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Coffee consumption is associated with reduced risk of conditions that share low-grade inflammation as their physiopathological basis. We therefore summarized the effects of coffee or coffee components on serum levels of inflammatory markers. Clinical trials assessing the effect of coffee, caffeine or other coffee components on inflammatory markers were searched without restriction to publication date. Fifteen studies (8 involving coffee and 7 caffeine) were included. Increased adiponectin levels were found in four of seven trials comparing filtered coffee/caffeinated coffee with placebo or comparing its levels at baseline and after consumption of medium or dark roasted coffee, but no change was seen in caffeine trials. None of the five studies assessing the effects of coffee found changes in C-reactive protein (CPR), but one out of three trials found decreased CPR levels in response to caffeine. Interleukin (IL)-6 was increased by caffeinated coffee compared with placebo in one of four coffee trials, and by caffeine in three out of five studies. Caffeine increased IL-10 levels in two of three trials. These data suggest a predominant anti-inflammatory action of coffee but not of caffeine consumption. Moreover, the proinflammatory and anti-inflammatory responses to caffeine point to its complex effects on the inflammatory response. [ABSTRACT FROM AUTHOR]

Objective: We investigated interferon-stimulated gene 15 (ISG15), a poorly understood ubiquitin-like modifier, and its enzymatic pathway in dermatomyositis (DM), an autoimmune disease primarily involving muscle and skin.Methods: We generated microarray data measuring transcript abundance for approximately 18,000 genes in each of 113 human muscle biopsy specimens, and studied biopsy specimens and cultured skeletal muscle using immunohistochemistry, immunoblotting proteomics, real-time quantitative polymerase chain reaction, and laser-capture microdissection.Results: Transcripts encoding ISG15-conjugation pathway proteins were markedly upregulated in DM with perifascicular atrophy (DM-PFA) muscle (ISG15 339-fold, HERC5 62-fold, and USP18 68-fold) compared with 99 non-DM samples. Combined analysis with publicly available microarray datasets showed that >50-fold ISG15 transcript elevation had 100% sensitivity and specificity for 28 biopsies from adult DM-PFA and juvenile DM patients compared with 199 muscle samples from other muscle diseases. Free ISG15 and ISG15-conjugated proteins were only found on immunoblots from DM-PFA muscle. Cultured human skeletal muscle exposed to type 1 interferons produced similar transcripts and ISG15 protein and conjugates. Laser-capture microdissection followed by proteomic analysis showed deficiency of titin in DM perifascicular atrophic myofibers.Interpretation: A large-scale microarray study of muscle samples demonstrated that among a diverse group of muscle diseases DM was uniquely associated with upregulation of the ISG15 conjugation pathway. Exposure of human skeletal muscle cell culture to type 1 interferons produced a molecular picture highly similar to that seen in human DM muscle. Perifascicular atrophic myofibers in DM were deficient in a number of skeletal muscle proteins including titin. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) is a plasticizer used to synthesize polycarbonate plastics and epoxy resins and is well-known for its endocrine-disrupting action. BPA occurrence in the environment is widespread, and there is a growing concern regarding exposure to this chemical during childhood, given the findings indicating the long-lasting hazards associated with exposure during early life compared to adulthood. We examined urinary BPA concentrations from 319 elementary school-aged Brazilian children, using high-performance liquid chromatography coupled to high-resolution mass spectrometry. We found that urinary BPA was detectable in the majority of children, and that urinary BPA levels were higher among children with lower family income and lower maternal educational levels. BPA levels found herein were compared with those from countries with different regulation policies concerning exposure to BPA. They were similar to those reported from studies conducted in Egypt and Australia. Despite more protective regulatory policies in the European Union, they were similar or lower than those reported in European studies. Our findings indicate that exposure of Brazilian children to BPA is widespread and comparable to or even lower than that of countries with stricter regulatory policies., (© 2024. The Author(s).)

Hypoparathyroidism is a rare disease that markedly reduces bone remodeling, leading to increased bone mineral density and changes in bone microarchitecture. However, it is currently unclear how these changes affect fracture risk. In this study, we investigated bone mass by dual-energy x-ray absorptiometry, the occurrence of morphometric vertebral fractures, and bone microarchitecture by assessing trabecular bone score in women with postsurgical hypoparathyroidism. We included 67 women with hypoparathyroidism aged 52.9 ± 12.3 years and 63 age- and body mass index-matched controls, which were assessed for femoral and lumbar spine bone mineral density, trabecular bone score, and vertebral fractures by dual-energy x-ray absorptiometry. Women with hypoparathyroidism had significantly higher bone mineral density at the lumbar spine, femoral neck, and total hip compared with controls despite similar trabecular bone score values. Vertebral fracture assessment indicated that two women with hypoparathyroidism presented vertebral fractures, both aged over 65 years. Conversely, no vertebral fractures were detected in control women. In a multivariate linear regression model, we found that older age, diabetes, and lower lumbar spine mineral density were significant predictors of lower trabecular bone score values. Our findings indicate that vertebral fractures are not common among women with postsurgical hypoparathyroidism aged under 65 years. Moreover, trabecular bone score values were similar in women with hypoparathyroidism and age-matched controls and were associated with traditional risk factors for fractures, such as older age, type 2 diabetes, and lower spine bone mineral density. LAY SUMMARY: Chronic parathyroid hormone deficiency decreases bone turnover and modifies skeletal properties, although the impact of these changes on fracture risk remains unclear. We studied 67 women with postsurgical hypoparathyroidism and 63 age and body mass index-matched healthy controls and found that bone mineral density is increased in women with hypoparathyroidism despite similar trabecular bone score values and a low occurrence of morphometric vertebral fractures. This suggests that the low bone turnover in hypoparathyroidism increases bone mass, but this is not accompanied by improved bone microarchitecture, indicating that trabecular bone score may be a valuable tool to complement the assessment of skeletal health and the risk of fractures in this condition., Competing Interests: Declaration of competing interest None declared., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Gut dysbiosis is linked to metabolic and neurodegenerative diseases and comprises a plausible link between high-fat diet (HFD) and brain dysfunction. Here we show that gut microbiota modulation by either antibiotic treatment for 5 weeks or a brief 3-day fecal microbiota transplantation (FMT) regimen from low-fat (control) diet-fed mice decreased weight gain, adipose tissue hypertrophy, and glucose intolerance induced by HFD in C57BL/6 male mice. Notably, gut microbiota modulation by FMT completely reversed impaired recognition memory induced by HFD, whereas modulation by antibiotics had less pronounced effect. Improvement in recognition memory by FMT was accompanied by decreased HFD-induced astrogliosis in the hippocampal cornu ammonis region. Gut microbiome composition analysis indicated that HFD diminished microbiota diversity compared to control diet, whereas FMT partially restored the phyla diversity. Our findings reinforce the role of the gut microbiota on HFD-induced cognitive impairment and suggest that modulating the gut microbiota may be an effective strategy to prevent metabolic and cognitive dysfunction associated with unfavorable dietary patterns., (© 2024 International Society for Neurochemistry.)

Objective: The prognosis of colorectal cancer has continuously improved in recent years thanks to continuous progress in both the therapeutic and diagnostic fields. The specific objective of this study is to contribute to the diagnostic field through the evaluation of the correlation between superior hemorrhoidal vein (SHV) ectasia detected on computed tomography (CT) and Tumor (T), Node (N), and distant metastasis (M) examination and mesorectal fascia (MRF) invasion in the preoperative staging of rectal cancer., Methods: Between January 2018 and April 2022, 46 patients with histopathological diagnosis of rectal cancer were retrospectively enrolled, and the diameter of the SHV was evaluated by CT examination. The cutoff value for SHV diameter used is 3.7 mm. The diameter was measured at the level of S2 during portal venous phase after 4× image zoom to reduce the interobserver variability. The parameters evaluated were tumor location, detection of MRF infiltration (defined as the distance < 1 mm between the tumor margins and the fascia), SHV diameter, detection of mesorectal perilesional lymph nodes, and detection of metastasis., Results: A total of 67.39% (31/46) of patients had SHV ectasia. All patients with MRF infiltration (4/46, 7.14%) presented SHV ectasia (average diameter of 4.4 mm), and SHV was significantly related with the development of liver metastases at the moment of primary staging and during follow-up., Conclusion: SHV ectasia may be related to metastasis and MRF involvement; therefore, it could become a tool for preoperative staging of rectal cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lucarelli, Mirabile, Maggialetti, Morelli, Calbi, Bartoli, Avella, Saccente, Greco and Ianora Stabile.)

The immune-mediated necrotizing myopathies (IMNM) are autoimmune myositides clinically characterized by proximal predominant weakness and elevated creatine kinase (CK). They may be associated with autoantibodies (anti-HMGCR, anti-SRP), triggered by statin use (e.g., anti-HMGCR myopathy), associated with cancer, or may be idiopathic. Immunotherapy is required to improve strength and decrease the CK level, but no therapies are currently approved by the U.S. Food and Drug Administration for the treatment of IMNM. The optimal treatment strategy for IMNM is currently unknown and wide practice variation exists in the management of this condition. However, observational studies and expert opinion suggest that certain therapies may be more effective for the different serological subtypes of IMNM. HMGCR IMNM often responds favorably to intravenous immunoglobulin (IVIG) even as monotherapy. Signal recognition peptide and seronegative IMNM typically require combination immunotherapy, most often consisting of an oral immunosuppressant, corticosteroids, and IVIG or rituximab. Patients often remain on immunotherapy for years and relapse is common during tapering of immunotherapy. Further studies are needed to guide the optimal management of these patients., (© 2024 by the American Association of Neuromuscular & Electrodiagnostic Medicine, Inc. All rights reserved.)

Background and Study Aims: This study aimed to examine the association between peripheral leukocyte telomere length and indicators of metabolic abnormalities in subjects with metabolic dysfunction-associated steatotic liver disease (MASLD) assessed by magnetic resonance imaging (MRI)., Patients and Methods: This cross-sectional study included adults over 20 years with body mass index (BMI) of over >25 kg/m 2 and sonographic evidence of hepatic steatosis. The subjects were evaluated by clinical and biochemical variables, determination of hepatic fat fraction by MRI and relative peripheral leukocyte telomere length by quantitative real-time polymerase chain reaction., Results: Thirty-two subjects (22 men and 10 women) with MASLD were included, with a median age of 40 years, median BMI of 33.75 kg/m 2 , median HFF 19 %, and median relative T/S ratio of 0.64. Subjects with relative T/S ratio below the median had significantly higher age, lower BMI, higher AST serum levels, higher GGT serum levels, lower serum ferritin levels, and higher FIB4 score. In a multivariable logistic regression model considering relative T/S ratio below or above the median only age was significantly associated with relative T/S ratio. Our findings suggest that age is the most important factor associated with telomere length among subjects with MASLD., Conclusion: Our findings suggest that age is the most important factor associated with telomere length among subjects with MASLD., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.)

Objectives: Facial-onset sensory and motor neuronopathy (FOSMN) is a rare neuromuscular disorder characterized by progressive facial sensory impairment followed by motor dysfunction in a rostro-caudal distribution. FOSMN is clinically and pathologically associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). In contrast to ALS/FTD, the genetic profile of patients with FOSMN and the role of genetic testing are poorly defined., Methods: A 66-year-old woman was evaluated in our neuromuscular clinic for progressive facial pain, dysphagia, and dysarthria. Her diagnostic evaluation included brain and cervical MRI, nerve conduction studies and EMG, and an ALS/FTD next-generation sequencing panel., Results: The patient was diagnosed with FOSMN, and we identified a N390D variant in transactive response DNA-binding protein (TDP-43/ TARDBP ). This variant has never been reported in FOSMN but was previously reported in 2 cases of ALS, and a N390S variant was also previously reported in FOSMN. A review of the literature revealed that TARDBP mutations are overrepresented in patients with FOSMN compared with patients with ALS/FTD. By contrast, other common familial forms of ALS, including C9ORF72 or SOD1 , are respectively absent or rare in FOSMN., Discussion: FOSMN is pathologically and genetically associated with TDP-43. Therefore, ALS genetic testing that includes specifically TARDBP should be considered in patients with FOSMN., Competing Interests: The authors report no relevant disclosures. Go to Neurology.org/NG for full disclosures., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: The ACR-EULAR Myositis Response Criteria (MRC) were developed as a composite measure using absolute percentage change in six core set measures (CSMs). We aimed to further validate the MRC by assessing the contribution of each CSM, frequency of strength vs extramuscular activity improvement, representation of patient-reported outcome measures (PROM), and frequency of CSM worsening., Methods: Data from adult dermatomyositis/polymyositis patients in the rituximab (n = 147), etanercept (n = 14), and abatacept (n = 19) trials, and consensus patient profiles (n = 232) were evaluated. The Total Improvement Score (TIS), number of improving vs worsening CSMs, frequency of improvement with and without muscle-related CSMs, and contribution of PROM were evaluated by MRC category. Regression analysis was performed to assess contribution of each CSM to the MRC., Results: Of 412 adults with dermatomyositis/polymyositis, there were 37%, 24%, 25%, and 14% with no, minimal, moderate, and major MRC improvement, respectively. The number of improving CSMs and absolute percentage change in all CSMs increased by improvement category. In minimal-moderate improvement, only physician-reported disease activity contributed significantly more than expected by MRC. Of patients with at least minimal improvement, 95% had improvement in muscle-related measures and a majority (84%) had improvement in PROM. Patients with minimal improvement had worsening in a median of 1 CSM, and most patients with moderate-major improvement had no worsening CSMs. Physician assessment of change generally agreed with MRC improvement categories., Conclusion: The ACR-EULAR MRC performs consistently across multiple studies, further supporting its use as an efficacy end point in future myositis therapeutic trials., (Published by Oxford University Press on behalf of the British Society for Rheumatology 2023.)

Background: Inclusion body myositis is the most common progressive muscle wasting disease in people older than 50 years, with no effective drug treatment. Arimoclomol is an oral co-inducer of the cellular heat shock response that was safe and well-tolerated in a pilot study of inclusion body myositis, reduced key pathological markers of inclusion body myositis in two in-vitro models representing degenerative and inflammatory components of this disease, and improved disease pathology and muscle function in mutant valosin-containing protein mice. In the current study, we aimed to assess the safety, tolerability, and efficacy of arimoclomol in people with inclusion body myositis., Methods: This multicentre, randomised, double-blind, placebo-controlled study enrolled adults in specialist neuromuscular centres in the USA (11 centres) and UK (one centre). Eligible participants had a diagnosis of inclusion body myositis fulfilling the European Neuromuscular Centre research diagnostic criteria 2011. Participants were randomised (1:1) to receive either oral arimoclomol 400 mg or matching placebo three times daily (1200 mg/day) for 20 months. The randomisation sequence was computer generated centrally using a permuted block algorithm with randomisation numbers masked to participants and trial staff, including those assessing outcomes. The primary endpoint was the change from baseline to month 20 in the Inclusion Body Myositis Functional Rating Scale (IBMFRS) total score, assessed in all randomly assigned participants, except for those who were randomised in error and did not receive any study medication, and those who did not meet inclusion criteria. Safety analyses included all randomly assigned participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02753530, and is completed., Findings: Between Aug 16, 2017 and May 22, 2019, 152 participants with inclusion body myositis were randomly assigned to arimoclomol (n=74) or placebo (n=78). One participant was randomised in error (to arimoclomol) but not treated, and another (assigned to placebo) did not meet inclusion criteria. 150 participants (114 [76%] male and 36 [24%] female) were included in the efficacy analyses, 73 in the arimoclomol group and 77 in the placebo group. 126 completed the trial on treatment (56 [77%] and 70 [90%], respectively) and the most common reason for treatment discontinuation was adverse events. At month 20, mean IBMFRS change from baseline was not statistically significantly different between arimoclomol and placebo (-3·26, 95% CI -4·15 to -2·36 in the arimoclomol group vs -2·26, -3·11 to -1·41 in the placebo group; mean difference -0·99 [95% CI -2·23 to 0·24]; p=0·12). Adverse events leading to discontinuation occurred in 13 (18%) of 73 participants in the arimoclomol group and four (5%) of 78 participants in the placebo group. Serious adverse events occurred in 11 (15%) participants in the arimoclomol group and 18 (23%) in the placebo group. Elevated transaminases three times or more of the upper limit of normal occurred in five (7%) participants in the arimoclomol group and one (1%) in the placebo group. Tubulointerstitial nephritis was observed in one (1%) participant in the arimoclomol group and none in the placebo group., Interpretation: Arimoclomol did not improve efficacy outcomes, relative to placebo, but had an acceptable safety profile in individuals with inclusion body myositis. This is one of the largest trials done in people with inclusion body myositis, providing data on disease progression that might be used for subsequent clinical trial design., Funding: US Food and Drug Administration Office of Orphan Products Development and Orphazyme., Competing Interests: Declaration of interests PMM has received consulting fees and funding support from Orphazyme, paid to his academic institution (University College London) for the oversight and conduct of this study, and has also received honoraria from Abbvie, Bristol Myers Squibb, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Pfizer, Roche, and UCB. MPM has received research funding from the US National Institutes of Health (NIH), the US Food and Drug Administration, Cure SMA, and PTC Therapeutics; received consulting fees from NeuroDerm and Fulcrum Therapeutics; and served on data and safety monitoring boards for NIH, Eli Lilly and Company, Catabasis Pharmaceuticals, Vaccinex, Neurocrine Biosciences, Voyager Therapeutics, Prilenia Therapeutics Development, ReveraGen BioPharma, and NS Pharma. TB, CS, AR, TDC, KB, ANJ, and KP are previous employees of Orphazyme. MF has received consulting fees from UCB, Argenx, Alexion, and CSL Behring; and research support paid to her institution (Ohio State University) from UCB, Argenx, Alexion, Fulcrum, Avidity, Pharnext, Janssen, and Roche. TEL has served as a consultant for Aavogen, Abata Therapeutics, Abcuro, Acceleron, DrenBio, EMD Serano, Kezar Life Sciences, Ono Pharma, Orphazyme, Regenacy, Sarepta, and Takeda; DSMB was Chair of the data and safety monitoring board for a Pharnext-sponsored clinical trial; and received research support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH (R01 AR076390), the Muscular Dystrophy Association (MDA630399), Horizon Therapeutics, and The Peter and Carmen Lucia Buck Foundation. TM has served as an advisor to Alexion (AstraZeneca), Amicus, AnnJi, Argenx, Arvinas, Ask-Bio, Audentes (now Astellas Gene Therapy), Horizon Therapeutics, Maze Therapeutics, Momenta (now Janssen), Sanofi, Sarepta, Spark Therapeutics, UCB/Ra Pharmaceuticals, and Modis/Zogenix (now UCB); has served on the speaker's bureau for Sanofi-Genzyme, Alexion, and Argenx; has served on the medical advisory board for the Myositis Association, Neuromuscular Disease Foundation, Myasthenia Gravis Foundation of California, and Myasthenia Gravis Foundation of America; has received research funding from the Myositis Association, the Muscular Dystrophy Association, NIH, and from the following commercial sponsors: Alexion, Amicus, AnnJi, Argenx, Audentes/Astellas Gene Therapy, Bristol Myers Squibb, Cartesian Therapeutics, Grifols, ML-Bio, Momenta, Ra Pharmaceuticals, Sanofi, Spark Therapeutics, UCB, and Valerion; and he serves on the data safety monitoring boards for Acceleron, Avexis, Sarepta, and NIH. RJB has received funding from the FDA Office Orphan Products Development grant for his role in this study. MGH receives research funding from the Medical Research Council UK and has previously acted as a consultant for Novartis and Orphazyme. MMD is a consultant for Orphazyme and received funding support, paid to his academic institution (University of Kansas Medical Center, Research Institute), from Orphazyme for the oversight and conduct of this study. He also serves or recently served as a consultant for Abcuro, Amazentis, ArgenX, Astellas, Catalyst, Cello, Covance/Labcorp, CSL-Behring, EcoR1, Janssen, Kezar, MDA, Medlink, Momenta, NuFactor, Octapharma, Priovant, RaPharma/UCB, Roivant Sciences, Sanofi Genzyme, Shire Takeda, Scholar Rock, Spark Therapeutics, Abata/Third Rock, UCB Biopharma and received research grants or contracts or educational grants from Alexion, Alnylam Pharmaceuticals, Amicus, Biomarin, Bristol Myers Squibb, Catalyst, Corbus, CSL-Behring, FDA Office of Orphan Products Development, GlaxoSmithKline, Genentech, Grifols, Kezar, Mitsubishi Tanabe Pharma, Muscular Dystrophy Association, NIH, Novartis, Octapharma, Orphazyme, Ra Pharma/UCB, Sanofi Genzyme, Sarepta Therapeutics, Shire Takeda, Spark Therapeutics, The Myositis Association, Ra Pharma/UCB, Viromed/Healixmith, and The Myositis Association. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Exposure to the xenoestrogen nonylphenol (NP) during critical windows of development leads to metabolic abnormalities in adult life. However, less is known about NP exposure outside the developmental period on metabolic outcomes. We investigated the effect of prolonged exposure to NP after sexual maturity and at environmentally relevant concentrations below the 'no observable adverse effects level' (0.5 and 2.5 mg/kg/d). Male Swiss mice fed a normal-fat diet exposed to 2.5 mg/kg/d NP showed reduced weight gain and hepatic fat content. In male and female C57BL/6 mice fed a high-fat diet, NP exposure modified the mRNA levels of estrogen receptor α (Esr1) and adipose lineage markers in a sexually dimorphic and adipose depot-dependent pattern. Moreover, in primary female but not male stromal vascular cells from C57BL/6 mouse inguinal WAT induced to differentiate into adipocytes, NP upregulated Fabp4 expression. Low-level exposure to NP outside critical developmental windows may affect the metabolic phenotype distinctly. DATA AVAILABILITY STATEMENT: All data not included in the manuscript, such as raw results, are available upon request and should be addressed to AAA., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Angelica Amorim Amato reports financial support was provided by National Council on Scientific and Technological Development. Angelica Amorim Amato reports financial support was provided by Federal District Research Foundation., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The advances in pediatric acute lymphoblastic leukemia (ALL) care have substantially increased survival, and the late effects of treatment are a growing concern. Obesity development is frequent following ALL therapy and may significantly contribute to long-term morbidity and mortality. We examined the body mass trajectory of 208 children with ALL, from the diagnosis to the completion of therapy. We found that 7.2% of children were overweight or obese at diagnosis, which increased to 19.7% at the end of induction therapy and 20.8% after completion of treatment. In a multivariable linear regression model, age at ALL diagnosis, the type of chemotherapy regimen, and body mass index (BMI) z-score at diagnosis were significant predictors of BMI z-score after induction therapy, whereas BMI z-score at diagnosis was the only significant predictor of BMI z-score at the completion of treatment. In a subgroup of 120 children, we found no association between nutrition status at diagnosis and the risk of ALL relapse or poorer overall survival. Our findings indicate that weight gain occurs early during ALL therapy and is predicted by weight status at diagnosis. Therefore, nutritional status should be assessed throughout treatment, and weight management interventions should be considered early, particularly for patients with higher weight at diagnosis., (© 2023. Springer Nature Limited.)

Introduction/aims: Myotonic dystrophies (DMs) are autosomal dominant diseases in which expression of a mutant expanded repeat mRNA leads to abnormal splicing of downstream effector genes thought to be responsible for their multisystem involvement. Cancer risk and cancer-related deaths are increased in DM patients relative to the general population. We aimed at determining the frequency and type of cancers in both DM1 and DM2 vs a non-DM muscular dystrophy cohort., Methods: A retrospective, cross-sectional study was carried out on patients with genetically confirmed DM1, DM2, facioscapulohumeral muscular dystrophy (FSHD), and oculopharyngeal muscular dystrophy (OPMD) at our institutions from 2000 to 2020., Results: One hundred eighty-five DM1, 67 DM2, 187 FSHD, and 109 OPMD patients were included. Relative to non-DM, DM patients had an increased cancer risk that was independent of age and sex. Specifically, an increased risk of sex-related (ovarian) and non-sex-related (non-melanoma skin, urological, and hematological) cancers was observed in DM1 and DM2, respectively. The length of CTG repeat expansion was not associated with cancer occurrence in the DM1 group., Discussion: In addition to current consensus-based care recommendations, our findings prompt consideration of screening for skin, urological, and hematological cancers in DM2 patients, and screening of ovarian malignancies in DM1 female patients., (© 2023 Wiley Periodicals LLC.)

Background: The association between early-life exposure to antibiotics and overweight/obesity is unclear. We conducted a systematic review and meta-analysis to address this issue., Methods: We searched PubMed, Web of Science, Scopus, and grey literature from inception to August 10, 2022, for cohort studies investigating the association between early-life exposure to antibiotics and weight outcomes. Two independent reviewers screened studies for eligibility, extracted data, assessed risk of bias, and examined the certainty of the evidence. Random-effects meta-analyses was used for pooling the data. The review was registered in PROSPERO, CRD42021265417., Results: We included 42 studies and data from 28 of them were pooled in the quantitative synthesis. Overall antenatal (OR 1.10, 95% CI 1.04-1.16; 518,095 children, very low certainty) and second trimester (OR 1.11, 95% CI 1.08-1.14, 248,469 children, low certainty) exposure to antibiotics were associated with increased risk of overweight/obesity in childhood/adolescence. Overall early postnatal antibiotic exposure was also associated with increased likelihood of overweight/obesity in childhood/adolescence (OR 1.09, 95% CI 1.05-1.12, 1,488,316 children, very low certainty). The magnitude of the association increased from exposure to one (OR 1.07, 95% CI 1.00-1.15, 512,954 children) to four or more courses of antibiotics (OR 1.31, 95% CI 1.17-1.46, 543,627 children)., Conclusion: Antenatal and early postnatal exposure to antibiotics is associated increased likelihood of overweight/obesity, although the findings are limited by the very low certainty of evidence. We highlight the need for homogeneous prospective studies addressing potential confounding factors to further explore the link between exposure to antibiotics and the risk of excess body weight., Competing Interests: Declaration of Competing Interest The authors of the manuscript entitled ‘Early-life exposure to antibiotics and excess body weight in childhood and adolescence: a systematic review and meta-analysis’ and whose names are listed immediately below certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2023 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.)

The impact of overnutrition early in life is not restricted to the onset of cardiovascular and metabolic diseases, but also affects critical brain functions related to cognition. This study aimed to evaluate the relationship between peripheral metabolic and bioenergetic changes induced by a two-hit protocol and their impact on cognitive function in juvenile mice. Three-week-old male C57BL/6 mice received a high-fat diet (HFD) or control diet for 7 weeks, associated with two low doses of streptozotocin (STZ) or vehicle. Despite the absence of obesity, HFD+STZ impaired glucose metabolism and induced a trend towards cholesterol increase. The two-hit protocol impaired recognition and spatial memories in juvenile mice, without inducing a depressive-like behavior. HFD+STZ mice presented increased immunoreactivity for GFAP and a trend towards a decrease in NeuN in the hippocampus. The treatment caused a bioenergetic impairment in the hippocampus, characterized by a decrease in both O 2 consumption related to ATP production and in the maximum respiratory capacity. The thermogenic capacity of brown adipose tissue was impaired by the two-hit protocol, here verified through the absence of a decrease in O 2 consumption after uncoupled protein-1 inhibition and an increase in the reserve respiratory capacity. Impaired mitochondrial function was also observed in the liver of HFD+STZ juvenile mice, but not in their heart. These results indicate that exposure to HFD+STZ early in life has a detrimental impact on the bioenergetic and mitochondrial function of tissues with metabolic and thermogenic activities, which is likely related to hippocampal metabolic changes and cognitive impairment., Competing Interests: Declaration of competing Interest The authors declare that they have no other competing financial interests or personal relationships that could have influenced this work., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To estimate the prevalence of unplanned pregnancy in eight public university hospitals, distributed in the five regions that make up Brazil., Methods: A secondary analysis of a national multicenter cross-sectional study, carried out in eight public university hospitals between June 1 and August 31, 2020, in Brazil. Convenience sample including women who gave birth within sixty consecutive days and met the following criteria: over 18 years old; gestational age over 36 weeks at delivery; with a single and live newborn, without malformations., Results: Sample composed of 1,120 postpartum women, of whom 756 (67.5%) declared that the pregnancy had not been planned. The median prevalence of unplanned pregnancy was 59.7%. The prevalence of unplanned pregnancy across hospitals differed significantly: Campinas (54.8%), Porto Alegre (58.2%), Florianópolis (59%), Teresina (61.2%), Brasília (64.3%), São Paulo (64.6%), Campo Grande (73.9%) and Manaus (95.3%) (p < 0.001). Factors significantly associated with unplanned pregnancy were maternal age, black color, lower family income, greater number of children, greater number of people living in household, and not having a partner., Conclusion: In the studied sample, about two thirds of the pregnancies were declared as unplanned. The prevalence of unplanned pregnancies was related to social and demographic factors and varied significantly across the university hospitals evaluated.

Background and Objectives: The existence of clinical anticipation, congenital form, and parent-of-origin effect in myotonic dystrophy type 2 (DM2) remains uncertain. Here, we aimed at investigating whether there is a parent-of-origin effect on the age at the first DM2-related clinical manifestation., Methods: We identified patients with genetically confirmed DM2 with known parental inheritance from (1) the electronic medical records of our institutions and (2) a systematic review of the literature following the PRISMA 2020 guidelines and recorded their age at and type of first disease-related symptom. We also interrogated the Myotonic Dystrophy Foundation Family Registry (MDFFR) for patients with DM2 who completed a survey including questions about parental inheritance and age at the first medical problem which they related to their DM2 diagnosis., Results: A total of 26 patients with DM2 from 18 families were identified at our institutions as having maternal (n = 14) or paternal (n = 12) inheritance of the disease, whereas our systematic review of the literature rendered a total of 61 patients with DM2 from 41 families reported by 24 eligible articles as having maternal (n = 40) or paternal (n = 21) inheritance of the disease. Both cohorts were combined for downstream analyses. Up to 61% and 58% of patients had muscle-related symptoms as the first disease manifestation in maternally and paternally inherited DM2 subgroups, respectively. Four patients developed hypotonia at birth and/or delayed motor milestones early in life, and 7 had nonmuscular presentations (2 had cardiac events within the second decade of life and 5 had cataracts), all of them with maternal inheritance. A maternal inheritance was associated with an earlier (within the first 3 decades of life) age at symptom onset relative to a paternal inheritance in this combined cohort, and this association was independent of the patient's sex (OR [95% CI] = 4.245 [1.429-13.820], p = 0.0117). However, this association was not observed in the MDFFR DM2 cohort (n = 127), possibly because age at onset was self-reported, and the information about the type of first symptom or medical problem that patients related to DM2 was lacking., Discussion: A maternal inheritance may increase the risk of an early DM2 onset and of cataracts and cardiovascular events as first DM2 manifestations., Competing Interests: P. Gonzalez-Perez is the on-site PI of the clinical trial NCT04886518 (Harmony Biosciences, LLC); E.S. D'Ambrosio reports no disclosures; V. Picher-Martel reports no disclosures; K. Chuang reports no disclosures; W.S. David reports no disclosures; A.A. Amato has served as WHAT on Medical Advisory Boards/Consultant for Abcuro, Argenx, Ra Pharmaceuticals, Alexion, EMD Serono, Takeda, and Johnson & Johnson (COVID-19 vaccination program). Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objectives: This systematic review and meta-analysis aimed to address whether non-surgical periodontal therapy (NSPT) can affect insulin resistance, estimated by the homeostasis model assessment (HOMA), in adults with prediabetes or type 2 diabetes mellitus and periodontitis., Materials and Methods: Six electronic databases and the gray literature were systematically searched for interventional studies reporting NSPT effect on insulin resistance. Seven studies met the eligibility criteria to be synthesized in the qualitative analysis, six reporting change in HOMA-IR, three reporting change in HOMA-%S, and two in HOMA-β. Among them, four were pooled in a meta-analysis of standardized mean difference (SMD) of HOMA-IR; comparing pre- and post-intervention values, three were pooled considering HOMA-%S as outcome, and two studies were summarized considering SMD of HOMA-%S between intervention and control groups. HOMA-β results were qualitatively synthetized., Results: With low level of certainty, NSPT significantly reduced HOMA-IR, when compared with pre-intervention data (SMD, -0.35, 95% CI -0.63 to 0.07, p=0.02). There were no significant changes in HOMA-%S or in HOMA-β scores. The level of certainty was very low and moderate, respectively., Conclusions: Assertions about a causal link between NSPT and insulin resistance are weak and conflicting, although our more robust results point out to the absence of effect. ., Clinical Relevance: Because further high-quality studies assessing the relationship between periodontitis and insulin resistance are need, the findings of the current systematic review are limited to give recommendations for clinicians. However, while identifying a lack of research in humans with T2D concerning periodontitis and insulin resistance, this study reinforces the need of multicenter well-designed randomized clinical trials., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Immune-mediated necrotizing myopathy (IMNM) is an autoimmune myopathy characterised by proximal muscle weakness, high creatine kinase (CK) values, and autoantibodies recognizing 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) or the signal recognition particle (SRP). There are currently no approved therapies for IMNM and many patients experience active disease despite off-label treatment with intravenous immunoglobulin, glucocorticoids, and immunosuppressants. Detection of complement-activating anti-HMGCR and anti-SRP autoantibodies and the presence of complement deposition on the sarcolemma of non-necrotic myofibers led to the hypothesis that complement activation may be pathogenic in IMNM, therefore zilucoplan, a complement component 5 (C5) inhibitor, could be a potential therapy., Methods: IMNM01, a phase 2, multicenter, randomised, double-blind, placebo-controlled study (NCT04025632) at 15 sites (four countries) evaluated efficacy, safety, and tolerability of zilucoplan in adult participants with anti-HMGCR or anti-SRP autoantibody-positive IMNM. Participants were randomised 1:1 to receive daily subcutaneous zilucoplan (0·3mg/kg) or placebo for eight weeks; with optional enrolment in the study open-label extension. Primary efficacy endpoint was percent change from baseline to Week 8 in CK levels. Secondary endpoints included safety., Findings: Between 07 November 2019 and 07 January 2021, 27 participants (13 female and 14 male) received zilucoplan (n=12) or placebo (n=15) and completed the 8-week main study. At Week 8 there were no clinically relevant or statistically significant differences, despite target engagement based on mode of action, between treatment arms in mean percent change (standard deviation) of CK levels versus baseline (-9·86% [26·06] versus -20·72% [31·22] in zilucoplan [n=10] and placebo arms [n=14], p=0·46, respectively) and no clinically relevant improvement over time within the treatment arm. There were no unexpected adverse safety or tolerability findings. Treatment emergent adverse events (TEAEs) and serious TEAEs were reported in n=9 (75·0%) vs n=13 (86·7%) and n=0 (0%) and n=3 (20·0%) participants, respectively. The most frequent TEAEs were headache (n=4 in both groups [33·3% and 26·7%, respectively]) and nausea (n=3 in both groups [25·0% and 20·0%, respectively])., Interpretation: C5 inhibition does not appear to be an effective treatment modality for IMNM. Rather than driving myofiber necrosis, complement activation may be secondary to muscle injury., Funding: Study funded by Ra Pharmaceuticals (now part of UCB Pharma)., Competing Interests: Declaration of interests ALM is a patent author for the anti-HMGCR test. AAA has participated in medical advisory boards/acted as a consultant for Argenx, Ra Pharmaceuticals, Alexion, EMD Serono, OnoPharma, Horizon Therapeutics, Takeda, Johnson & Johnson (COVID-19 vaccination program) MD has served or recently served as a consultant for Amazentis, ArgenX, Catalyst, Cello, Covance/Labcorp, CSL-Behring, EcoR1, Janssen, Kezar, Medlink, Momenta, NuFactor, Octapharma, RaPharma/UCB, Roivant Sciences Inc, RMS Medical, Sanofi Genzyme, Shire Takeda, Scholar Rock, Spark Therapeutics, Abata/Third Rock, UCB Biopharma, and UpToDate. Dr. Dimachkie received research grants or contracts or educational grants from Alexion, Alnylam Pharmaceuticals, Amicus, Biomarin, Bristol-Myers Squibb, Catalyst, Corbus, CSL-Behring, FDA/OOPD, GlaxoSmithKline, Genentech, Grifols, Kezar, Mitsubishi Tanabe Pharma, MDA, NIH, Novartis, Octapharma, Orphazyme, Ra Pharma/UCB, Sanofi Genzyme, Sarepta Therapeutics, Shire Takeda, Spark Therapeutics, UCB Biopharma / RaPharma, Viromed/Healixmith & TMA. HC has received personal compensation for activities with Novartis, UCB, Lilly, Biogen, Orphazyme, Astra Zeneca as a speaker, advisory board member or consultancy, grants via The University of Manchester from Novartis, UCB and MedImmune, and has received travel support from Abbvie and Janssen. JBL has received speakers fees, travel support, and/or consultancy fees from Sanofi Genzyme, Roche, and Biogen. Yves Allenbach: has received personal compensation for activities with Lilly, and CSL-Berhing as a speaker or consultancy. Mark Vanderkelen: Employee and stockholder of UCB Pharma Eumorphia Delicha: Contractor of UCB Pharma Ramin Farzaneh-Far: was an employee of Ra Pharma at the time of the study BB, HK, PWD, CS* and OB are employees and stockholders of UCB Pharma IPF and YH have no competing interests to declare *Employee at the time to the study

In this chapter, we discuss the indications for muscle, nerve, and skin biopsies, the techniques and normal processing of biopsy specimens, normal histological appearance, and the commonest histopathological abnormalities of different myopathies and neuropathies., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction/aims: Safety and outcomes data on eculizumab for generalized myasthenia gravis (gMG) in clinical practice remain limited. Outcomes and concomitant medication use may differ in practice compared with clinical trials. We analyzed the clinical and safety outcomes of patients who received eculizumab at our institutions., Methods: Patients with acetylcholine receptor antibody positive (AChR+) gMG, who received ≥1 dose of eculizumab and had ≥1 follow-up before December 10, 2021, were identified. Data were abstracted by chart review. Outcomes included MG Foundation of America Post Intervention Status (MGFA-PIS), Clinical Classification (MGFA-CC), MG-Activities of Daily Living (MG-ADL), concurrent immunomodulatory therapy use, and adverse events., Results: Twelve patients were included. Mean age at eculizumab initiation was 57.4 y (range, 21-77). Eight had refractory MG. Four had history of thymoma and thymectomy. A mean of 3.2 (range, 2-5) immunomodulatory therapies were previously tried. Mean follow-up duration was 18 mo (range, 2-21.6). Clinical improvement occurred rapidly; MGFA-PIS was improved in 80%, and MGFA-CC improved in 83% at 1 mo. Mean MG-ADL decreased from 8.7 to 2.8 at 1 mo, and remained ≤ 3 .5 over 1.5 y. Mean daily prednisone dose decreased from 22.5 mg to 7.2 mg at 1.5 y. Five of 7 patients discontinued maintenance IVIG or PLEX. No patients had meningococcal infections and adverse events were mild., Discussion: Clinical improvement occurred in most patients after eculizumab initiation, beginning as quickly as 1 mo. Steroids were tapered and maintenance IVIG and PLEX were discontinued in most. Eculizumab had a favorable safety profile even when combined with other immunosuppressants., (© 2022 Wiley Periodicals LLC.)

The discovery of microbiome metabolites has enlivened the field of fecal transplantation for therapeutic purposes. However, the transfer of pathogenic living organisms was recently observed to limit its therapeutic potential by increasing the risk of infection. Lipids produced by gut microbiota enter the circulation and control many phenotypic changes associated with microbiota composition. Fecal lipids significantly impact the regulation of several cell signaling pathways, including inflammation. Focusing on these molecules, we review how bioactive gut microbiota-associated lipids affect cellular functioning and clinical outcome. Here, we interrogate whether the gut microbiota can be considered a cutting-edge biotechnological tool for rapid metabolic engineering of meaningful lipids to offer a novel personalized therapy., Competing Interests: Declaration of interests The authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Adipose tissue undergoes significant anatomical and functional changes with aging, leading to an increased risk of metabolic diseases. Age-related changes in adipose tissue include overall defective adipogenesis, dysfunctional adipokine secretion, inflammation, and impaired ability to produce heat by nonshivering thermogenesis. Thermogenesis in adipose tissue is accomplished by brown and beige adipocytes, which also play a role in regulating energy homeostasis. Brown adipocytes develop prenatally, are found in dedicated depots, and involute in early infancy in humans. In contrast, beige adipocytes arise postnatally in white adipose tissue and persist throughout life, despite being lost with aging. In recent years, there have been significant advances in the understanding of age-related reduction in thermogenic adipocyte mass and function. Mechanisms underlying such changes are beginning to be delineated. They comprise diminished adipose precursor cell pool size and adipogenic potential, mitochondrial dysfunction, decreased sympathetic signaling, and altered paracrine and endocrine signals. This review presents current evidence from animal models and human studies for the mechanisms underlying thermogenic adipocyte loss and discusses potential strategies targeting brown and beige adipocytes to increase health span and longevity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Silva and Amato.)

Introduction/aims: Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive muscular dystrophy without approved therapies. In this study we evaluated whether locally acting ACE-083 could safely increase muscle volume and improve functional outcomes in adults with FSHD., Methods: Participants were at least 18 years old and had FSHD1/FSHD2. Part 1 was open label, ascending dose, assessing safety and tolerability (primary objective). Part 2 was randomized, double-blind for 6 months, evaluating ACE-083240 mg/muscle vs placebo injected bilaterally every 3 weeks in the biceps brachii (BB) or tibialis anterior (TA) muscles, followed by 6 months of open label. Magnetic resonance imaging measures included total muscle volume (TMV; primary objective), fat fraction (FF), and contractile muscle volume (CMV). Functional measures included 6-minute walk test, 10-meter walk/run, and 4-stair climb (TA group), and performance of upper limb midlevel/elbow score (BB group). Strength, patient-reported outcomes (PROs), and safety were also evaluated., Results: Parts 1 and 2 enrolled 37 and 58 participants, respectively. Among 55 participants evaluable in Part 2, the least-squares mean (90% confidence interval, analysis of covariance) treatment difference for TMV was 16.4% (9.8%-23.0%) in the BB group (P < .0001) and 9.5% (3.2%-15.9%) in the TA group (P = .01). CMV increased significantly in the BB and TA groups and FF decreased in the TA group. There were no consistent improvements in functional or PRO measures in either group. The most common adverse events were mild or moderate injection-site reactions., Discussion: Significant increases in TMV with ACE-083 vs placebo did not result in consistent functional or PRO improvements with up to 12 months of treatment., (© 2022 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)