Disease-associated comorbidities, medication records and anthropometric measures in adults with Duchenne muscular dystrophy.

We investigated the comorbidities, associated factors, and the relationship between anthropometric measures and respiratory function and functional abilities in adults with Duchenne muscular dystrophy (DMD). This was a single-centre cross-sectional study in genetically diagnosed adults with DMD (>16 years old). Univariate and multivariate analyses identified factors associated with dysphagia, constipation, Body Mass Index (BMI), and weight. Regression analysis explored associations between BMI, weight, and respiratory/motor abilities. We included 112 individuals (23.4 ± 5.2 years old), glucocorticoid-treated 66.1 %. The comorbidities frequency was 61.6 % scoliosis (61.0 % of them had spinal surgery), 36.6 % dysphagia, 36.6 % constipation, and 27.8 % urinary conditions. The use of glucocorticoids delayed the time to spinal surgery. The univariate analysis revealed associations between dysphagia and constipation with age, lack of glucocorticoid treatment, and lower respiratory and motor function. In the multivariate analysis, impaired cough ability remained as the factor consistently linked to both conditions. Constipation associated with lower BMI and weight. BMI and weight positively correlated with respiratory parameters, but they did not associate with functional abilities. Glucocorticoids reduce the frequency of comorbidities in adults with DMD. The ability to cough can help identifying dysphagia and constipation. Lower BMI and weight in individuals with DMD with compromised respiratory function may suggest a higher calories requirement.

Emery-Dreifuss muscular dystrophy Type 1 is associated with a high risk of malignant ventricular arrhythmias and end-stage heart failure.

BACKGROUND AND AIMS: Emery-Dreifuss muscular dystrophy (EDMD) is caused by variants in EMD (EDMD1) and LMNA (EDMD2). Cardiac conduction defects and atrial arrhythmia are common to both, but LMNA variants also cause end-stage heart failure (ESHF) and malignant ventricular arrhythmia (MVA). This study aimed to better characterize the cardiac complications of EMD variants. METHODS: Consecutively referred EMD variant-carriers were retrospectively recruited from 12 international cardiomyopathy units. MVA and ESHF incidences in male and female variant-carriers were determined. Male EMD variant-carriers with a cardiac phenotype at baseline (EMDCARDIAC) were compared with consecutively recruited male LMNA variant-carriers with a cardiac phenotype at baseline (LMNACARDIAC). RESULTS: Longitudinal follow-up data were available for 38 male and 21 female EMD variant-carriers [mean (SD) ages 33.4 (13.3) and 43.3 (16.8) years, respectively]. Nine (23.7%) males developed MVA and five (13.2%) developed ESHF during a median (inter-quartile range) follow-up of 65.0 (24.3-109.5) months. No female EMD variant-carrier had MVA or ESHF, but nine (42.8%) developed a cardiac phenotype at a median (inter-quartile range) age of 58.6 (53.2-60.4) years. Incidence rates for MVA were similar for EMDCARDIAC and LMNACARDIAC (4.8 and 6.6 per 100 person-years, respectively; log-rank P = .49). Incidence rates for ESHF were 2.4 and 5.9 per 100 person-years for EMDCARDIAC and LMNACARDIAC, respectively (log-rank P = .09). CONCLUSIONS: Male EMD variant-carriers have a risk of progressive heart failure and ventricular arrhythmias similar to that of male LMNA variant-carriers. Early implantable cardioverter defibrillator implantation and heart failure drug therapy should be considered in male EMD variant-carriers with cardiac disease.

Biological and JAK inhibitor therapy outcomes for severe psoriasis in trisomy 21.

Little is known about biological outcomes for severe psoriasis in trisomy 21 (T21). Our aim was to review outcomes of patients with T21 and severe psoriasis treated with biologic or Janus kinase inhibitors (JAKi). Information on demographics, co-morbidities, and therapeutic responses was retrospectively collated. Twenty-one patients were identified (mean age 24.7 years). Ninety percent (18/20) of TNFα inhibitor trials failed. Almost two-thirds (7/11) of patients achieved an adequate response with ustekinumab. All three patients treated with tofacitinib achieved an adequate response following at least three biologic failures. The mean number of biologic/JAKi therapies received was 2.1 with overall survival of 36%. Eighty-one percent (17/21) of patients required conversion from their index biologic treatment due to failure. In patients with T21 and severe psoriasis, failure of TNFα inhibition is common and ustekinumab therapy should be considered as first-line therapy. The role of JAKi is emerging.

Radiation-induced morphea of the breast-A case series.

Radiation-induced morphea (RIM) is a rare but recognized late complication of radiotherapy. It was first described in 1905, not long after the initial discovery of X-rays by Roentgen. Characterized by the deposition of excess collagen in the dermis, it results in thickening of the skin. Its frequency is approximately 2 in 1000. We present a series of three cases involving patients receiving radiotherapy treatment for breast cancer, each of which subsequently developed RIM. Because of its rarity, RIM is often misdiagnosed as infection or metastatic disease. This can lead to delayed diagnosis and treatment, leading to poorer outcomes such as chronic pain issues. Early dermatological involvement and tissue sampling to examine histopathological features can avoid this, leading to better care and improved results. A variety of treatment options are available, ranging from topical to systemic, with early induction more likely to result in a positive response.

Pembrolizumab-associated erythema nodosum in the treatment of metastatic melanoma.

A 66-year-old woman receiving pembrolizumab for metastatic melanoma presented with tender red nodules on her shins and forearms. Biopsy was consistent with erythema nodosum (EN). The eruption responded to oral minocycline and potent topical steroids. Subsequent investigations detected bihilar lymphadenopathy, biopsied as granulomatous lymphadenitis, confirming the diagnosis of pembrolizumab-associated sarcoidosis. Pembrolizumab was stopped for two cycles and was restarted without recrudescence of EN or bihilar lymphadenopathy. Immunotherapy-associated sarcoidosis is a rare but recognized adverse event related to therapy with immune checkpoint inhibitors. EN is an uncommon manifestation of immunotherapy-induced sarcoidosis. New-onset bihilar lymphadenopathy in the context of immunotherapy requires prompt histological evaluation to differentiate between immunotherapy-associated sarcoidosis and metastatic progression. We review the literature related to immunotherapy-associated EN.

Pembrolizumab (trade name Keytruda^®) is a type of immune therapy that stimulates the body's immune system to fight cancer cells. This immune therapy can cause a variety of rashes. In this article, we describe a patient who developed a red lumpy rash on her limbs that is not commonly described with pembrolizumab. A woman was diagnosed with advanced melanoma and was treated with pembrolizumab. She developed a red lumpy rash on her arms and legs, and a biopsy showed signs of a condition called erythema nodosum. Treatment with an antibiotic tablet and strong steroid ointment were helpful. Scans of her chest showed signs of sarcoidosis in her lungs, which can be associated with erythema nodosum. Pembrolizumab was stopped, and both the rash and lung sarcoidosis stayed away when it was restarted. This type of rash has rarely been described with this kind of immune therapy, and it can be a sign of lung involvement.

Novel agents for atopic dermatitis in patients over 50 years of age: A case series.

Lan et al recently highlighted the under-representation of older adults in clinical trials of systemic therapies for atopic dermatitis (AD). Late-onset AD is increasingly recognized in older adults. Spontaneous remission is uncommon with this phenotype. Existing drug treatments such as corticosteroids, methotrexate, ciclosporin, and azathioprine are complicated by adverse effects including increased malignancy risk, immunosuppression in the context of immunosenescence, and drug interactions in the setting of polypharmacy. A case series is presented of seven patients over 50 years of age with AD who were prescribed dupilumab or tofacitinib or upadacitinib for at least 6 months. All patients were clear or almost clear (investigator global assessment score 0/1) after 1 month of therapy. No significant adverse events were seen. This case series provides preliminary evidence about the safety and efficacy of these novel drugs for AD in older adults. Further studies with higher numbers of participants are needed to obtain real-world evidence for these drugs in older adults, given the limited data in clinical trials.

Bifidobacterium infantis 35624 modulates host inflammatory processes beyond the gut.

Certain therapeutic microbes, including Bifidobacteria infantis (B. infantis) 35624 exert beneficial immunoregulatory effects by mimicking commensal-immune interactions; however, the value of these effects in patients with non-gastrointestinal inflammatory conditions remains unclear. In this study, we assessed the impact of oral administration of B. infantis 35624, for 6‒8 weeks on inflammatory biomarker and plasma cytokine levels in patients with ulcerative colitis (UC) (n = 22), chronic fatigue syndrome (CFS) (n = 48) and psoriasis (n = 26) in three separate randomized, double-blind, placebo-controlled interventions. Additionally, the effect of B. infantis 35624 on immunological biomarkers in healthy subjects (n = 22) was assessed. At baseline, both gastrointestinal (UC) and non-gastrointestinal (CFS and psoriasis) patients had significantly increased plasma levels of C-reactive protein (CRP) and the pro-inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) compared with healthy volunteers. B. infantis 35624 feeding resulted in reduced plasma CRP levels in all three inflammatory disorders compared with placebo. Interestingly, plasma TNF-α was reduced in CFS and psoriasis while IL-6 was reduced in UC and CFS. Furthermore, in healthy subjects, LPS-stimulated TNF-α and IL-6 secretion by peripheral blood mononuclear cells (PBMCs) was significantly reduced in the B. infantis 35624-treated groups compared with placebo following eight weeks of feeding. These results demonstrate the ability of this microbe to reduce systemic pro-inflammatory biomarkers in both gastrointestinal and non-gastrointestinal conditions. In conclusion, these data show that the immunomodulatory effects of the microbiota in humans are not limited to the mucosal immune system but extend to the systemic immune system.

Defining cardiac adaptations and safety of endurance training in patients with m.3243A>G-related mitochondrial disease.

BACKGROUND: Cardiac hypertrophic remodelling and systolic dysfunction are common in patients with mitochondrial disease and independent predictors of morbidity and early mortality. Endurance exercise training improves symptoms and skeletal muscle function, yet cardiac adaptations are unknown. METHODS AND RESULTS: Before and after 16-weeks of training, exercise capacity, cardiac magnetic resonance imaging and phosphorus-31 spectroscopy, disease burden, fatigue, quality of life, heart rate variability (HRV) and blood pressure variability (BPV) were assessed in 10 adult patients with m.3243A>G-related mitochondrial disease, and compared to age- and gender-matched sedentary control subjects. At baseline, patients had increased left ventricular mass index (LVMI, p<0.05) and LV mass to end-diastolic volume ratio, and decreased longitudinal shortening and myocardial phosphocreatine/adenosine triphosphate ratio (all p<0.01). Peak arterial-venous oxygen difference (p<0.05), oxygen uptake (VO2) and power were decreased in patients (both p<0.01) with no significant difference in cardiac power output. All patients remained stable and completed ≥80% sessions. With training, there were similar proportional increases in peak VO2, anaerobic threshold and work capacity in patients and controls. LVMI increased in both groups (p<0.01), with no significant effect on myocardial function or bioenergetics. Pre- and post-exercise training, HRV and BPV demonstrated increased low frequency and decreased high frequency components in patients compared to controls (all p<0.05). CONCLUSION: Patients with mitochondrial disease and controls achieved similar proportional benefits of exercise training, without evidence of disease progression, or deleterious effects on cardiac function. Reduced exercise capacity is largely mediated through skeletal muscle dysfunction at baseline and sympathetic over-activation may be important in pathogenesis.

Cardiac involvement in mitochondrial DNA disease: clinical spectrum, diagnosis, and management.

Mitochondrial disease refers to a heterogenous group of genetic disorders that result from dysfunction of the final common pathway of energy metabolism. Mitochondrial DNA mutations affect key components of the respiratory chain and account for the majority of mitochondrial disease in adults. Owing to critical dependence of the heart on oxidative metabolism, cardiac involvement in mitochondrial disease is common and may occur as the principal clinical manifestation or part of multisystem disease. Recent advances in our understanding of the clinical spectrum and genetic aetiology of cardiac involvement in mitochondrial DNA disease have important implications for cardiologists in terms of the investigation and multi-disciplinary management of patients.

Sudden cardiac death among competitive adult athletes: a review.

Sudden cardiac death is the leading cause of mortality among young athletes with an incidence of 1-2 per 100,000 athletes per annum. It is described as 'an event that is non-traumatic, non-violent, unexpected, and resulting from sudden cardiac arrest within six hours of previously witnessed normal health'. Most predisposed athletes have no symptoms and there is no warning for the impending tragic event. The majority of cases are caused by an underlying structural cardiac abnormality, most commonly hypertrophic cardiomyopathy. More recently, the understanding of non-structural causes such as long QT syndrome and Brugada syndrome has grown and diagnostic criteria have been developed. This review presents the known aetiologies of sudden cardiac death among athletes and outlines their identification and management including implications for future sporting participation as laid out in the consensus documents produced by the European Society of Cardiology and the 36th Bethesda Conference.

A disappearing neonatal skin lesion.

A preterm baby girl was noted at birth to have a firm, raised, non-tender skin lesion located over her right hip. She developed three similar smaller lesions on her ear, buttock and right knee. All lesions had resolved by 2 months of age.

Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study.

BACKGROUND: We report clinical safety and biochemical efficacy from a dose-ranging study of intravenously administered AVI-4658 phosphorodiamidate morpholino oligomer (PMO) in patients with Duchenne muscular dystrophy. METHOD: We undertook an open-label, phase 2, dose-escalation study (0·5, 1·0, 2·0, 4·0, 10·0, and 20·0 mg/kg bodyweight) in ambulant patients with Duchenne muscular dystrophy aged 5-15 years with amenable deletions in DMD. Participants had a muscle biopsy before starting treatment and after 12 weekly intravenous infusions of AVI-4658. The primary study objective was to assess safety and tolerability of AVI-4658. The secondary objectives were pharmacokinetic properties and the ability of AVI-4658 to induce exon 51 skipping and dystrophin restoration by RT-PCR, immunohistochemistry, and immunoblotting. The study is registered, number NCT00844597. FINDINGS: 19 patients took part in the study. AVI-4658 was well tolerated with no drug-related serious adverse events. AVI-4658 induced exon 51 skipping in all cohorts and new dystrophin protein expression in a significant dose-dependent (p=0·0203), but variable, manner in boys from cohort 3 (dose 2 mg/kg) onwards. Seven patients responded to treatment, in whom mean dystrophin fluorescence intensity increased from 8·9% (95% CI 7·1-10·6) to 16·4% (10·8-22·0) of normal control after treatment (p=0·0287). The three patients with the greatest responses to treatment had 21%, 15%, and 55% dystrophin-positive fibres after treatment and these findings were confirmed with western blot, which showed an increase after treatment of protein levels from 2% to 18%, from 0·9% to 17%, and from 0% to 7·7% of normal muscle, respectively. The dystrophin-associated proteins α-sarcoglycan and neuronal nitric oxide synthase were also restored at the sarcolemma. Analysis of the inflammatory infiltrate indicated a reduction of cytotoxic T cells in the post-treatment muscle biopsies in the two high-dose cohorts. INTERPRETATION: The safety and biochemical efficacy that we present show the potential of AVI-4658 to become a disease-modifying drug for Duchenne muscular dystrophy. FUNDING: UK Medical Research Council; AVI BioPharma.

Ablation of atrial tachyarrhythmias late after surgical repair of tetralogy of Fallot.

BACKGROUND: Patients with repaired tetralogy of Fallot may develop symptomatic and haemodynamic deterioration for many reasons such as arrhythmia, pulmonary regurgitation, and impairment in ventricular function. We describe a consecutive group of patients whose main clinical problem was atrial tachyarrhythmias. AIMS: To describe the clinical outcome of atrial tachyarrhythmias occurring late after surgical repair of tetralogy of Fallot; to define the circuits/foci responsible for these atrial tachyarrhythmias; to evaluate the outcome of computer-assisted mapping and catheter ablation in this patient group. METHODS AND RESULTS: Consecutive patients with surgically repaired tetralogy of Fallot and atrial tachyarrhythmias, who underwent catheter ablation between January, 2001 and June, 2007, were identified retrospectively from case records. Computer-assisted mapping was performed in all using either EnSite® (St Jude Medical Inc.) arrhythmia mapping and intra-cardiac catheter guidance system or CARTO™ (Biosense Webster Inc.) electroanatomical mapping systems. Ten patients (four males) with a median age of 39 plus or minus 8 years were studied. The total number of atrial tachyarrhythmias identified was 22 (six macro-reentrant, 16 micro-reentrant/focal). In nine patients, catheter ablation led to improvement in arrhythmia episodes and/or symptoms during follow-up of 41 plus or minus 20 months. Following ablation(s), five patients required pacing for pre-existing conduction disease and five needed further surgery for haemodynamic indications. All patients remained on anti-arrhythmic drugs. CONCLUSIONS: Patients with surgically repaired tetralogy of Fallot and atrial tachyarrhythmias typically have multiple arrhythmic circuits/foci arising from a scarred right atrium. Catheter ablation reduces arrhythmia frequency and improves symptoms. However, hybrid management is often required, comprising drugs, pacing, and further surgery tailored to the individual.

Carotid endarterectomy: a Southern North Island regional consensus statement.

AIMS: The aim of this project was to employ interdepartmental and cross district health board collaboration to reach a regional consensus on the management of patients who may benefit from carotid endarterectomy. METHODS: All regional stroke physicians, neurologists, and vascular surgeons met to review relevant literature and local audits and to discuss best management strategies suited to the region. RESULTS: A consensus statement was agreed upon and is presented here along with a summary of the supporting scientific evidence. DISCUSSION: Regional interdisciplinary collaboration proved an effective way to reach a carotid endarterectomy management consensus across a wider geographical area that is served by a single vascular surgery department. This approach could serve as a model for other regional initiatives.