Formation of frameshift-stimulating RNA pseudoknots is facilitated by remodeling of their folding intermediates.

Programmed -1 ribosomal frameshifting is an essential regulation mechanism of translation in viruses and bacteria. It is stimulated by mRNA structures inside the coding region. As the structure is unfolded repeatedly by consecutive translating ribosomes, whether it can refold properly each time is important in performing its function. By using single-molecule approaches and molecular dynamics simulations, we found that a frameshift-stimulating RNA pseudoknot folds sequentially through its upstream stem S1 and downstream stem S2. In this pathway, S2 folds from the downstream side and tends to be trapped in intermediates. By masking the last few nucleotides to mimic their gradual emergence from translating ribosomes, S2 can be directed to fold from the upstream region. The results show that the intermediates are greatly suppressed, suggesting that mRNA refolding may be modulated by ribosomes. Moreover, masking the first few nucleotides of S1 favors the folding from S2 and yields native pseudoknots, which are stable enough to retrieve the masked nucleotides. We hypothesize that translating ribosomes can remodel an intermediate mRNA structure into a stable conformation, which may in turn stimulate backward slippage of the ribosome. This supports an interactive model of ribosomal frameshifting and gives an insightful account addressing previous experimental observations.

MPS I: Early diagnosis, bone disease and treatment, where are we now?

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder characterized by α-L-iduronidase deficiency. Patients present with a broad spectrum of disease severity ranging from the most severe phenotype (Hurler) with devastating neurocognitive decline, bone disease and early death to intermediate (Hurler-Scheie) and more attenuated (Scheie) phenotypes, with a normal life expectancy. The most severely affected patients are preferably treated with hematopoietic stem cell transplantation, which halts the neurocognitive decline. Patients with more attenuated phenotypes are treated with enzyme replacement therapy. There are several challenges to be met in the treatment of MPS I patients. First, to optimize outcome, early recognition of the disease and clinical phenotype is needed to guide decisions on therapeutic strategies. Second, there is thus far no effective treatment available for MPS I bone disease. The pathophysiological mechanisms behind bone disease are largely unknown, limiting the development of effective therapeutic strategies. This article is a state of the art that comprehensively discusses three of the most urgent open issues in MPS I: early diagnosis of MPS I patients, pathophysiology of MPS I bone disease, and emerging therapeutic strategies for MPS I bone disease.

The Reporting on ERAS Compliance, Outcomes, and Elements Research (RECOvER) Checklist: A Joint Statement by the ERAS® and ERAS® USA Societies.

BACKGROUND: Enhanced recovery after surgery (ERAS) programs are multimodal care pathways designed to minimize the physiological and psychological impact of surgery for patients. Increased compliance with ERAS guidelines is associated with improved patient outcomes across surgical types. As ERAS programs have proliferated, an unintentional effect has been significant variation in how ERAS-related studies are reported in the literature. METHODS: To improve the quality of ERAS reporting, ERAS® USA and the ERAS® Society launched an effort to create an instrument to assist authors in manuscript preparation. Criteria to include were selected by a combination of literature review and expert opinion. The final checklist was refined by group consensus. RESULTS: The Societies present the Reporting on ERAS Compliance, Outcomes, and Elements Research (RECOvER) Checklist. The tool contains 20 items including best practices for reporting clinical pathways, compliance auditing, and formatting guidelines. CONCLUSIONS: The RECOvER Checklist is intended to provide a standardized framework for the reporting of ERAS-related studies. The checklist can also assist reviewers in evaluating the quality of ERAS-related manuscripts. Authors are encouraged to include the RECOvER Checklist when submitting ERAS-related studies to peer-reviewed journals.

A clinical and neurophysiological motor signature of Unverricht-Lundborg disease.

OBJECTIVES: Unverricht-Lundborg disease (ULD) is the most common form of progressive myoclonus epilepsy. Cerebellar dysfunction may appear over time, contributing along with myoclonus to motor disability. The purpose of the present work was to clarify the motor and neurophysiological characteristics of ULD patients. METHODS: Nine patients with genetically proven ULD were evaluated clinically (medical history collected from patient charts, the Scale for the Assessment and Rating of Ataxia and Unified Myoclonus Rating Scale). Neurophysiological investigations included EEG, surface polymyography, long-loop C-reflexes, somatosensory evoked potentials, EEG jerk-locked back-averaging (JLBA) and oculomotor recordings. All patients underwent brain MRI. Non-parametric Mann-Whitney tests were used to compare ULD patients' oculomotor parameters with those of a matched group of healthy volunteers (HV). RESULTS: Myoclonus was activated by action but was virtually absent at rest and poorly induced by stimuli. Positive myoclonus was multifocal, often rhythmic and of brief duration, with top-down pyramidal temporospatial propagation. Cortical neurophysiology revealed a transient wave preceding myoclonus on EEG JLBA (n=8), enlarged somatosensory evoked potentials (n=7) and positive long-loop C-reflexes at rest (n=5). Compared with HV, ULD patients demonstrated decreased saccadic gain, increased gain dispersion and a higher frequency of hypermetric saccades associated with decreased peak velocity. CONCLUSION: A homogeneous motor pattern was delineated that may represent a ULD clinical and neurophysiological signature. Clinical and neurophysiological findings confirmed the pure cortical origin of the permanent myoclonus. Also, oculomotor findings shed new light on ULD pathophysiology by evidencing combined midbrain and cerebellar dysfunction.

Primary skeletal muscle myoblasts from chronic heart failure patients exhibit loss of anti-inflammatory and proliferative activity.

BACKGROUND: Peripheral skeletal muscle wasting is a common finding with adverse effects in chronic heart failure (HF). Whereas its clinical relevance is beyond doubt, the underlying pathophysiological mechanisms are not yet fully elucidated. We aimed to introduce and characterize the primary culture of skeletal muscle cells from individual HF patients as a supportive model to study this muscle loss. METHODS AND RESULTS: Primary myoblast and myotubes cultures were successfully propagated from the m. vastus lateralis of 6 HF patients with reduced ejection fraction (HFrEF; LVEF <45 %) and 6 age and gender-matched healthy donors. HFrEF cultures were not different from healthy donors in terms of morphology, such as myoblast size, shape and actin microfilament. Differentiation and fusion indexes were identical between groups. Myoblast proliferation in logarithmic growth phase, however, was attenuated in the HFrEF group (p = 0.032). In addition, HFrEF myoblasts are characterized by a reduced TNFR2 expression and IL-6 secretion (p = 0.017 and p = 0.016; respectively). CONCLUSION: Biopsy derived primary skeletal muscle myoblasts of HFrEF patients produce similar morphological and myogenic differentiation responses as myoblasts of healthy donors, though demonstrate loss of anti-inflammatory and proliferative activity.

Antihistamines for the common cold.

BACKGROUND: The common cold is an upper respiratory tract infection, most commonly caused by a rhinovirus. It affects people of all age groups and although in most cases it is self limiting, the common cold still causes significant morbidity. Antihistamines are commonly offered over the counter to relieve symptoms for patients affected by the common cold, however there is not much evidence of their efficacy. OBJECTIVES: To assess the effects of antihistamines on the common cold. SEARCH METHODS: We searched CENTRAL (2015, Issue 6), MEDLINE (1948 to July week 4, 2015), EMBASE (2010 to August 2015), CINAHL (1981 to August 2015), LILACS (1982 to August 2015) and Biosis Previews (1985 to August 2015). SELECTION CRITERIA: We selected randomised controlled trials (RCTs) using antihistamines as monotherapy for the common cold. We excluded any studies with combination therapy or using antihistamines in patients with an allergic component in their illness. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We collected adverse effects information from the included trials. MAIN RESULTS: We included 18 RCTs, which were reported in 17 publications (one publication reports on two trials) with 4342 participants (of which 212 were children) suffering from the common cold, both naturally occurring and experimentally induced. The interventions consisted of an antihistamine as monotherapy compared with placebo. In adults there was a short-term beneficial effect of antihistamines on severity of overall symptoms: on day one or two of treatment 45% had a beneficial effect with antihistamines versus 38% with placebo (odds ratio (OR) 0.74, 95% confidence interval (CI) 0.60 to 0.92). However, there was no difference between antihistamines and placebo in the mid term (three to four days) to long term (six to 10 days). When evaluating individual symptoms such as nasal congestion, rhinorrhoea and sneezing, there was some beneficial effect of the sedating antihistamines compared to placebo (e.g. rhinorrhoea on day three: mean difference (MD) -0.23, 95% CI -0.39 to -0.06 on a four- or five-point severity scale; sneezing on day three: MD -0.35, 95% CI -0.49 to -0.20 on a four-point severity scale), but this effect is clinically non-significant. Adverse events such as sedation were more commonly reported with sedating antihistamines although the differences were not statistically significant. Only two trials included children and the results were conflicting. The majority of the trials had a low risk of bias although some lacked sufficient trial quality information. AUTHORS' CONCLUSIONS: Antihistamines have a limited short-term (days one and two of treatment) beneficial effect on severity of overall symptoms but not in the mid to long term. There is no clinically significant effect on nasal obstruction, rhinorrhoea or sneezing. Although side effects are more common with sedating antihistamines, the difference is not statistically significant. There is no evidence of effectiveness of antihistamines in children.

A complex V ATP5A1 defect causes fatal neonatal mitochondrial encephalopathy.

Whole exome sequencing is a powerful tool to detect novel pathogenic mutations in patients with suspected mitochondrial disease. However, the interpretation of novel genetic variants is not always straightforward. Here, we present two siblings with a severe neonatal encephalopathy caused by complex V deficiency. The aim of this study was to uncover the underlying genetic defect using the combination of enzymatic testing and whole exome sequence analysis, and to provide evidence for causality by functional follow-up. Measurement of the oxygen consumption rate and enzyme analysis in fibroblasts were performed. Immunoblotting techniques were applied to study complex V assembly. The coding regions of the genome were analysed. Three-dimensional modelling was applied. Exome sequencing of the two siblings with complex V deficiency revealed a heterozygous mutation in the ATP5A1 gene, coding for complex V subunit α. The father carried the variant heterozygously. At the messenger RNA level, only the mutated allele was expressed in the patients, whereas the father expressed both the wild-type and the mutant allele. Gene expression data indicate that the maternal allele is not expressed, which is supported by the observation that the ATP5A1 expression levels in the patients and their mother are reduced to ∼50%. Complementation with wild-type ATP5A1 restored complex V in the patient fibroblasts, confirming pathogenicity of the defect. At the protein level, the mutation results in a disturbed interaction of the α-subunit with the ß-subunit of complex V, which interferes with the stability of the complex. This study demonstrates the important value of functional studies in the diagnostic work-up of mitochondrial patients, in order to guide genetic variant prioritization, and to validate gene defects.

Natural history of three late-diagnosed classic Galactosemia patients.

The authors report the natural history of three patients with late-diagnosed Classic Galactosemia (CG) (at 16, 19 and 28 years). This was due to a combination of factors: absence of neonatal screening, absence of some typical acute neonatal symptoms, and negative galactosemia screening. This report underlines the value of neonatal screening and the importance of further diagnostic testing in case of late-onset manifestations.

Different antibiotic treatments for group A streptococcal pharyngitis.

BACKGROUND: Antibiotics provide only modest benefit in treating sore throat, although effectiveness increases in participants with positive throat swabs for group A beta-haemolytic streptococci (GABHS). It is unclear which antibiotic is the best choice if antibiotics are indicated. OBJECTIVES: To assess the evidence on the comparative efficacy of different antibiotics in: (a) alleviating symptoms (pain, fever); (b) shortening the duration of the illness; (c) preventing relapse; and (d) preventing complications (suppurative complications, acute rheumatic fever, post-streptococcal glomerulonephritis). To assess the evidence on the comparative incidence of adverse effects and the risk-benefit of antibiotic treatment for streptococcal pharyngitis. SEARCH METHODS: We searched CENTRAL 2012, Issue 10, MEDLINE (1966 to October week 2, 2012), EMBASE (1974 to October 2012) and Web of Science (2010 to October 2012). SELECTION CRITERIA: Randomised, double-blind trials comparing different antibiotics and reporting at least one of the following: clinical cure, clinical relapse, complications, adverse events. DATA COLLECTION AND ANALYSIS: Two authors independently screened trials for inclusion and extracted data. MAIN RESULTS: Seventeen trials (5352 participants) were included; 16 compared with penicillin (six with cephalosporins, six with macrolides, three with carbacephem and one with sulfonamides), one trial compared clindamycin and ampicillin. Randomisation reporting, allocation concealment and blinding were poor.There was no difference in symptom resolution between cephalosporins and penicillin (intention-to-treat (ITT) analysis; N = 5; n = 2018; odds ratio for absence of resolution of symptoms (OR) 0.79, 95% confidence interval (CI) 0.55 to 1.12). Clinical relapse was lower with cephalosporins (N = 4; n = 1386; OR 0.55, 95% CI 0.31 to 0.99; overall number needed to treat to benefit (NNTB) 50), but found only in adults (OR 0.42, 95% CI 0.20 to 0.88; NNTB 33). There were no differences between macrolides and penicillin. Carbacephem showed better symptom resolution post-treatment (N = 3; n = 795; OR 0.70, 95% CI 0.49 to 0.99; NNTB 14), but only in children (N = 2; n = 233; OR 0.57, 95% CI 0.33 to 0.99; NNTB 8.3). Children experienced more adverse events with macrolides (N = 1, n = 489; OR 2.33; 95% CI 1.06 to 5.15). AUTHORS' CONCLUSIONS: Evidence is insufficient to show clinically meaningful differences between antibiotics for GABHS tonsillopharyngitis. Limited evidence in adults suggests cephalosporins are more effective than penicillin for relapse, but the NNTB is high. Limited evidence in children suggests carbacephem is more effective for symptom resolution. Data on complications are too scarce to draw conclusions. Based on these results and considering the low cost and absence of resistance, penicillin can still be recommended as first choice.

Withdrawal versus continuation of chronic antipsychotic drugs for behavioural and psychological symptoms in older people with dementia.

BACKGROUND: Antipsychotic agents are often used to treat neuropsychiatric symptoms (NPS) in dementia, although the literature is sceptical about their long-term use for this indication. Their effectiveness is limited and there is concern about adverse effects, including higher mortality with long-term use. When behavioural strategies have failed and drug therapy is instituted, regular attempts to withdraw these drugs are recommended. Physicians, nurses and families of older people with dementia are often reluctant to try to stop antipsychotics, fearing deterioration of NPS. Strategies to reduce antipsychotic use have been proposed, but a systematic review of interventions aimed at withdrawal of antipsychotic agents in older people with dementia has not yet been performed. OBJECTIVES: To evaluate whether withdrawal of antipsychotic agents is successful in older people with dementia in community or nursing home settings, to list the different strategies for withdrawal of antipsychotic agents in older people with dementia and NPS, and to measure the effects of withdrawal of antipsychotic agents on behaviour. SEARCH METHODS: ALOIS, the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS, clinical trials registries and grey literature sources were searched on 23 November 2012. The search included the following terms: antipsychotic* or neuroleptic* or phenothiazines or butyrophenones or risperidone or olanzapine or haloperidol or prothipendyl or methotrimeprazine or clopenthixol or flupenthixol or clothiapine or metylperon or droperidol or pipamperone or benperidol or bromperidol or fluspirilene or pimozide or penfluridol or sulpiride or veralipride or levosulpiride or sultopride or aripiprazole or clozapine or quetiapine or thioridazine combined wither terms such as discontinu* or withdraw* or cessat* or reduce* or reducing or reduct* or taper* or stop*.ALOIS contains records from all major healthcare databases (The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS), as well as from many clinical trials registries and grey literature sources. SELECTION CRITERIA: Randomised, placebo-controlled trials comparing an antipsychotic withdrawal strategy to continuation of antipsychotics in people with dementia. DATA COLLECTION AND ANALYSIS: Review authors independently assessed trials for inclusion, rated their risk of bias and extracted data. MAIN RESULTS: We included nine trials with 606 randomised participants. Seven trials were conducted in nursing homes, one trial in an outpatient setting and one in both settings. In these trials, different types of antipsychotics prescribed at different doses were withdrawn. Both abrupt and gradual withdrawal schedules were used. The risk of bias of the included studies was generally low regarding blinding and outcome reporting and unclear for randomisation procedures and recruitment of participants.There was a wide variety of outcome measures. Our primary efficacy outcomes were success of withdrawal (i.e. remaining in study off antipsychotics) and NPS. Eight of nine trials reported no overall significant difference between groups on the primary outcomes, although in one pilot study of people with psychosis and agitation that had responded to haloperidol, time to relapse was significantly shorter in the discontinuation group (Chi(2) = 4.1, P value = 0.04). The ninth trial included people with psychosis or agitation who had responded well to risperidone therapy for four to eight months and reported that discontinuation led to an increased risk of relapse, that is, increase in the Neuropsychiatric Inventory (NPI)-core score of 30% or greater (P value = 0.004, hazard ratio (HR) 1.94, 95% confidence interval (CI) 1.09 to 3.45 at four months). The only outcome that could be pooled was the full NPI-score, used in two studies. For this outcome there was no significant difference between people withdrawn from and those continuing on antipsychotics at three months (mean difference (MD) -1.49, 95% CI -5.39 to 2.40). These two studies reported subgroup analyses according to baseline NPI-score (14 or less versus > 14). In one study, those with milder symptoms at baseline were significantly less agitated at three months in the discontinuation group (NPI-agitation, Mann-Whitney U test z = 2.4, P value = 0.018). In both studies, there was evidence of significant behavioural deterioration in people with more severe baseline NPS who were withdrawn from antipsychotics (Chi(2) = 6.8; P value = 0.009 for the marked symptom score in one study).Individual studies did not report significant differences between groups on any other outcome except one trial that found a significant difference in a measure of verbal fluency, favouring discontinuation. Most trials lacked power to detect clinically important differences between groups.Adverse events were not systematically assessed. In one trial there was a non-significant increase in mortality in people who continued antipsychotic treatment (5% to 8% greater than placebo, depending on the population analysed, measured at 12 months). This trend became significant three years after randomisation, but due to dropout and uncertainty about the use of antipsychotics in this follow-up period this result should be interpreted with caution. AUTHORS' CONCLUSIONS: Our findings suggest that many older people with Alzheimer's dementia and NPS can be withdrawn from chronic antipsychotic medication without detrimental effects on their behaviour. It remains uncertain whether withdrawal is beneficial for cognition or psychomotor status, but the results of this review suggest that discontinuation programmes could be incorporated into routine practice. However, two studies of people whose agitation or psychosis had previously responded well to antipsychotic treatment found an increased risk of relapse or shorter time to relapse after discontinuation. Two other studies suggest that people with more severe NPS at baseline could benefit from continuing their antipsychotic medication. In these people, withdrawal might not be recommended.

Cellular localization of the Huntington's disease protein and discrimination of the normal and mutated form.

Huntington's disease (HD) results from the expansion of a polyglutamine encoding CAG repeat in a gene of unknown function. The wide expression of this transcript does not correlate with the pattern of neuropathology in HD. To study the HD gene product (huntingtin), we have developed monoclonal antibodies raised against four different regions of the protein. On western blots, these monoclonals detect the approximately 350 kD huntingtin protein in various human cell lines and in neural and non-neural rodent tissues. In cell lines from HD patients, a doublet protein is detected corresponding to the mutated and normal huntingtin. Immunohistochemical studies in the human brain using two of these antibodies detects the huntingtin in perikarya of some neurons, neuropiles, varicosities and as punctate staining likely to be nerve endings.

First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene.

Major advances in the identification of genes implicated in idiopathic epilepsy have been made. Generalized epilepsy with febrile seizures plus (GEFS+), benign familial neonatal convulsions and nocturnal frontal lobe epilepsy, three autosomal dominant idiopathic epilepsies, result from mutations affecting voltage-gated sodium and potassium channels, and nicotinic acetylcholine receptors, respectively. Disruption of GABAergic neurotransmission mediated by gamma-aminobutyric acid (GABA) has been implicated in epilepsy for many decades. We now report a K289M mutation in the GABA(A) receptor gamma2-subunit gene (GABRG2) that segregates in a family with a phenotype closely related to GEFS+ (ref. 8), an autosomal dominant disorder associating febrile seizures and generalized epilepsy previously linked to mutations in sodium channel genes. The K289M mutation affects a highly conserved residue located in the extracellular loop between transmembrane segments M2 and M3. Analysis of the mutated and wild-type alleles in Xenopus laevis oocytes confirmed the predicted effect of the mutation, a decrease in the amplitude of GABA-activated currents. We thus provide the first genetic evidence that a GABA(A) receptor is directly involved in human idiopathic epilepsy.

Effects of Music Therapy on Spiritual Well-Being among Patients with Advanced Cancer in Palliative Care: A Meta-Analysis of Randomized Controlled Trials.

PURPOSE: Patients with advanced cancer in palliative care often experience physical and psychological symptoms that negatively impact their quality of life (QoL) and spiritual well-being. Music therapy can be used for symptom management in these patients. However, the effectiveness is uncertain. To determine the effectiveness of music therapy on spiritual well-being, QoL, pain, and psychological distress using randomized controlled trials (RCTs). DATA SOURCE: A systematic search was conducted in EMBASE, PubMed, Cochrane Library, CINAHL, Web of Science, and the ClinicalTrial.gov registry up to September 2022. CONCLUSION: The meta-analysis included seven RCTs with a total of 747 advanced cancer patients. Music therapy was found to significantly improve spiritual well-being with a mean difference of 0.43 (95% CI: 0.25 to 0.61, P < .001) in the intervention group compared to the control group. However, no significant group differences were found between the intervention and control groups for QoL (SMD: 0.53, 95% CI: -0.12 to 1.13, P = .11), pain (MD: -0.81, 95% CI: -2.06 to 0.44, P = .20), and psychological distress (SMD: -0.05, 95% CI: -0.41 to 0.32, P = .81). Music therapy can effectively improve the spiritual well-being of palliative care patients. However, its beneficial effects on QoL, pain, and psychological distress were minimal. IMPLICATIONS FOR NURSING PRACTICE: Music therapy interventions can be introduced to help patients deal with spiritual/existential needs. Future studies should identify optimal characteristics of music therapy interventions to aid in enhancing the quality of palliative care for patients with advanced cancer.

Effects of Walking Combined With Resistance Band Exercises on Alleviating Cancer-Related Fatigue: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Cancer-related fatigue (CRF) is a common symptom, and exercise has shown potential in alleviating CRF. However, there is a need for diverse exercise options tailored to individual patient needs. OBJECTIVE: To evaluate the overall effects of a combined walking and resistance band exercise intervention in relieving CRF among cancer patients through randomized controlled trials. METHODS: Comprehensive searches were conducted in multiple databases to identify relevant studies up until March 2023. Inclusion criteria required the intervention to involve walking combined with elastic band training, with a clear exercise protocol description. The primary outcome was CRF, and secondary outcomes included walking steps, distance, mood distress, and quality of life. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated using random-effects models. RESULTS: Ten trials were included. The intervention group showed significant improvements in CRF (SMD, -0.40; 95% CI, -0.60 to -0.20), mood distress (SMD, -0.30; 95% CI, -0.53 to -0.07), and daily walking steps (SMD, 0.52; 95% CI, 0.07-0.96) compared with the control group. Although the 6-Minute Walk Test and quality of life did not show significant differences, a trend toward improvement was observed in the intervention group. Adverse events related to the intervention were infrequent. CONCLUSION: A combined walking and resistance band exercise intervention can effectively alleviate CRF and improve mood distress and daily walking steps among cancer patients. IMPLICATIONS FOR PRACTICE: This exercise option may provide an additional strategy to manage CRF. Further research is needed to explore the optimal exercise prescription for individual patients.

Metachromatic leukodystrophy: To screen or not to screen?

Metachromatic leukodystrophy (MLD) is a neurodegenerative lysosomal storage disorder caused by biallelic pathogenic variants in the gene encoding arylsulfatase A. Disease onset is variable (with late infantile, early and late juvenile, and adult forms) and treatment options depend on age and disease symptoms at onset. In the past, allo-hematopoietic stem cell transplantation (allo-HSCT) has been the best treatment option, following strict selection criteria. The outcome however is variable and morbidity remains high. This paved the way to the development of new treatment options, some of them aiming to be curative. In the light of this changing therapeutic field, newborn screening is becoming a valuable option. This narrative review aims to describe the outcome of allo-HSCT in the different MLD disease forms, and, in addition, reviews new treatment options. Finally, the shift of the field towards newborn screening for MLD is discussed.

Prognosis and prediction of antibiotic benefit in adults with clinically diagnosed acute rhinosinusitis: an individual participant data meta-analysis.

BACKGROUND: A previous individual participant data meta-analysis (IPD-MA) of antibiotics for adults with clinically diagnosed acute rhinosinusitis (ARS) showed a marginal overall effect of antibiotics, but was unable to identify patients that are most likely to benefit from antibiotics when applying conventional (i.e. univariable or one-variable-at-a-time) subgroup analysis. We updated the systematic review and investigated whether multivariable prediction of patient-level prognosis and antibiotic treatment effect may lead to more tailored treatment assignment in adults presenting to primary care with ARS. METHODS: An IPD-MA of nine double-blind placebo-controlled trials of antibiotic treatment (n=2539) was conducted, with the probability of being cured at 8-15 days as the primary outcome. A logistic mixed effects model was developed to predict the probability of being cured based on demographic characteristics, signs and symptoms, and antibiotic treatment assignment. Predictive performance was quantified based on internal-external cross-validation in terms of calibration and discrimination performance, overall model fit, and the accuracy of individual predictions. RESULTS: Results indicate that the prognosis with respect to risk of cure could not be reliably predicted (c-statistic 0.58 and Brier score 0.24). Similarly, patient-level treatment effect predictions did not reliably distinguish between those that did and did not benefit from antibiotics (c-for-benefit 0.50). CONCLUSIONS: In conclusion, multivariable prediction based on patient demographics and common signs and symptoms did not reliably predict the patient-level probability of cure and antibiotic effect in this IPD-MA. Therefore, these characteristics cannot be expected to reliably distinguish those that do and do not benefit from antibiotics in adults presenting to primary care with ARS.

Mitochondrial ATP synthase: architecture, function and pathology.

Human mitochondrial (mt) ATP synthase, or complex V consists of two functional domains: F(1), situated in the mitochondrial matrix, and F(o), located in the inner mitochondrial membrane. Complex V uses the energy created by the proton electrochemical gradient to phosphorylate ADP to ATP. This review covers the architecture, function and assembly of complex V. The role of complex V di-and oligomerization and its relation with mitochondrial morphology is discussed. Finally, pathology related to complex V deficiency and current therapeutic strategies are highlighted. Despite the huge progress in this research field over the past decades, questions remain to be answered regarding the structure of subunits, the function of the rotary nanomotor at a molecular level, and the human complex V assembly process. The elucidation of more nuclear genetic defects will guide physio(patho)logical studies, paving the way for future therapeutic interventions.

Oral antihistamine-decongestant-analgesic combinations for the common cold.

BACKGROUND: Although combination formulas containing antihistamines, decongestants and/or analgesics are sold over-the-counter (OTC) in large quantities for the common cold, the evidence of effectiveness is limited. OBJECTIVES: To assess the effectiveness of antihistamine-decongestant-analgesic combinations in reducing the duration and alleviating the symptoms of the common cold in adults and children. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 4), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, OLDMEDLINE (1953 to 1965), MEDLINE (1966 to November Week 3, 2011) and EMBASE (1990 to December 2011). SELECTION CRITERIA: Randomised controlled trials (RCTs) investigating the effectiveness of antihistamine-decongestant-analgesic combinations compared with placebo, other active treatment (excluding antibiotics) or no treatment in children and adults with the common cold. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted and summarised data on general recovery, nasal obstruction, rhinorrhoea, sneezing, cough and side effects. We categorised the trials according to the active ingredients. MAIN RESULTS: We included 27 trials (5117 participants) of common cold treatments. Fourteen trials studied antihistamine-decongestant combinations; two antihistamine-analgesic; six analgesic-decongestant; and five antihistamine-analgesic-decongestant combinations. In 21 trials the control intervention was placebo and in six trials an active substance. Reporting of methods in most trials was poor and there were large differences in design, participants, interventions and outcomes. Pooling was only possible for a limited number of studies and outcomes.Antihistamine-decongestant: 12 trials. Eight trials report on global effectiveness, six could be pooled; n = 309 on active treatment, n = 312 placebo) the odds ratio (OR) of treatment failure was 0.27 (95% confidence interval (CI) 0.15 to 0.50); the number needed to treat for an additional beneficial outcome (NNTB) was four (95% CI 3 to 5.6). On the final evaluation day 41% of participants in the placebo group had a favourable response compared to 66% on active treatment. Of the two trials that were not included in the pooling, one showed some global effect, the other showed no effect.Antihistamine-analgesic: three trials. Two reported on global effectiveness, data from one study was presented. (n = 290 on active treatment, n = 292 ascorbic acid). The OR of treatment failure was 0.33 (95% CI 0.23 to 0.46) and the NNTB was 6.67 (95% CI 4.76 to 12.5). After six days of treatment 43% were cured in the control group and 70% in the active treatment group. The second study also showed an effect in favour of active treatment.Analgesic-decongestant: six trials. One trial reported on global effectiveness: 73% benefited compared with 52% in the control group (paracetamol) (OR 0.28, 95% CI 0.15 to 0.52).Antihistamine-analgesic-decongestant: Five trials. Four trials reported on global effectiveness, two could be pooled: global effect reported (less than one severity point on a four or five-point scale) with active treatment (52%) and placebo (34%); the OR of treatment failure was 0.47 (95% CI 0.33 to 0.67) and the NNTB was 5.6 (95% CI 3.8 to 10.2). Two other trials found no beneficial effect. Two other studies did not show any effect.Two studies with antihistamine-decongestant (113 children) could not be pooled. There was no significant effect of the active treatment.Adverse effects: the combination of antihistamine-decongestant had more adverse effects than the control intervention but the difference was not significant: 157/810 (19%) versus 60/477 (13%) participants suffered one or more adverse effects (OR 1.58, 95% CI 0.78 to 3.21). Analgesic-decongestant combinations had significantly more adverse effects than control (OR 1.71, 95% CI 1.23 to 2.37); the number needed to treat for an additional harmful outcome (NNTH) was 14. None of the other two combinations caused significantly more adverse effects. Antihistamine-analgesic: 11/90 with combination suffered one or more adverse effects (12%) versus 9/91 (10%) with control (OR 1.27, 95% CI 0.50 to 3.23). Antihistamine-analgesic-decongestant: in one study 5/224 (2%) suffered adverse effects with active treatment versus 9/208 (4%) with placebo. Two other trials reported no differences between treatment groups but numbers were not reported. AUTHORS' CONCLUSIONS: Current evidence suggests that antihistamine-analgesic-decongestant combinations have some general benefit in adults and older children. These benefits must be weighed against the risk of adverse effects. There is no evidence of effectiveness in young children.

Antibiotics for clinically diagnosed acute rhinosinusitis in adults.

BACKGROUND: In primary care settings, the diagnosis of rhinosinusitis is generally based on clinical signs and symptoms. Technical investigations are not routinely performed, nor recommended. Individual trials show a trend in favour of antibiotics, but the balance of benefit versus harm is unclear. OBJECTIVES: To assess the effect of antibiotics in adults with clinically diagnosed rhinosinusitis in primary care settings. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2012), MEDLINE (January 1950 to February week 4, 2012) and EMBASE (January 1974 to February 2012). SELECTION CRITERIA: Randomised controlled trials (RCTs) of antibiotics versus placebo in participants with rhinosinusitis-like signs or symptoms. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed the risk of bias. We contacted trial authors for additional information. We collected information on adverse effects from the trials. MAIN RESULTS: We included 10 trials involving 2450 participants. Overall, the risk of bias in these studies was low. Irrespective of the treatment group, 47% of participants were cured after one week and 71% after 14 days. Antibiotics can shorten the time to cure, but only five more participants per 100 will cure faster at any time point between 7 and 14 days if they receive antibiotics instead of placebo (number needed to treat to benefit (NNTB)) 18 (95% confidence interval (CI) 10 to 115, I(2) statistic 0%, eight trials). Purulent secretion resolves faster with antibiotics (odds ratio (OR) 1.58 (95% CI 1.13 to 2.22)), (NNTB 11, 95% CI 6 to 51, I(2) statistic 0%, three trials). However, 27% of the participants who received antibiotics and 15% of those who received placebo experienced adverse events (OR 2.10, 95% CI 1.60 to 2.77) (number needed to treat to harm (NNTH)) 8 (95% CI 6 to 13, I(2) statistic 13%, seven trials). More participants in the placebo group needed to start antibiotic therapy because of an abnormal course of rhinosinusitis (OR 0.49, 95% CI 0.36 to 0.66), NNTH 20 (95% CI 14 to 35, I(2) statistic 0%, eight trials). Only one disease-related complication (brain abscess) occurred in a patient treated with antibiotics. AUTHORS' CONCLUSIONS: The potential benefit of antibiotics in the treatment of clinically diagnosed acute rhinosinusitis needs to be seen in the context of a high prevalence of adverse events. Taking into account antibiotic resistance and the very low incidence of serious complications, we conclude that there is no place for antibiotics for the patient with clinically diagnosed, uncomplicated acute rhinosinusitis. This review cannot make recommendations for children, patients with a suppressed immune system and patients with severe disease, as these populations were not included in the available trials.

General practitioners' perspectives on discontinuation of long-term antidepressants in nursing homes.

BACKGROUND: Long-term use of antidepressant drugs (AD), much longer than recommended by guidelines, in nursing homes (NH) is common. NH home residents may have a relatively higher risk of adverse events. Moreover, in an NH setting nursing staff and relatives are intensively involved in the decision-making process. In many countries, General Practitioners' (GPs) provide care for residents in NHs. Little is known about GPs' perspectives on discontinuation of long-term AD in NH residents. OBJECTIVES: To explore GPs' views of discontinuing long-term AD in NH residents. METHODS: An exploratory qualitative study, with semi-structured interviews, was conducted with a purposive sample of 20 Belgian GPs. Interviews, conducted over six months in 2019, were analysed by thematic analysis. RESULTS: Twenty interviews were conducted until data saturation. The first theme, 'reluctance to rock the boat: not worth taking the risk', describes that GPs perceive discontinuation as an unpredictable risk without clear benefits. GPs' main concern was the risk of destabilising the fragile balance in an older patient. Second, 'it takes at least three to tango', captures the unspoken alliance between GPs, nursing staff and relatives and suggests that agreement of at least these three partners is required. The third, 'Opening the door: triggers to discontinue', points to severe health problems and dementia as strong facilitators for discontinuation. CONCLUSION: Discontinuation of long-term AD in NHs is a complex process for GPs. More evidence and attention to the role nursing staff and relatives play are needed to better guide the discontinuation of AD in older NH patients.