall rate were also observed in EG1 (- 44.2%) and EG2 (- 63.0%) (p <  0.05). During the follow-up period, these improvements in attention were maintained, while those in balance were reversed in both EGs. No significant differences between groups were found. CONCLUSIONS: These study results suggest that both multimodal exercise programs were effective for fall prevention and were well tolerated by the participants. Specifically, EG1 and EG2 showed identical improvements in attention, and EG2 presented a slightly larger enhancement in balance and a larger decrease in the fall rate. Our findings demonstrate the benefits of maintaining the psychomotor intervention program by itself or in combination with the whole-body vibration program to prevent cognitive and physical function deterioration. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03446352 . Date of registration: February 26, 2018.

SARS-CoV-2 Membrane Protein: From Genomic Data to Structural New Insights.

Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) is composed of four structural proteins and several accessory non-structural proteins. SARS-CoV-2's most abundant structural protein, Membrane (M) protein, has a pivotal role both during viral infection cycle and host interferon antagonism. This is a highly conserved viral protein, thus an interesting and suitable target for drug discovery. In this paper, we explain the structural nature of M protein homodimer. To do so, we developed and applied a detailed and robust in silico workflow to predict M protein dimeric structure, membrane orientation, and interface characterization. Single Nucleotide Polymorphisms (SNPs) in M protein were retrieved from over 1.2 M SARS-CoV-2 genomes and proteins from the Global Initiative on Sharing All Influenza Data (GISAID) database, 91 of which were located at the predicted dimer interface. Among those, we identified SNPs in Variants of Concern (VOC) and Variants of Interest (VOI). Binding free energy differences were evaluated for dimer interfacial SNPs to infer mutant protein stabilities. A few high-prevalent mutated residues were found to be especially relevant in VOC and VOI. This realization may be a game-changer to structure-driven formulation of new therapeutics for SARS-CoV-2.

Dynamic performance-exposure algorithm for falling risk assessment and prevention of falls in community-dwelling older adults.

This study aimed to design a dynamic performance-exposure algorithm for falling risk assessment and prevention of falls in community-dwelling older adults. It involved a cross-sectional and follow-up survey assessing retrospective and prospective falls and respective performance-related, exposure and performance-exposure risk factors. In total, 500 Portuguese community-dwelling adults participated. Data modelling showed significant (p<0.05) relationships between the above risk factors and selected nine key ordered outcomes explaining falls to include in the algorithm: previous falls; health conditions; balance; lower strength; perceiving action boundaries; fat mass; environmental hazards; rest periods; and physical activity. Respective high-, moderate- and low-risk cutoffs were established. The results demonstrated a dynamic relationship between older adults' performance capacity and the exposure to fall opportunity, counterbalanced by the action boundary perception, supporting the build algorithm's conceptual framework. Fall prevention measures should consider the factors contributing most to the individual risk of falling and their distance from low-risk safe values.

Risk factors for cage subsidence and clinical outcomes after transforaminal and posterior lumbar interbody fusion.

BACKGROUND: Cage subsidence is a very common complication after lumbar interbody fusion. It may compromise vertebral interbody fusion through progressive spinal deformity and consequently cause compression of neural elements. Clinical relevance remains, however, unclear, with few studies on this subject and even less information regarding its correlation with clinical findings. The aim of this study was to identify risk factors for cage subsidence and clinical evaluation after transforaminal (TLIF) and posterior (PLIF) lumbar interbody fusion. METHODS: A retrospective study in patients submitted to TLIF and PLIF between 2008 and 2017 was conducted. RESULTS: A total of 165 patients were included (123 TLIF and 42 PLIF). Univariate analysis showed an increased risk of cage subsidence in spondylolisthesis comparing with degenerative disk disease (p = 0.007). A higher preoperative lumbar lordosis angle (p = 0.014) and cage placement in L2-L3 (p = 0.012) were associated with higher risk of subsidence. The posterior cage positioning on vertebral endplate was associated with a higher risk of subsidence (p = 0.028) and significant subsidence (p = 0.005), defined as cage migration > 50% of cage height. PLIF presented a higher risk when comparing with TLIF (p = 0.024). Hounsfield unit (HU) values < 135 (OR6; 95% CI [1.95-34]) and posterior positioning (OR7; 95% CI [1.7-27.3]) were independent risk factors for cage subsidence and significant subsidence, respectively, in multivariate analysis. There was a tendency for significant subsidence in degrees ≥ 2 of Meyerding spondylolisthesis (OR4; 95% CI [0.85-21.5]). Significant cage subsidence was not associated with worse clinical results. Other analyzed factors, such as age (p = 0.008), low bone mineral density (BMD) (p = 0.029) and type of surgery (TLIF) (p = 0.004), were associated with worse results. CONCLUSION: The present study shows that lower BMD and posterior cage positioning are relevant risk factors for lumbar cage subsidence. Low BMD is also a predictor of poor clinical results, so it must be properly evaluated and considered, through HU values measurement in CT scan, a feasible and reliable tool in perioperative planning.

Synchronous nonmonotonic changes in functional connectivity and white matter integrity in a rat model of sporadic Alzheimer's disease.

Brain glucose hypometabolism has been singled out as an important contributor and possibly main trigger to Alzheimer's disease (AD). Intracerebroventricular injections of streptozotocin (icv-STZ) cause brain glucose hypometabolism without systemic diabetes. Here, a first-time longitudinal study of brain glucose metabolism, functional connectivity and white matter microstructure was performed in icv-STZ rats using PET and MRI. Histological markers of pathology were tested at an advanced stage of disease. STZ rats exhibited altered functional connectivity and intra-axonal damage and demyelination in brain regions typical of AD, in a temporal pattern of acute injury, transient recovery/compensation and chronic degeneration. In the context of sustained glucose hypometabolism, these nonmonotonic trends - also reported in behavioral studies of this animal model as well as in human AD - suggest a compensatory mechanism, possibly recruiting ketone bodies, that allows a partial and temporary repair of brain structure and function. The early acute phase could thus become a valuable therapeutic window to strengthen the recovery phase and prevent or delay chronic degeneration, to be considered both in preclinical and clinical studies of AD. In conclusion, this work reveals the consequences of brain insulin resistance on structure and function, highlights signature nonmonotonic trajectories in their evolution and proposes potent MRI-derived biomarkers translatable to human AD and diabetic populations.