Hereditary C1q Deficiency is Associated with Type 1 Interferon-Pathway Activation and a High Risk of Central Nervous System Inflammation.

Hereditary C1q deficiency (C1QDef) is a rare monogenic disorder leading to defective complement pathway activation and systemic lupus erythematosus (SLE)-like manifestations. The link between impairment of the complement cascade and autoimmunity remains incompletely understood. Here, we assessed type 1 interferon pathway activation in patients with C1QDef. Twelve patients with genetically confirmed C1QDef were recruited through an international collaboration. Clinical, biological and radiological data were collected retrospectively. The expression of a standardized panel of interferon stimulated genes (ISGs) in peripheral blood was measured, and the level of interferon alpha (IFNα) protein in cerebrospinal fluid (CSF) determined using SIMOA technology. Central nervous system (encompassing basal ganglia calcification, encephalitis, vasculitis, chronic pachymeningitis), mucocutaneous and renal involvement were present, respectively, in 10, 11 and 2 of 12 patients, and severe infections recorded in 2/12 patients. Elevated ISG expression was observed in all patients tested (n = 10/10), and serum and CSF IFNα elevated in 2/2 patients. Three patients were treated with Janus-kinase inhibitors (JAKi), with variable outcome; one displaying an apparently favourable response in respect of cutaneous and neurological features, and two others experiencing persistent disease despite JAKi therapy. To our knowledge, we report the largest original series of genetically confirmed C1QDef yet described. Additionally, we present a review of all previously described genetically confirmed cases of C1QDef. Overall, individuals with C1QDef demonstrate many characteristics of recognized monogenic interferonopathies: particularly, cutaneous involvement (malar rash, acral vasculitic/papular rash, chilblains), SLE-like disease, basal ganglia calcification, increased expression of ISGs in peripheral blood, and elevated levels of CSF IFNα.

Correlates and predictors of paediatric leg pain: a case-control study.

Paediatric leg pains, long described as 'growing pains', frequently present to clinicians, are prevalent in early childhood, disrupt sleep, and distress affected children and parents. There are many cited associations, but no defined leg pain sub-types, nor revealed predictive factors. We explored the implicated factors (viz. foot arches, foot strength, joint mobility, vitamin D, iron) in children with leg pain versus a control group. Leg pain sub-groups-growing pains (GP), restless legs (RLS), both (mixed)-are defined for the first time. A case controlled study design, in a primary care setting, Mumbai, India. A total of 77 children with leg pains (n = 64) and controls (n = 13), aged 3-12 years, identified by paediatricians, completed data collection. Blood assays for iron and vitamin D, pain, Beighton score, foot arch, foot strength and anthropometrical data were collected. All outcome measures were validated, with standardised protocols. Leg pain (all groups) was predicted by increased joint mobility and increased ankle dorsiflexion strength (ß = 0.56, P < 0.05). GP sub-group was predicted by increased ankle dorsiflexion strength (ß = - 0.06, P < 0.05). Mixed (GP/RLS) and RLS sub-groups were predicted by increased ankle dorsiflexion strength (ß = 0.66, P < 0.05) and pain questionnaire (ß = 0.11, P < 0.05). Hypovitaminosis D was detected in 87% of the sample, and anaemia in 13%. Increased strength of ankle dorsiflexors and joint flexibility were each found predictive for leg pain. Increased body weight, waist girth, and BMI were all associated with leg pain.

The risk of refeeding syndrome among severely malnourished tuberculosis patients in Chhattisgarh, India.

BACKGROUND: A secondary care hospital in rural India serving a highly tuberculosis (TB) and malnutrition endemic region. OBJECTIVE: In this study conducted on patients with chronic protein energy malnutrition (PEM) and TB, we sought to compare nurse-estimated vs. smartphone photograph analytic methods for assessing caloric intake and determine the incidence of refeeding hypophosphatemia (RH) and refeeding syndrome (RFS) in patients with TB. METHODS: Inpatients were prospectively enrolled. Baseline demographic, comorbidity and preadmission caloric data were collected. Nurse estimated caloric intake was compared with digital "before and after" meal images. Serum phosphorus was measured on days 1, 3 and 7 post admission. Patients with RH underwent further evaluation for RFS-associated findings. RESULTS: 27 patients were enrolled. 85% were at risk of RFS by National Institute for Health and Care Excellence (NICE) criteria. Significant discrepancy (>700 calories) was noted between nurse-estimated caloric intake compared to digital images. RH was found in 37% (10/27). None developed clinical RFS. CONCLUSIONS: Our study suggests more standardized methods of caloric intake are needed in resource-limited settings with high co-prevalence of PEM and TB. We noted that despite RH being common in inpatients with PEM+TB given high caloric diets, RFS was not detected.

Ruptured Hepatocellular Carcinoma in a Child with Budd-Chiari Syndrome.

BACKGROUND: Hepatocellular carcinoma is an uncommon complication described in patients with Budd-Chiari syndrome. CASE CHARACTERISTICS: A 12-year-old boy with Budd-Chiari syndrome, who was earlier treated with Transjugular intrahepatic porto-systemic shunt (TIPS), presented with acute onset hemoperitoneum and hypotension. OUTCOME: It was diagnosed to be a case of ruptured hepatocellular carcinoma. MESSAGE: Successful TIPS may not prevent the development of hepatocellular carcinoma, and children with Budd Chiari syndrome should be monitored for the same.

Long-term clinical outcome of Budd-Chiari syndrome in children after radiological intervention.

OBJECTIVES: Budd-Chiari syndrome (BCS) is an uncommon cause of chronic liver disease in children. The literature on the management of pediatric BCS is scarce. Our aim was to determine the long-term outcome of patients undergoing a radiological intervention for the treatment of BCS. METHODS: Thirty-two children diagnosed with BCS between 2004 and 2014 were included. Data on the course of disease, medical management, response, and complications related to radiological interventions and outcome were collected. MAIN RESULTS: Twenty-five patients who were on regular follow-up were analyzed. The median age of the patients at presentation was 9 months (4.5-214). Sixteen patients initially received anticoagulation alone. This was associated with a high failure rate of 66%. Twenty patients underwent a radiological intervention in the form of angioplasty (n=7), hepatic vein stenting (n=3) or transjugular intrahepatic portosystemic shunt (TIPS) (n=14). Success with angioplasty was achieved in 43% of cases. Hepatic vein stenting was successful in 66%, whereas TIPS was successful in 72% of cases. TIPS was feasible in all patients. The median follow-up duration was 44 months (5-132). Four patients developed hepatopulmonary syndrome after a median period of 3 years (1.5-5.25) and one patient developed hepatocellular carcinoma. CONCLUSION: BCS commonly presents during infancy. Anticoagulation alone and angioplasty of the hepatic veins are associated with a high failure rate. Hepatic vein stenting or TIPS is feasible and efficacious in improving liver function, portal hypertension, and growth. It is associated with good long-term outcome and delays the need for liver transplantation, but may not prevent complications such as hepatopulmonary syndrome and hepatocellular carcinoma.

Comprehensive Analysis of Established Dyslipidemia-Associated Loci in the Diabetes Prevention Program.

BACKGROUND: We assessed whether 234 established dyslipidemia-associated loci modify the effects of metformin treatment and lifestyle intervention (versus placebo control) on lipid and lipid subfraction levels in the Diabetes Prevention Program randomized controlled trial. METHODS AND RESULTS: We tested gene treatment interactions in relation to baseline-adjusted follow-up blood lipid concentrations (high-density lipoprotein [HDL] and low-density lipoprotein-cholesterol, total cholesterol, and triglycerides) and lipoprotein subfraction particle concentrations and size in 2993 participants with pre-diabetes. Of the previously reported single-nucleotide polymorphism associations, 32.5% replicated at P<0.05 with baseline lipid traits. Trait-specific genetic risk scores were robustly associated (3×10-4>P>1.1×10-16) with their respective baseline traits for all but 2 traits. Lifestyle modified the effect of the genetic risk score for large HDL particle numbers, such that each risk allele of the genetic risk scores was associated with lower concentrations of large HDL particles at follow-up in the lifestyle arm (ß=-0.11 µmol/L per genetic risk scores risk allele; 95% confidence interval, -0.188 to -0.033; P=5×10-3; Pinteraction=1×10-3 for lifestyle versus placebo), but not in the metformin or placebo arms (P>0.05). In the lifestyle arm, participants with high genetic risk had more favorable or similar trait levels at 1-year compared with participants at lower genetic risk at baseline for 17 of the 20 traits. CONCLUSIONS: Improvements in large HDL particle concentrations conferred by lifestyle may be diminished by genetic factors. Lifestyle intervention, however, was successful in offsetting unfavorable genetic loading for most lipid traits. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique Identifier: NCT00004992.

Prevention of Diabetes Through the Lifestyle Intervention: Lessons Learned from the Diabetes Prevention Program and Outcomes Study and its Translation to Practice.

A number of strategies have been used to delay or prevent the development of type 2 diabetes mellitus (T2D) in high-risk adults. Among them were diet, exercise, medications and surgery. This report focuses on the nutritional lessons learned from implementation of the Intensive Lifestyle Intervention (ILI) in the DPP and its follow-up DPPOS that looked at weight loss through modification of diet and exercise. The Diabetes Prevention Program (DPP) is a large clinical trial, sponsored by the National Institutes of Health, designed to look at several strategies to prevent conversion to type 2 diabetes (T2D) by adults with prediabetes (IGT/IFG) including an Intensive Lifestyle Intervention (ILI). The ∼3800 ethnically diverse participants (46% reported non-white race) were overweight, had impaired glucose tolerance (IGT) and impaired fasting glucose (IFG). Treatments were assigned randomly. The Diabetes Prevention Program Outcomes Study (DPPOS) is a follow up study evaluating the long-term outcomes of the clinical trial.