A Mild Presentation of X-Linked Hypophosphatemia Caused by a Non-Canonical Splice Site Variant in the PHEX Gene.

X-linked hypophosphatemia (XLH) is a rare inherited disorder of renal phosphate wasting with a highly variable phenotype caused by loss-of-function variants in the PHEX gene. The diagnosis of individuals with mild phenotypes can be challenging and often delayed. Here, we describe a three-generation family with a very mild clinical presentation of XLH. The diagnosis was unexpectedly found in a 39-year-old woman who was referred for genetic testing due to an unclear childhood diagnosis of a tubulopathy. Genetic testing performed by next-generation sequencing using a kidney disease gene panel identified a novel non-canonical splice site variant in the PHEX gene. Segregation analysis detected that the consultand's father, who presented with hypophosphatemia and decreased tubular phosphate reabsorption, and the consultand's son also carried this variant. RNA studies demonstrated that the non-canonical splice site variant partially altered the splicing of the PHEX gene, as both wild-type and aberrant splicing transcripts were detected in the two male members with only one copy of the PHEX gene. In conclusion, this case contributes to the understanding of the relationship between splicing variants and the variable expressivity of XLH disease. The mild phenotype of this family can be explained by the coexistence of PHEX transcripts with aberrant and wild-type splicing.

Cognitive Profile and Cardiovascular Risk Factors in Older Adults with Mild Cognitive Impairment.

The prevalence of cardiovascular risk factors (CVRFs) in the older adults population and their specific impact on their cognitive profiles still requires further research. For this purpose, a cross-sectional study was carried out to describe the presence of CVRFs and their association with cognitive performance in a sample of older adults (65-85 years old) with Mild Cognitive Impairment (MCI). Participants (n = 185) were divided into three groups concerning their cardiovascular risk level determined by the presence of different CVRFs, including Type 2 Diabetes (T2D), dyslipidemia, hypertension, and obesity. The primary outcome measures were the participant's scores in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Sociodemographic, clinical, and psychosocial data were collected. Non-parametrical statistical analyses and effect sizes were calculated. Findings revealed that a greater presence of CVRFs was not associated with a worse overall cognitive performance. High-risk patients were more likely to have significantly worse performance in the attentional domain compared to medium-risk (p = 0.029, r = 0.42) and compared to low-risk (p = 0.041, r = 0.35), specifically in the digits repetition subtest (p = 0.042). T2D alone was the CVRF associated with cognitive differences (p = 0.037, r = 0.32), possibly mediated by the duration of the condition. Consequently, a higher presence of CVRFs did not lead to a worse overall cognitive performance. However, high-risk individuals were more likely to experience cognitive impairment, particularly in the attentional domain. T2D played a significant role in these cognitive profile differences, possibly influenced by its duration.

Increased prevalence of Kidney cysts in individuals carrying heterozygous COL4A3 or COL4A4 pathogenic variants.

BACKGROUND: Clinical variability among individuals with heterozygous pathogenic/likely pathogenic (P/LP) variants in the COL4A3/COL4A4 genes (also called autosomal dominant Alport syndrome or COL4A3/COL4A4 related disorder) is huge; many individuals are asymptomatic or show microhematuria, while others may develop proteinuria and chronic kidney disease (CKD). The prevalence of simple kidney cysts (KC) in the general population varies according to age, and patients with advanced CKD are prone to have them. A possible association between heterozygous COL4A3, COL4A4, and COL4A5 P/LP variants and KC has been described in small cohorts. The presence of KC in a multicenter cohort of individuals with heterozygous P/LP variants in the COL4A3/COL4A4 genes is assessed in this study. METHODS: We evaluated the presence of KC by ultrasound in 157 individuals with P/LP variants in COL4A3 (40.7%) or COL4A4 (53.5%) without kidney replacement therapy. The association between presence of KC and age, proteinuria, eGFR, and causative gene was analyzed. Prevalence of KC was compared with historical case series in the general population. RESULTS: Half of the individuals with P/LP variants in COL4A3/COL4A4 showed KC, which is a significantly higher percentage than in the general population. Only 3.8% (6/157) had cystic nephromegaly. Age and eGFR showed an association with the presence of KC (p<0.001). No association was found between KC and proteinuria, sex, or causative gene. CONCLUSIONS: Individuals with COL4A3/COL4A4 P/LP variants are prone to develop KC more frequently than the general population, and their presence is related to age and to eGFR. Neither proteinuria, sex nor the causative gene influences the presence of KC in these individuals.

Patterns of multimorbidity in primary care electronic health records: A systematic review.

Background: Multimorbidity, the coexistence of multiple chronic conditions in an individual, is a complex phenomenon that is highly prevalent in primary care settings, particularly in older individuals. This systematic review summarises the current evidence on multimorbidity patterns identified in primary care electronic health record (EHR) data. Methods: Three databases were searched from inception to April 2022 to identify studies that derived original multimorbidity patterns from primary care EHR data. The quality of the included studies was assessed using a modified version of the Newcastle-Ottawa Quality Assessment Scale. Results: Sixteen studies were included in this systematic review, none of which was of low quality. Most studies were conducted in Spain, and only one study was conducted outside of Europe. The prevalence of multimorbidity (i.e. two or more conditions) ranged from 14.0% to 93.9%. The most common stratification variable in disease clustering models was sex, followed by age and calendar year. Despite significant heterogeneity in clustering methods and disease classification tools, consistent patterns of multimorbidity emerged. Mental health and cardiovascular patterns were identified in all studies, often in combination with diseases of other organ systems (e.g. neurological, endocrine). Discussion: These findings emphasise the frequent coexistence of physical and mental health conditions in primary care, and provide useful information for the development of targeted preventive and management strategies. Future research should explore mechanisms underlying multimorbidity patterns, prioritise methodological harmonisation to facilitate the comparability of findings, and promote the use of EHR data globally to enhance our understanding of multimorbidity in more diverse populations.

Ground-Based Mobile Measurements to Track Urban Methane Emissions from Natural Gas in 12 Cities across Eight Countries.

To mitigate methane emission from urban natural gas distribution systems, it is crucial to understand local leak rates and occurrence rates. To explore urban methane emissions in cities outside the U.S., where significant emissions were found previously, mobile measurements were performed in 12 cities across eight countries. The surveyed cities range from medium size, like Groningen, NL, to large size, like Toronto, CA, and London, UK. Furthermore, this survey spanned across European regions from Barcelona, ES, to Bucharest, RO. The joint analysis of all data allows us to focus on general emission behavior for cities with different infrastructure and environmental conditions. We find that all cities have a spectrum of small, medium, and large methane sources in their domain. The emission rates found follow a heavy-tailed distribution, and the top 10% of emitters account for 60-80% of total emissions, which implies that strategic repair planning could help reduce emissions quickly. Furthermore, we compare our findings with inventory estimates for urban natural gas-related methane emissions from this sector in Europe. While cities with larger reported emissions were found to generally also have larger observed emissions, we find clear discrepancies between observation-based and inventory-based emission estimates for our 12 cities.

Impact on physical function of the +AGIL Barcelona program in community-dwelling older adults with cognitive impairment: an interventional cohort study.

BACKGROUND: Older adults with cognitive impairment (CI) have higher multimorbidity and frailty prevalence, lower functional status and an increased likelihood to develop dementia, non-cognitive deficits, and adverse health-related events. +AGIL, a real-world program for frail older adults in a primary care area of Barcelona, is a pragmatic, multi-component and integrated intervention implemented since 2016. It includes physical activity, nutrition, sleep hygiene, revision and adequacy of pharmacological treatment, detection of undesired loneliness and screening for CI; to improve physical function in community-dwelling older adults. We aimed to assess the + AGIL longitudinal impact on physical function among community-dwelling frail older persons with CI. METHODS: An interventional cohort study included data from all the + AGIL consecutive participants from July 2016 until March 2020. Based on the comprehensive geriatric assessment, participants were offered a tailored multi-component community intervention, including a 10-week physical activity program led by an expert physical therapist. Physical performance was measured at baseline, three and six months follow-up. The pre-post impact on physical function was assessed by paired sample t-test for repeated samples. Linear mixed models were applied to analyze the + AGIL longitudinal impact. P-values < 0.05 were considered statistically significant. RESULTS: 194 participants were included (82 with CI, based on previous diagnosis or the Mini-COG screening tool), 68% women, mean age 81.6 (SD = 5.8) yo. Participants were mostly independent in Activities of Daily Living (mean Barthel = 92.4, SD = 11.1). The physical activity program showed high adherence (87.6% attended ≥ 75% sessions). At three months, there was a clinically and statistically significant improvement in the Short Physical Performance Battery (SPPB) and its subcomponents in the whole sample and after stratification for CI [CI group improvements: SPPB = 1.1 (SD = 1.8) points, gait speed (GS) = 0.05 (SD = 0.13) m/s, Chair stand test (CST)=-2.6 (SD = 11.4) s. Non-CI group improvements: SPPB = 1.6 (SD = 1.8) points, GS = 0.08 (SD = 0.13) m/s, CST=-6.4 (SD = 12.1) seg]. SPPB and gait speed remained stable at six months in the study sample and subgroups. CI had no significant impact on SPPB or GS improvements. CONCLUSION: Our results suggest that older adults with CI can benefit from a multidisciplinary integrated and comprehensive geriatric intervention to improve physical function, a component of frailty.

Physical activity and exercise for the prevention and management of mild cognitive impairment and dementia: a collaborative international guideline.

BACKGROUND: Physical activity and exercise have been suggested as effective interventions for the prevention and management of mild cognitive impairment (MCI) and dementia, but there are no international guidelines. OBJECTIVES: To create a set of evidence- and expert consensus-based prevention and management recommendations regarding physical activity (any bodily movement produced by skeletal muscles that results in energy expenditure) and exercise (a subset of physical activity that is planned, structured, repetitive), applicable to a range of individuals from healthy older adults to those with MCI/dementia. METHODS: Guideline content was developed with input from several scientific and lay representatives' societies. A systematic search across multidisciplinary databases was carried out until October 2021. Recommendations for prevention and management were developed according to the GRADE and complemented by consensus statements from the expert panels. RECOMMENDATIONS: Physical activity may be considered for the primary prevention of dementia. In people with MCI there is continued uncertainty about the role of physical activity in slowing the conversion to dementia. Mind-body interventions have the greatest supporting evidence. In people with moderate dementia, exercise may be used for maintaining disability and cognition. All these recommendations were based on a very low/low certainty of evidence. CONCLUSIONS: Although the scientific evidence on the beneficial role of physical activity and exercise in preserving cognitive functions in subjects with normal cognition, MCI or dementia is inconclusive, this panel, composed of scientific societies and other stakeholders, recommends their implementation based on their beneficial effects on almost all facets of health.

AMR Sign - An Arthroscopic S-shaped Fold Signifying Adequate Medial Meniscus Repair.

Introduction: The preferred management of medial meniscus tears has notably moved from meniscectomies towards repair. With a higher volume of meniscal repairs being done all across the world with every passing day, the lack of an objective and definitive sign suggesting the adequacy of its repair is daunting. The purpose of our study was to introduce a unique and novel arthroscopic sign formed after adequate repair of the medial meniscus, the AMR (Adequacy of Medial meniscus Repair) sign. We hypothesised that it is not only the objective end point for repair, but can also form the indicator for excellent clinical, functional, and radiological outcome even in the long term. Materials and methods: This was a multicentric, prospective study initiated by the corresponding author, and the findings validated subsequently by the other authors. Overall, it included 804 patients of isolated medial meniscus tear operated with arthroscopic all-inside technique between January 2014 and December 2017. Patients were segregated into three groups based on whether an S-shaped curve in the free, inner edge of the medial meniscus sign was formed post-repair, lost after further tightening, or not formed upon subjective completion of repair. All the patients were followed-up and evaluated based of medial joint line tenderness, McMurray's test for medial meniscus, IKDC score, WOMET score, and radiologically using an MRI at the terminal follow-up. Results: The mean terminal follow-up was 42.34±4.54 months. There was significant (p<0.01) improvement in all patients at the terminal follow-up post-surgery, irrespective of the group. The group in which AMR sign was formed and maintained showed a significantly better functional outcome on terminal follow-up as well as lower failure rates compared to the other two groups. Conclusion: AMR sign is an S-shaped fold at the inner, free edge of medial meniscus, formed after an adequate repair of isolated medial meniscus tear, as viewed on arthroscopy. It is an objective sign denoting regained integrity of the collagen architecture of the medial meniscus following repair. It is also a reliable indicator of excellent long term functional, clinical, and radiological outcome and also lower failure rates in patients after arthroscopic medial meniscus repair.

Sustained improvement of intrinsic capacity in community-dwelling older adults: The +AGIL Barcelona multidomain program.

BACKGROUND: Different programs promote healthy ageing through the optimization of intrinsic capacity. However, a major challenge is to assess their sustained effects over time. +AGIL Barcelona, a consolidated multidomain program, aims to optimize older adults' intrinsic capacity through a coordinated approach among primary care, geriatrics and community resources, in agreement with the integrated care for older people (ICOPE) guidelines. We aimed to evaluate the +AGIL Barcelona longitudinal effect on older adults' physical performance. METHODS: All +AGIL Barcelona consecutive participants since 2016 were enrolled. After a comprehensive geriatric assessment, a tailored, multidisciplinary intervention aligned with the ICOPE guidelines is offered. It includes a 10-week boost multicomponent exercise program, nutritional and sleep-hygiene counselling, revision and optimization of pharmacological treatments and screening for cognitive impairment, depression and loneliness. Changes in physical performance after 3 and 6 months were assessed using mixed models including baseline frailty degree, time and all potential significant confounders. RESULTS: We included 194 participants in the analysis (mean age = 81.6 [standard deviation = 5.8], 68% women). An independent, clinically and statistically significant improvement in physical performance (Short Physical Performance Battery [SPPB] test, combining gait speed, strength and balance) was found at 3 months (SPPB mean change: 1.4; 95% CI: 1.1-1.6) and 6 months (SPPB mean change: 1.1; 95% CI 0.8-1.5). Equivalent results were observed for all the SPPB sub-tests. CONCLUSIONS: A coordinated, multidisciplinary and integrated program can benefit older adults' intrinsic capacity. The participants' empowerment and the connection with the available community resources are critical points for a successful intervention.

The E3 ubiquitin ligase FBXL6 controls the quality of newly synthesized mitochondrial ribosomal proteins.

In mammals, about 99% of mitochondrial proteins are synthesized in the cytosol as precursors that are subsequently imported into the organelle. The mitochondrial health and functions rely on an accurate quality control of these imported proteins. Here, we show that the E3 ubiquitin ligase F box/leucine-rich-repeat protein 6 (FBXL6) regulates the quality of cytosolically translated mitochondrial proteins. Indeed, we found that FBXL6 substrates are newly synthesized mitochondrial ribosomal proteins. This E3 binds to chaperones involved in the folding and trafficking of newly synthesized peptide and to ribosomal-associated quality control proteins. Deletion of these interacting partners is sufficient to hamper interactions between FBXL6 and its substrate. Furthermore, we show that cells lacking FBXL6 fail to degrade specifically mistranslated mitochondrial ribosomal proteins. Finally, showing the role of FBXL6-dependent mechanism, FBXL6-knockout (KO) cells display mitochondrial ribosomal protein aggregations, altered mitochondrial metabolism, and inhibited cell cycle in oxidative conditions.

A comprehensive performance analysis of sequence-based within-sample testing NIPT methods.

BACKGROUND: Non-Invasive Prenatal Testing is often performed by utilizing read coverage-based profiles obtained from shallow whole genome sequencing to detect fetal copy number variations. Such screening typically operates on a discretized binned representation of the genome, where (ab)normality of bins of a set size is judged relative to a reference panel of healthy samples. In practice such approaches are too costly given that for each tested sample they require the resequencing of the reference panel to avoid technical bias. Within-sample testing methods utilize the observation that bins on one chromosome can be judged relative to the behavior of similarly behaving bins on other chromosomes, allowing the bins of a sample to be compared among themselves, avoiding technical bias. RESULTS: We present a comprehensive performance analysis of the within-sample testing method Wisecondor and its variants, using both experimental and simulated data. We introduced alterations to Wisecondor to explicitly address and exploit paired-end sequencing data. Wisecondor was found to yield the most stable results across different bin size scales while producing more robust calls by assigning higher Z-scores at all fetal fraction ranges. CONCLUSIONS: Our findings show that the most recent available version of Wisecondor performs best.

Correlation of X chromosome inactivation with clinical presentation of Fabry disease in a case report.

Fabry disease or also called Anderson-Fabry disease (FD) is a rare disease caused by pathogenic variants in the GLA gene, located on the X chromosome. This gene is involved in the metabolism of glycosphingolipids and its pathogenic variants cause a deficit or absence of α-galactosidase A causing the deposition of globotriaosylceramide throughout the body. Females have a variable phenotypic expression and a better prognosis than males. This is due to the X chromosome inactivation phenomenon. We present a clinical case of Fabry disease in a female with predominantly renal involvement and demonstrate how the X chromosome inactivation phenomenon is tissue dependent, showing preferential inactivation of the mutated allele at the renal level.

AMR Sign - An Arthroscopic S-shaped Fold Signifying Adequate Medial Meniscus Repair

@#Introduction: The preferred management of medial meniscus tears has notably moved from meniscectomies towards repair. With a higher volume of meniscal repairs being done all across the world with every passing day, the lack of an objective and definitive sign suggesting the adequacy of its repair is daunting. The purpose of our study was to introduce a unique and novel arthroscopic sign formed after adequate repair of the medial meniscus, the AMR (Adequacy of Medial meniscus Repair) sign. We hypothesised that it is not only the objective end point for repair, but can also form the indicator for excellent clinical, functional, and radiological outcome even in the long term. Materials and methods: This was a multicentric, prospective study initiated by the corresponding author, and the findings validated subsequently by the other authors. Overall, it included 804 patients of isolated medial meniscus tear operated with arthroscopic all-inside technique between January 2014 and December 2017. Patients were segregated into three groups based on whether an S-shaped curve in the free, inner edge of the medial meniscus sign was formed post-repair, lost after further tightening, or not formed upon subjective completion of repair. All the patients were followed-up and evaluated based of medial joint line tenderness, McMurray’s test for medial meniscus, IKDC score, WOMET score, and radiologically using an MRI at the terminal follow-up. Results: The mean terminal follow-up was 42.34±4.54 months. There was significant (p<0.01) improvement in all patients at the terminal follow-up post-surgery, irrespective of the group. The group in which AMR sign was formed and maintained showed a significantly better functional outcome on terminal follow-up as well as lower failure rates compared to the other two groups. Conclusion: AMR sign is an S-shaped fold at the inner, free edge of medial meniscus, formed after an adequate repair of isolated medial meniscus tear, as viewed on arthroscopy. It is an objective sign denoting regained integrity of the collagen architecture of the medial meniscus following repair. It is also a reliable indicator of excellent long term functional, clinical, and radiological outcome and also lower failure rates in patients after arthroscopic medial meniscus repair.

Effectiveness of home-based exercise delivered by digital health in older adults: a systematic review and meta-analysis.

BACKGROUND: regular physical exercise is essential to maintain or improve functional capacity in older adults. Multimorbidity, functional limitation, social barriers and currently, coronavirus disease of 2019, among others, have increased the need for home-based exercise (HBE) programmes and digital health interventions (DHI). Our objective was to evaluate the effectiveness of HBE programs delivered by DHI on physical function, health-related quality of life (HRQoL) improvement and falls reduction in older adults. DESIGN: systematic review and meta-analysis. PARTICIPANTS: community-dwelling older adults over 65 years. INTERVENTION: exercises at home through DHI. OUTCOMES MEASURES: physical function, HRQoL and falls. RESULTS: twenty-six studies have met the inclusion criteria, including 5,133 participants (range age 69.5 ± 4.0-83.0 ± 6.7). The HBE programmes delivered with DHI improve muscular strength (five times sit-to-stand test, -0.56 s, 95% confidence interval, CI -1.00 to -0.11; P = 0.01), functional capacity (Barthel index, 5.01 points, 95% CI 0.24-9.79; P = 0.04) and HRQoL (SMD 0.18; 95% CI 0.05-0.30; P = 0.004); and reduce events of falls (odds ratio, OR 0.77, 95% CI 0.64-0.93; P = 0.008). In addition, in the subgroup analysis, older adults with diseases improve mobility (SMD -0.23; 95% CI -0.45 to -0.01; P = 0.04), and balance (SMD 0.28; 95% CI 0.09-0.48; P = 0.004). CONCLUSION: the HBE programmes carried out by DHI improve physical function in terms of lower extremity strength and functional capacity. It also significantly reduces the number of falls and improves the HRQoL. In addition, in analysis of only older adults with diseases, it also improves the balance and mobility.

Differentiating and Mitigating Methane Emissions from Fugitive Leaks from Natural Gas Distribution, Historic Landfills, and Manholes in Montréal, Canada.

Rapidly reducing urban methane (CH4) emissions is a critical component of strategies aimed at limiting climate change. Individual source measurements provide the details necessary to develop actionable mitigation strategies and are highly complementary to mobile surveys and other top-down methods. Here, we perform 615 individual source measurements in Montréal, Canada, to quantify CH4 emissions from historic landfills, manholes, and fugitive emissions from natural gas (NG) distribution systems. We find that in 2020, historic landfills produced 901 (452 to 1541, 95% c.i.) tons of CH4, manholes emitted 786 (32 to 2602, 95% c.i.) tons of CH4, and NG distribution systems emitted 451 (176-843, 95% c.i.) tons of CH4, placing them all within the top four CH4 sources in Montréal. Methane emissions from both historic landfills and manholes are not accounted for in any greenhouse gas inventory. We find that geochemistry alone cannot positively identify source subcategories (e.g., type of manhole or NG infrastructure) in almost all cases, although C2/C1 ratios can distinguish NG distribution sources from biogenic sources (historic landfills and manholes). Using our individual source measurement data, we show that historic landfills have the greatest potential for CH4 reductions but the highest mitigation costs, unless we target the highest emitting landfills. In contrast, CH4 emissions from manholes can be reduced at low costs, but reduction methods are commercially unavailable. For NG distribution, methods such as increasing repair rates for high-emitting industrial meters can greatly reduce mitigation costs and emissions. Overall, our results highlight the role of individual source measurements in developing actionable CH4 mitigation strategies to meet municipal, regional, and national climate action plans.

Consensus document on autosomal dominant polycystic kindey disease from the Spanish Working Group on Inherited Kindey Diseases. Review 2020.

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent cause of genetic renal disease and accounts for 6-10% of patients on kidney replacement therapy (KRT). Very few prospective, randomized trials or clinical studies address the diagnosis and management of this relatively frequent disorder. No clinical guidelines are available to date. This is a revised consensus statement from the previous 2014 version, presenting the recommendations of the Spanish Working Group on Inherited Kidney Diseases, which were agreed to following a literature search and discussions. Levels of evidence mostly are C and D according to the Centre for Evidence-Based Medicine (University of Oxford). The recommendations relate to, among other topics, the use of imaging and genetic diagnosis, management of hypertension, pain, cyst infections and bleeding, extra-renal involvement including polycystic liver disease and cranial aneurysms, management of chronic kidney disease (CKD) and KRT and management of children with ADPKD. Recommendations on specific ADPKD therapies are provided as well as the recommendation to assess rapid progression.