Clinical, Neuroimaging, and Metabolic Footprint of the Neurodevelopmental Disorder Caused by Monoallelic HK1 Variants.

Background and Objectives: Hexokinase 1 (encoded by HK1) catalyzes the first step of glycolysis, the adenosine triphosphate-dependent phosphorylation of glucose to glucose-6-phosphate. Monoallelic HK1 variants causing a neurodevelopmental disorder (NDD) have been reported in 12 individuals. Methods: We investigated clinical phenotypes, brain MRIs, and the CSF of 15 previously unpublished individuals with monoallelic HK1 variants and an NDD phenotype. Results: All individuals had recurrent variants likely causing gain-of-function, representing mutational hot spots. Eight individuals (c.1370C>T) had a developmental and epileptic encephalopathy with infantile onset and virtually no development. Of the other 7 individuals (n = 6: c.1334C>T; n = 1: c.1240G>A), 3 adults showed a biphasic course of disease with a mild static encephalopathy since early childhood and an unanticipated progressive deterioration with, e.g., movement disorder, psychiatric disease, and stroke-like episodes, epilepsy, starting in adulthood. Individuals who clinically presented in the first months of life had (near)-normal initial neuroimaging and severe cerebral atrophy during follow-up. In older children and adults, we noted progressive involvement of basal ganglia including Leigh-like MRI patterns and cerebellar atrophy, with remarkable intraindividual variability. The CSF glucose and the CSF/blood glucose ratio were below the 5th percentile of normal in almost all CSF samples, while blood glucose was unremarkable. This biomarker profile resembles glucose transporter type 1 deficiency syndrome; however, in HK1-related NDD, CSF lactate was significantly increased in all patients resulting in a substantially different biomarker profile. Discussion: Genotype-phenotype correlations appear to exist for HK1 variants and can aid in counseling. A CSF biomarker profile with low glucose, low CSF/blood glucose, and high CSF lactate may point toward monoallelic HK1 variants causing an NDD. This can help in variant interpretation and may aid in understanding the pathomechanism. We hypothesize that progressive intoxication and/or ongoing energy deficiency lead to the clinical phenotypes and progressive neuroimaging findings.

Targeted Proteomics Reveals Quantitative Differences in Low-Abundance Glycosyltransferases of Patients with Congenital Disorders of Glycosylation.

Protein glycosylation is an essential post-translational modification in all domains of life. Its impairment in humans can result in severe diseases named congenital disorders of glycosylation (CDGs). Most of the glycosyltransferases (GTs) responsible for proper glycosylation are polytopic membrane proteins that represent challenging targets in proteomics. We established a multiple reaction monitoring (MRM) assay to comprehensively quantify GTs involved in the processes of N-glycosylation and O- and C-mannosylation in the endoplasmic reticulum. High robustness was achieved by using an enriched membrane protein fraction of isotopically labeled HEK 293T cells as an internal protein standard. The analysis of primary skin fibroblasts from eight CDG type I patients with impaired ALG1, ALG2, and ALG11 genes, respectively, revealed a substantial reduction in the corresponding protein levels. The abundance of the other GTs, however, remained unchanged at the transcript and protein levels, indicating that there is no fail-safe mechanism for the early steps of glycosylation in the endoplasmic reticulum. The established MRM assay was shared with the scientific community via the commonly used open source Skyline software environment, including Skyline Batch for automated data analysis. We demonstrate that another research group could easily reproduce all analysis steps, even while using different LC-MS hardware.

"Hide and seek": Misleading transferrin variants in PMM2-CDG complicate diagnostics.

PURPOSE: Congenital disorders of glycosylation (CDG) are one of the fastest growing groups of inborn errors of metabolism. Despite the availability of next-generation sequencing techniques and advanced methods for evaluation of glycosylation, CDG screening mainly relies on the analysis of serum transferrin (Tf) by isoelectric focusing, HPLC or capillary electrophoresis. The main pitfall of this screening method is the presence of Tf protein variants within the general population. Although reports describe the role of Tf variants leading to falsely abnormal results, their significance in confounding diagnosis in patients with CDG has not been documented so far. Here, we describe two PMM2-CDG cases, in which Tf variants complicated the diagnostic. EXPERIMENTAL DESIGN: Glycosylation investigations included classical screening techniques (capillary electrophoresis, isoelectric focusing and HPLC of Tf) and various confirmation techniques (two-dimensional electrophoresis, western blot, N-glycome, UPLC-FLR/QTOF MS with Rapifluor). Tf variants were highlighted following neuraminidase treatment. Sequencing of PMM2 was performed. RESULTS: In both patients, Tf screening pointed to CDG-II, while second-line analyses pointed to CDG-I. Tf variants were found in both patients, explaining these discrepancies. PMM2 causative variants were identified in both patients. CONCLUSION AND CLINICAL RELEVANCE: We suggest that a neuraminidase treatment should be performed when a typical CDG Tf pattern is found upon initial screening analysis.

Evolution of 1500-m Olympic Running Performance.

PURPOSE: This study determined the evolution of performance and pacing for each winner of the men's Olympic 1500-m running track final from 1924 to 2020. METHODS: Data were obtained from publicly available sources. When official splits were unavailable, times from sources such as YouTube were included and interpolated from video records. Final times, lap splits, and position in the peloton were included. The data are presented relative to 0 to 400 m, 400 to 800 m, 800 to 1200 m, and 1200 to 1500 m. Critical speed and D' were calculated using athletes' season's best times. RESULTS: Performance improved ∼25 seconds from 1924 to 2020, with most improvement (∼19 s) occurring in the first 10 finals. However, only 2 performances were world records, and only one runner won the event twice. Pacing evolved from a fast start-slow middle-fast finish pattern (reverse J-shaped) to a slower start with steady acceleration in the second half (J-shaped). The coefficient of variation for lap speeds ranged from 1.4% to 15.3%, consistent with a highly tactical pacing pattern. With few exceptions, the eventual winners were near the front throughout, although rarely in the leading position. There is evidence of a general increase in both critical speed and D' that parallels performance. CONCLUSIONS: An evolution in the pacing pattern occurred across several "eras" in the history of Olympic 1500-m racing, consistent with better trained athletes and improved technology. There has been a consistent tactical approach of following opponents until the latter stages, and athletes should develop tactical flexibility, related to their critical speed and D', in planning prerace strategy.

PPA1 Deficiency Causes a Deranged Galactose Metabolism Recognizable in Neonatal Screening.

Two siblings showed increased galactose and galactose-related metabolites in neonatal screening. Diagnostic workup did not reveal abnormalities in any of the known disease-causing enzymes involved in galactose metabolism. Using whole-exome sequencing, we identified a homozygous missense variant in PPA1 encoding the cytosolic pyrophosphatase 1 (PPA1), c.557C>T (p.Thr186Ile). The enzyme activity of PPA1 was determined using a colorimetric assay, and the protein content was visualized via western blotting in skin fibroblasts from one of the affected individuals. The galactolytic activity of the affected fibroblasts was determined by measuring extracellular acidification with a Seahorse XFe96 analyzer. PPA1 activity decreased to 22% of that of controls in the cytosolic fraction of homogenates from patient fibroblasts. PPA1 protein content decreased by 50% according to western blot analysis, indicating a reduced stability of the variant protein. The extracellular acidification rate was reduced in patient fibroblasts when galactose was used as a substrate. Untargeted metabolomics of blood samples revealed an elevation of other metabolites related to pyrophosphate metabolism. Besides hyperbilirubinemia in the neonatal period in one child, both children were clinically unremarkable at the ages of 3 and 14 years, respectively. We hypothesize that the observed metabolic derangement is a possible mild manifestation of PPA1 deficiency. Unresolved abnormalities in galactosemia screening might result in the identification of more individuals with PPA1 deficiency, a newly discovered inborn metabolic disorder (IMD).

Carnosinase-1 Knock-Out Reduces Kidney Fibrosis in Type-1 Diabetic Mice on High Fat Diet.

Carnosine and anserine supplementation markedLy reduce diabetic nephropathy in rodents. The mode of nephroprotective action of both dipeptides in diabetes, via local protection or improved systemic glucose homeostasis, is uncertain. Global carnosinase-1 knockout mice (Cndp1-KO) and wild-type littermates (WT) on a normal diet (ND) and high fat diet (HFD) (n = 10/group), with streptozocin (STZ)-induced type-1 diabetes (n = 21-23/group), were studied for 32 weeks. Independent of diet, Cndp1-KO mice had 2- to 10-fold higher kidney anserine and carnosine concentrations than WT mice, but otherwise a similar kidney metabolome; heart, liver, muscle and serum anserine and carnosine concentrations were not different. Diabetic Cndp1-KO mice did not differ from diabetic WT mice in energy intake, body weight gain, blood glucose, HbA1c, insulin and glucose tolerance with both diets, whereas the diabetes-related increase in kidney advanced glycation end-product and 4-hydroxynonenal concentrations was prevented in the KO mice. Tubular protein accumulation was lower in diabetic ND and HFD Cndp1-KO mice, interstitial inflammation and fibrosis were lower in diabetic HFD Cndp1-KO mice compared to diabetic WT mice. Fatalities occurred later in diabetic ND Cndp1-KO mice versus WT littermates. Independent of systemic glucose homeostasis, increased kidney anserine and carnosine concentrations reduce local glycation and oxidative stress in type-1 diabetic mice, and mitigate interstitial nephropathy in type-1 diabetic mice on HFD.

Complex metabolic disharmony in PMM2-CDG paves the way to new therapeutic approaches.

PMM2-CDG is the most common defect among the congenital disorders of glycosylation. In order to investigate the effect of hypoglycosylation on important cellular pathways, we performed extensive biochemical studies on skin fibroblasts of PMM2-CDG patients. Among others, acylcarnitines, amino acids, lysosomal proteins, organic acids and lipids were measured, which all revealed significant abnormalities. There was an increased expression of acylcarnitines and amino acids associated with increased amounts of calnexin, calreticulin and protein-disulfid-isomerase in combination with intensified amounts of ubiquitinylated proteins. Lysosomal enzyme activities were widely decreased as well as citrate and pyruvate levels indicating mitochondrial dysfunction. Main lipid classes such as phosphatidylethanolamine, cholesterol or alkyl-phosphatidylcholine, as well as minor lipid species like hexosylceramide, lysophosphatidylcholines or phosphatidylglycerol, were abnormal. Biotinidase and catalase activities were severely reduced. In this study we discuss the impact of metabolite abnormalities on the phenotype of PMM2-CDG. In addition, based on our data we propose new and easy-to-implement therapeutic approaches for PMM2-CDG patients.

Myofascial force transmission between the calf and the dorsal thigh is dependent on knee angle: an ultrasound study.

A recent in-vivo experiment has shown that force can be transmitted between the gastrocnemius and the hamstring muscles due to a direct tissue continuity. However, it remains unclear if this mechanical interaction is affected by the stiffness of the structural connection. This study therefore aimed to investigate the impact of the knee angle on myofascial force transmission across the dorsal knee. A randomized, cross-over study was performed, including n = 56 healthy participants (25.36 ± 3.9 years, 25 females). On two separate days, they adopted a prone position on an isokinetic dynamometer (knee extended or 60° flexed). In each condition, the device moved the ankle three times from maximal plantarflexion to maximal dorsal extension. Muscle inactivity was ensured using EMG. High-resolution ultrasound videos of the semimembranosus (SM) and the gastrocnemius medialis (GM) soft tissue were recorded. Maximal horizontal tissue displacement, obtained using cross-correlation, was examined as a surrogate of force transmission. SM tissue displacement was higher at extended (4.83 ± 2.04 mm) than at flexed knees (3.81 ± 2.36 mm). Linear regression demonstrated significant associations between (1) SM and GM soft tissue displacement (extended: R2 = 0.18, p = 0.001; flexed: R2 = 0.17, p = 0.002) as well as (2) SM soft tissue displacement and ankle range of motion (extended: R2 = 0.103, p = 0.017; flexed: R2 = 0.095, p = 0.022). Our results further strengthen the evidence that local stretching induces a force transmission to neighboring muscles. Resulting remote exercise effects such as increased range of motion, seem to depend on the stiffness of the continuity.Trial registration: DRKS (Deutsches Register Klinischer Studien), registration number DRKS00024420, first registered 08/02/2021, https://drks.de/search/de/trial/DRKS00024420 .

Smartphone-assisted training with education for patients with hip and/or knee osteoarthritis (SmArt-E): study protocol for a multicentre pragmatic randomized controlled trial.

INTRODUCTION: Hip and knee osteoarthritis are associated with functional limitations, pain and restrictions in quality of life and the ability to work. Furthermore, with growing prevalence, osteoarthritis is increasingly causing (in)direct costs. Guidelines recommend exercise therapy and education as primary treatment strategies. Available options for treatment based on physical activity promotion and lifestyle change are often insufficiently provided and used. In addition, the quality of current exercise programmes often does not meet the changing care needs of older people with comorbidities and exercise adherence is a challenge beyond personal physiotherapy. The main objective of this study is to investigate the short- and long-term (cost-)effectiveness of the SmArt-E programme in people with hip and/or knee osteoarthritis in terms of pain and physical functioning compared to usual care. METHODS: This study is designed as a multicentre randomized controlled trial with a target sample size of 330 patients. The intervention is based on the e-Exercise intervention from the Netherlands, consists of a training and education programme and is conducted as a blended care intervention over 12 months. We use an app to support independent training and the development of self-management skills. The primary and secondary hypotheses are that participants in the SmArt-E intervention will have less pain (numerical rating scale) and better physical functioning (Hip Disability and Osteoarthritis Outcome Score, Knee Injury and Osteoarthritis Outcome Score) compared to participants in the usual care group after 12 and 3 months. Other secondary outcomes are based on domains of the Osteoarthritis Research Society International (OARSI). The study will be accompanied by a process evaluation. DISCUSSION: After a positive evaluation, SmArt-E can be offered in usual care, flexibly addressing different care situations. The desired sustainability and the support of the participants' behavioural change are initiated via the app through audio-visual contact with their physiotherapists. Furthermore, the app supports the repetition and consolidation of learned training and educational content. For people with osteoarthritis, the new form of care with proven effectiveness can lead to a reduction in underuse and misuse of care as well as contribute to a reduction in (in)direct costs. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00028477. Registered on August 10, 2022.

Competition Between Desired Competitive Result, Tolerable Homeostatic Disturbance, and Psychophysiological Interpretation Determines Pacing Strategy.

Scientific interest in pacing goes back >100 years. Contemporary interest, both as a feature of athletic competition and as a window into understanding fatigue, goes back >30 years. Pacing represents the pattern of energy use designed to produce a competitive result while managing fatigue of different origins. Pacing has been studied both against the clock and during head-to-head competition. Several models have been used to explain pacing, including the teleoanticipation model, the central governor model, the anticipatory-feedback-rating of perceived exertion model, the concept of a learned template, the affordance concept, the integrative governor theory, and as an explanation for "falling behind." Early studies, mostly using time-trial exercise, focused on the need to manage homeostatic disturbance. More recent studies, based on head-to-head competition, have focused on an improved understanding of how psychophysiology, beyond the gestalt concept of rating of perceived exertion, can be understood as a mediator of pacing and as an explanation for falling behind. More recent approaches to pacing have focused on the elements of decision making during sport and have expanded the role of psychophysiological responses including sensory-discriminatory, affective-motivational, and cognitive-evaluative dimensions. These approaches have expanded the understanding of variations in pacing, particularly during head-to-head competition.

Additional effects of pain neuroscience education combined with physiotherapy on the headache frequency of adult patients with migraine: A randomized controlled trial.

Aim To assess the efficacy of pain neuroscience education combined with physiotherapy for the management of migraine.Background Physiotherapy can significantly reduce the frequency of migraine, but the evidence is based only on a few studies. Pain neuroscience education might pose a promising treatment, as it addresses migraine as a chronic pain disease.Methods In this non-blinded randomized controlled trial, migraine patients received physiotherapy + pain neuroscience education or physiotherapy alone, preceded by a three-month waiting period. Primary outcomes were frequency of headache (with and without migraine features), frequency of migraine and associated disability.Results Eighty-two participants were randomized and analyzed. Both groups showed a decrease of headache frequency (p = 0.02, d = 0.46) at post-treatment (physiotherapy: 0.77 days, 95%CI: -0.75 to 2.29 and physiotherapy + pain neuroscience education: 1.25 days, 95%CI: -0.05 to 2.55) and at follow-up (physiotherapy: 1.93, 95%CI: 0.07 to 3.78 and physiotherapy + pain neuroscience education: 3.48 days, 95%CI: 1.89 to 5.06), with no difference between groups (p = 0.26, d = 0.26). Migraine frequency was reduced significantly in the physiotherapy + pain neuroscience education group, and not in the physiotherapy group, at post-treatment (1.28 days, 95%CI: 0.34 to 2.22, p = 0.004) and follow-up (3.05 days, 95%CI: 1.98 to 5.06, p < 0.0001), with a difference between groups at follow-up (2.06 days, p = 0.003). Migraine-related disability decreased significantly in both groups (physiotherapy: 19.8, physiotherapy + pain neuroscience education: 24.0 points, p < 0.001, d = 1.15) at follow-up, with no difference between groups (p = 0.583). Secondary outcomes demonstrated a significant effect of time with no interaction between time and group. No harm or adverse events were observed during the study.Conclusion In comparison to physiotherapy alone, pain neuroscience education combined with physiotherapy can further reduce the frequency of migraine, but had no additional effect on general headache frequency or migraine-related disability.Trial Registration The study was pre-registered at the German Clinical Trials Register (DRKS00020804).

Quantification of Dolichyl Phosphates Using Phosphate Methylation and Reverse-Phase Liquid Chromatography-High Resolution Mass Spectrometry.

Dolichyl monophosphates (DolPs) are essential lipids in glycosylation pathways that are highly conserved across almost all domains of life. The availability of DolP is critical for all glycosylation processes, as these lipids serve as membrane-anchored building blocks used by various types of glycosyltransferases to generate complex post-translational modifications of proteins and lipids. The analysis of DolP species by reverse-phase liquid chromatography-mass spectrometry (RPLC-MS) remains a challenge due to their very low abundance and wide range of lipophilicities. Until now, a method for the simultaneous qualitative and quantitative assessment of DolP species from biological membranes has been lacking. Here, we describe a novel approach based on simple sample preparation, rapid and efficient trimethylsilyl diazomethane-dependent phosphate methylation, and RPLC-MS analysis for quantification of DolP species with different isoprene chain lengths. We used this workflow to selectively quantify DolP species from lipid extracts derived of Saccharomyces cerevisiae, HeLa, and human skin fibroblasts from steroid 5-α-reductase 3- congenital disorders of glycosylation (SRD5A3-CDG) patients and healthy controls. Integration of this workflow with global lipidomics analyses will be a powerful tool to expand our understanding of the role of DolPs in pathophysiological alterations of metabolic pathways downstream of HMG-CoA reductase, associated with CDGs, hypercholesterolemia, neurodegeneration, and cancer.

A new bipolar device for sealing and cutting: ex and in vivo studies for performance evaluation.

INTRODUCTION: A novel multipurpose bipolar radiofrequency instrument, the Erbe Dissector (EDS), which simultaneously seals and cuts tissue, was developed. Ex vivo sealing rate and time, burst pressure, jaw temperature and thermal spread were studied in porcine renal arteries. MATERIAL AND METHODS: In vivo, 13 surgical tasks were performed in two pigs: beside sealing rate and time, overall performance in sharp and blunt dissection, tissue sticking, hemostasis, precision, etc., were evaluated by four surgeons compared with ENSEAL G2 (EG2) using surveys on a Likert scale (1 = very poor; 5 = very good). RESULTS: Ex vivo, the EDS sealing rate was 91.7% (33/36 arteries) at an average sealing time of 2.1 s (range 1.7-2.8) and a burst pressure of 1040 ± 350 mmHg. The maximum jaw temperature was 87 ± 4 °C and the mean lateral thermal spread was 0.8 ± 0.2 mm. In vivo, the sealing rate for arteries and veins was 92.6% (50/54) and the median seal and cut time was 1.6 s (range: 1.3-2.9). The average EDS performance score across all tasks was 4.4 ± 0.6 Likert points. For five shared tasks, EDS was better than EG2 (4.4 ± 0.5 versus 3.4 ± 0.6 Likert points; p = 0.016). CONCLUSIONS: EDS seals and cuts arteries and veins rapidly with good safety and user-friendliness.

Standardized procedure prevents perioperative and early complications in totally implantable venous-access ports-a complication analysis of more than 1000 TIVAP implantations.

PURPOSE: Since their invention 40 years ago, totally implantable venous-access ports (TIVAPs) have become indispensable in cancer treatment. The aim of our study was to analyze complications under standardized operative and perioperative procedures and to identify risk factors for premature port catheter explantation. METHODS: A total of 1008 consecutive TIVAP implantations were studied for success rate, perioperative, early, and late complications. Surgical, clinical, and demographic factors were analyzed as potential risk factors for emergency port catheter explantation. RESULTS: Successful surgical TIVAP implantation was achieved in 1005/1008 (99.7%) cases. No intraoperative or perioperative complications occurred. A total of 32 early complications and 88 late complications were observed leading to explantation in 11/32 (34.4%) and 34/88 (38.6%) cases, respectively. The most common complications were infections in 4.7% followed by thrombosis in 3.6%. Parameters that correlated with unplanned TIVAP explantation were gender (port in situ: female 95% vs. male 91%, p = 0.01), underlying disease (breast cancer 97% vs. gastrointestinal 89%, p = 0.004), indication (chemotherapy 95% vs. combination of chemotherapy and parenteral nutrition 64%, p < 0.0001), and type of complication (infection 13.4% vs. TIVAP-related complication 54% and thrombosis 95%, p < 0.0001). CONCLUSION: Standardized operative and perioperative TIVAP implantation procedures provide excellent results and low explantation rate.

Early biomarkers predicting outcome in a porcine model of acetaminophen intoxication: A pilot study.

BACKGROUND: Acetaminophen intoxication has become the leading cause of acute liver failure (ALF) in Europe and the USA. OBJECTIVES: To identify early biomarkers in order to predict the development of ALF in a porcine model of acetaminophen intoxication. MATERIAL AND METHODS: Six German Landrace pigs received a single acetaminophen bolus of 1 g/kg body weight via a jejunal catheter. Cytokines and laboratory parameters were analyzed at 8-hour intervals for a total of 40 h. RESULTS: Three of the 6 animals survived the intoxication. The nonsurviving animals had an increase in serum lactate and interleukin (IL)-6, with a simultaneous decrease in prothrombin time (PT) and albumin concentration 8 h after intoxication. In all nonsurviving animals, elevated levels of tumor necrosis factor alpha (TNF-α) at baseline before intoxication and during the course of ALF were observed. The acetaminophen serum concentrations and toxicokinetics did not differ between the nonsurviving and surviving animals. Methemoglobinemia was proportional to the administered doses and acetaminophen blood levels, but methemoglobinemia did not affect survival. CONCLUSIONS: Tumor necrosis factor alpha, IL-6, lactate, prothrombin time, and albumin blood concentration were identified as early predictors of outcome after acetaminophen intoxication. An elevated TNF-α level before acetaminophen exposure was the earliest prognostic marker for a lethal outcome. Therefore, it could serve as a very early indicator of prognosis.

Beware of gastric tube in esophagectomy after gastric radiotherapy: A case report.

BACKGROUND: Gastric tube formation and pull-up is the most common technique of reconstruction following esophagectomy for esophageal cancer. If previous treatment with radiotherapy for gastric mucosa-associated lymphoid tissue (MALT)-lymphoma restricts suitability of the stomach for anastomosis to the esophagus is unknown. CASE SUMMARY: A 57-year-old man underwent sequential chemotherapy and radiotherapy for gastric MALT-lymphoma seven years prior to diagnosis of esophageal adenocarcinoma. Esophagectomy without neoadjuvant treatment was recommended by the multidisciplinary tumor board due to early tumor stage [uT1 (sm2) uN+ cM0 according to TNM-classification of malignant tumors, 8th edition] without lymph node involvement. Minimal invasive esophageal resection with esophagogastrostomy was performed. Due to gastric tube necrosis with anastomotic leakage on the twelfth postoperative day, diverting resection with construction of a cervical salivary fistula was necessary. Rapid recovery facilitated colonic interposition without any complications six months afterwards. CONCLUSION: This case report may represent the start for further investigation to know if it is reasonable to refrain from esophagogastrostomy in patients with a long interval between gastric radiotherapy and surgery.

Association of clinical outcome assessments of mobility capacity and incident disability in community-dwelling older adults - a systematic review and meta-analysis.

The objective of the present review is to synthesize all available research on the association between mobility capacity and incident disability in non-disabled older adults. MEDLINE, EMBASE and CINAHL databases were searched without any limits or restrictions until February 2021. Published reports of longitudinal cohort studies that estimated a direct association between baseline mobility capacity, assessed with a standardized outcome assessment, and subsequent development of disability, including initially non-disabled older adults were included. The risk of bias was assessed using the Quality in Prognosis Studies (QUIPS) tool. Random-effect models were used to explore the objective. The certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. The main outcome measures were the pooled relative risks (RR) per one conventional unit per mobility assessment for incident disability. A total of 40 reports (85,515 participants at baseline) were included. For usual and fast gait speed, the RR per -0.1 m/s was 1.23 (95% CI: 1.18-1.28; 26,638 participants) and 1.28 (95% CI: 1.19-1.38; 8161 participants), respectively. Each point decrease in Short Physical Performance Battery score increased the risk of incident disability by 30% (RR = 1.30, 95% CI: 1.23-1.38; 9183 participants). The RR of incident disability by each second increase in Timed Up and Go test and Chair Rise Test performance was 1.15 (95% CI: 1.09-1.21; 30,426 participants) and 1.07 (95% CI: 1.04-1.10; 9450 participants), respectively. The review concludes that among community-dwelling non-disabled older adults, poor mobility capacity is a potent modifiable risk factor for incident disability. Mobility impairment should be mandated as a quality indicator of health for older people.

Missense variant c.1460 T > C (p.L487P) enhances protein degradation of ER mannosyltransferase ALG9 in two new ALG9-CDG patients presenting with West syndrome and review of the literature.

ALG9-CDG is a CDG-I defect within the group of Congenital Disorders of Glycosylation (CDG). We here describe the clinical symptoms of two new and unrelated ALG9-CDG patients, both carrying the novel homozygous missense variant c.1460 T > C (p.L487P) in the ALG9 gene which led to global developmental delay, psychomotor disability, facial dysmorphisms, brain and heart defects, hearing loss, hypotonia, as well as feeding problems. New clinical symptoms comprised West syndrome with hypsarrhythmia. Quantitative RT-PCR analysis revealed a significantly enhanced ALG9 mRNA transcript level, whereas the protein amount in fibroblasts was significantly reduced. This could be ascribed to a stronger degradation of the mutated ALG9 protein in patient fibroblasts. Lipid-linked oligosaccharide analysis showed an ALG9-CDG characteristic accumulation of Man6GlcNAc2-PP-dolichol and Man8GlcNAc2-PP-dolichol in patient cells. The clinical findings of our patients and of all previously published ALG9-CDG patients are brought together to further expand the knowledge about this rare N-glycosylation disorder. SYNOPSIS: Homozygosity for p.L487P in ALG9 causes protein degradation and leads to West syndrome.

Feasibility of smartphone-supported, combined physical and cognitive activities in the Neighbourhood for stimulating social participation of the elderly.

BACKGROUND: Combining smartphone-assisted group activities in the neighbourhood and training in physical and cognitive skills may offer the potential to promote social participation and connectedness of older adults. This non-controlled proof-of-concept, retrospectively registered study aimed to determine the feasibility of such an intervention approach, including its evaluation. METHODS: In two consecutive six-month intervention cycles, 39 community-dwelling adults were provided with weekly smartphone, physical and cognitive training by two tutors. Using a specifically designed app, the participants were also encouraged to join and later self-organise physically and cognitively stimulating activities related to hot spots in their Bochum neighbourhood. Indicators of feasibility were documented. RESULTS: The recruitment and assessments took 3 hours per participant. Excluding smartphone support, the preparation and the implementation of the intervention amounted to nine person-hours per week. Six participants dropped out, and 13 did not complete one or more assessments. The participants attended 76 ± 15% of the weekly training sessions. The instructors deemed the programme feasible, but familiarisation with the smartphone and the app was very time-consuming. Twenty-seven of 29 participants reported high overall satisfaction, and 22 agreed that the programme helped them to establish social contacts. The smartphones attracted substantial interest and were used frequently, despite mixed satisfaction with the project-specific app. From baseline to follow-up, the six-minute walking distance, lower extremity strength and moderate to vigorous physical activity, as well as quality of life, were preserved at a high level, while balance performance was significantly improved. Of the 11 tests related to cognitive functioning, 4 tests (a memory test, the Stroop test and 2 tests of verbal fluency) indicated significant improvement. No moderate or serious adverse events occurred in relation to the assessments or the intervention. CONCLUSIONS: The multimodal approach seems safe and feasible and offers the potential to promote social connectedness, bonds in the residential neighbourhood and smartphone competency, as well as to preserve or improve physical and cognitive functions. Adaptations of the intervention and of the outcome assessments may contribute to better assessment and exploitation of the potential of this approach in a future study involving socially, physically and cognitively less active elderly persons.

Retrospective analysis of different therapeutic approaches for retroperitoneal duodenal perforations.

Surgical therapy of duodenal perforation into the retroperitoneum entails high morbidity. Conservative treatment and endoscopic negative pressure therapy have been suggested as promising therapeutic alternatives. We aimed to retrospectively assess outcomes of patients treated for duodenal perforation to the retroperitoneum at our department. A retrospective analysis of all patients that were treated for duodenal perforation to the retroperitoneum at our institution between 2010 and 2021 was conducted. Different therapeutic approaches with associated complications within 30 days, length of in-hospital stay, number of readmissions and necessity of parenteral nutrition were assessed. We included thirteen patients in our final analysis. Six patients underwent surgery, five patients were treated conservatively and two patients received interventional treatment by endoscopic negative pressure therapy. Length of stay was shorter in patients treated conservatively. One patient following conservative and surgical treatment each was readmitted to hospital within 30 days after initial therapy whereas no readmissions after interventional treatment occurred. There was no failure of therapy in patients treated without surgery whereas four (66.7%) of six patients required revision surgery following primary surgical therapy. Conservative and interventional treatment were associated with fewer complications than surgical therapy which involves high morbidity. Conservative and interventional treatment using endoscopic negative pressure therapy in selected patients might constitute appropriate therapeutic alternatives for duodenal perforations to the retroperitoneum.