Citations

Abstract Background Hypothyroidism is known to be associated with adverse clinical outcomes in heart failure. The association between hypothyroidism and cardiac resynchronization therapy outcomes in patients with severe heart failure is not clear. Methods The study included 1,316 patients who received cardiac resynchronization therapy between 2002 and 2015. Baseline demographics and cardiac resynchronization therapy outcomes, including left ventricular ejection fraction, New York Heart Association class, appropriate implantable cardioverter-defibrillator therapy, and all-cause mortality, were collected from the electronic health record. Results Of the study cohort, 350 patients (26.6%) were classified as the hypothyroidism group. The median duration of follow-up was 3.6 years (interquartile range, 1.7-6.2). Hypothyroidism was not associated with a higher risk of all-cause mortality in patients receiving CRT for heart failure. The risk of appropriate implantable cardioverter-defibrillator therapy significantly increased in association with increased baseline thyroid -stimulating hormone level in the entire cohort (hazard ratio, 1.23 per 5mIU/L increase; 95% CI, 1.01-1.5; P=0.04) as well as in the hypothyroid group (hazard ratio, 1.44 per 5mIU/L increase; 95% CI, 1.13-1.84; P=0.004). Conclusions CRT improves cardiac function in hypothyroid patients. The ventricular arrhythmic events requiring ICD therapies are associated with baseline TSH level, which might be considered as an important biomarker to stratify the risk of sudden death for patients with heart failure and hypothyroidism.

Abstract Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two‐sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low‐density lipoprotein [LDL] and high‐density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels ( P < 5 × 10 −8 ) were identified as instrumental variables, and assessed using genome‐wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non‐endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non‐endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non‐endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non‐endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.

The absence of neuroendocrine (NE) cells in the intestinal mucosa in autoimmune enteropathy (AIE) has been occasionally reported. However, the status of NE cells has not been studied in detail in AIE. Small bowel and colonic biopsies were retrospectively retrieved from 18 AIE patients (26 baseline [18 small bowel and 8 colon]; and 15 follow-up [11 duodenum and 4 colon] biopsies in 11 patients). Thirty-three common variable immunodeficiency (CVID) patients (30 small bowel and 16 colon), 15 inflammatory bowel disease patients (5 duodenum and 10 colon), 13 immunoglobulinA deficiency patients (13 duodenum and 5 colon), and 10 normal controls (5 colon and 5 duodenum) were selected as control groups. Histologic features (villous atrophy, intraepithelial lymphocytosis, acute inflammation, crypt apoptosis, and absence or presence of goblet cells, Paneth cells and plasma cells) were recorded. Chromogranin immunostain was performed and chromogranin-positive NE cells were counted per 10 consecutive, well-oriented crypts. On the basis of the number of chromogranin-positive NE cells, cases were graded as being absent (≤3 NE cells), markedly decreased (≤15), and intact (>15). The NE cell status correlated with histologic features. The median age of 18 AIE patients was 38.5 years (range: 11 to 74 y) and 14 patients were male. Fourteen of 18 (78%) patients showed loss (absent or markedly decreased) of NE cells in the small bowel and/or colon in the baseline biopsies including 12 (of 18) small bowel and 6 (of 8) colon biopsies. Follow-up biopsy was available in 11 patients. Six of 7 (85%) patients who showed loss of NE cells in the baseline biopsies regained NE cells in the follow-up biopsies, and 1 patient continued to show loss of NE cells. Four patients who showed intact NE cells in the baseline remained unchanged in the follow-up. Among the control groups, 3 of 33 (9%) CVID patients showed loss of NE cells. NE cells were not lost in the biopsies of all 15 and 13 patients with inflammatory bowel disease and immunoglobulinA deficiency, respectively, or the 10 normal controls. In all 41 biopsies (26 baseline plus 15 follow-up) with AIE, NE cell loss was significantly associated with increased crypt apoptosis and loss of goblet cells (P=0.001, both) but not with other histologic findings. In conclusion, our study suggests that NE cells may also be the target cells in AIE and commonly lost in the intestinal crypts in AIE, and consequently loss of NE cells can be used as an adjunct histologic feature for diagnosis of AIE.

ABSTRACT Background Implementation of checklists has been shown to be effective in improving patient safety. This study aims to evaluate the effectiveness of implementation of a checklist for daily care processes into clinical practice of pediatric intensive care units (PICUs) with limited resources. Methods Prospective before–after study in eight PICUs from China, Congo, Croatia, Fiji, and India after implementation of a daily checklist into the ICU rounds. Results Seven hundred and thirty-five patients from eight centers were enrolled between 2015 and 2017. Baseline stage had 292 patients and post-implementation 443. The ICU length of stay post-implementation decreased significantly [9.4 (4–15.5) vs. 7.3 (3.4–13.4) days, p = 0.01], with a nominal improvement in the hospital length of stay [15.4 (8.4–25) vs. 12.6 (7.5–24.4) days, p = 0.055]. The hospital mortality and ICU mortality between baseline group and post-implementation group did not show a significant difference, 14.4% vs. 11.3%; p = 0.22 for each. There was a variable impact of checklist implementation on adherence to various processes of care recommendations. A decreased exposure in days was noticed for; mechanical ventilation from 42.6% to 33.8%, p &lt; 0.01; central line from 31.3% to 25.3%, p &lt; 0.01; and urinary catheter from 30.6% to 24.4%, p &lt; 0.01. Although there was an increased utilization of antimicrobials (89.9–93.2%, p &lt; 0.01). Conclusions Checklists for the treatment of acute illness and injury in the PICU setting marginally impacted the outcome and processes of care. The intervention led to increasing adherence with guidelines in multiple ICU processes and led to decreased length of stay.

Background Adolescent idiopathic scoliosis (AIS) is a genetically heterogeneous disease characterised by three-dimensional deformity of the spine in the absence of a congenital spinal anomaly or neurological musculoskeletal disorder. The clinical variability and incomplete penetrance of some genes linked with AIS indicate that this disease constitutes an oligogenic trait. Objective We aimed to explore the oligogenic nature of this disease and identify novel AIS genes. Methods We analysed rare damaging variants within AIS-associated genes by using exome sequencing in 40 AIS trios and 183 sporadic patients. Results Multiple variants within AIS-associated genes were identified in eight AIS trios, and five individuals harboured rare damaging variants in the FLNB gene. The patients showed more frequent oligogenicity than the controls. In the gene-based burden test, the top signal resided in FLNB . In functional studies, we found that the AIS-associated FLNB variants altered the protein’s conformation and subcellular localisation and its interaction with other proteins (TTC26 and OFD1) involved in AIS. The most compelling evidence of an oligogenic basis was that the number of rare damaging variants was recognised as an independent prognostic factor for curve progression in Cox regression analysis. Conclusion Our data indicate that AIS is an oligogenic disease and identify FLNB as a susceptibility gene for AIS.

Abstract OBJECTIVEOsteoarthritis (OA) is the most common form of joint disease which usually affects load-bearing joints such as hip and knee joints. Most guidelines recommend the use non-steroidal anti-inflammatory drugs (NSAIDs), duloxetine and tramadol for the non-operative treatment of OA, the use of them is limited by the tolerability and safety concerns. Lutikizumab is a novel anti–IL-1α/β dual variable domain immunoglobulin that can simultaneously binds and inhibits IL-1α and IL-1β to relieve the pain and dysfunction symptoms. We conducted this network meta-analysis to comprehensively compare the clinical efficacy and safety of lutikizumab with other drugs recommended by guidelines.DESIGNSystematic review and Bayesian network meta-analysis.DATA SOURCESAll eligible studies in PubMed, CKNI, EMBASE and Web of Science databases, from January 2000 to January 2020.METHODSBayesian network and conventional meta-analyses were conducted. Pain relief, function improvement and risk of adverse effects (AEs) were assessed.RESULTS24 articles with 11858 patients were included. Lutikizumab showed no benifit compared with placebo for both pain relief (SMD 1.11, 95% CI [-2.29 to 4.52]) and function improvement (SMD 0.992, 95% CI [-0.433 to 4.25]). Lutikizumab and all other drugs are of favorable tolerance for patients in treatment of OA compared with placebo.CONCLUSIONSThe results show that lutikizumab, the new anti–Interleukin-1α/β dual variable domain immunoglobulin, did not improve pain or function in the comparison with placebo. Selective cox-2 inhibitors remain the most effective and safest treatment for osteoarthritis. More high-quality trials are still needed to reconfirm the findings of this study.

Background and objectives Shared decision making in patients with glomerular disease remains challenging because outcomes important to patients remain largely unknown. We aimed to identify and prioritize outcomes important to patients and caregivers and to describe reasons for their choices. Design, setting, participants, & measurements We purposively sampled adult patients with glomerular disease and their caregivers from Australia, Hong Kong, the United Kingdom, and the United States. Participants identified, discussed, and ranked outcomes in focus groups using the nominal group technique; a relative importance score (between zero and one) was calculated. Qualitative data were analyzed thematically. Results Across 16 focus groups, 134 participants (range, 19–85 years old; 51% women), including 101 patients and 33 caregivers, identified 58 outcomes. The ten highest-ranked outcomes were kidney function (importance score of 0.42), mortality (0.29), need for dialysis or transplant (0.22), life participation (0.18), fatigue (0.17), anxiety (0.13), family impact (0.12), infection and immunity (0.12), ability to work (0.11), and BP (0.11). Three themes explained the reasons for these rankings: constraining day-to-day experience, impaired agency and control over health, and threats to future health and family. Conclusions Patients with glomerular disease and their caregivers highly prioritize kidney health and survival, but they also prioritize life participation, fatigue, anxiety, and family impact.

Abstract Background Hypothyroidism is known to be associated with adverse clinical outcomes in heart failure. The association between hypothyroidism and cardiac resynchronization therapy outcomes in patients with severe heart failure is not clear. Methods The study included 1,316 patients who received cardiac resynchronization therapy between 2002 and 2015. Baseline demographics and cardiac resynchronization therapy outcomes, including left ventricular ejection fraction, New York Heart Association class, appropriate implantable cardioverter-defibrillator therapy, and all-cause mortality, were collected from the electronic health record. Results Of the study cohort, 349 patients (26.5%) were classified as the hypothyroidism group. The median duration of follow-up was 3.6 years (interquartile range, 1.7-6.2). Hypothyroidism was associated with a greater all-cause mortality than euthyroidism (hazard ratio, 1.19; 95% CI, 1.01-1.38; P=0.04). In this group, the risk of appropriate implantable cardioverter-defibrillator therapy significantly increased in association with increased baseline thyroid-stimulating hormone level (hazard ratio, 1.27 per 5 mIU/L increase, 95% CI, 1.00-1.53, P=0.04). Conclusions Cardiac resynchronization therapy improves cardiac function in hypothyroid patients. Hypothyroidism has adverse effects on cardiac resynchronization therapy outcomes with reduced survival and increased implantable cardioverter-defibrillator therapies for ventricular arrhythmic events.

Abstract POEMS syndrome is defined by the presence of peripheral neuropathy (P), organomegaly (O), endocrinopathy (E), monoclonal protein expression (M), and skin changes (S). In addition, patients also have sclerotic bone lesions, papilledema, extravascular volume overload, thrombocytosis, and restrictive lung disease/pulmonary hypertension. A striking but inexplicable feature of the clonal plasma cells in patients with POEMS is that they are virtually always lambda restricted. More surprising is that of the 81 functional immunoglobulin light-chain variable-region genes (IgVL) available in the plasma cell/B cell repertoire, among the 13 cases in which variable gene light chain usage has been reported, all have been either IgVL1-40 or IgVL1-44. The molecular mechanisms triggering the initiation and the progression of POEMS syndrome or the clonal expansion of plasma cells marking this condition remain unclear. We have analyzed the immunoglobulin heavy and light chains sequences in the plasma cells of POEMS patients at the Mayo Clinic Rochester. We found that in 8 out of the 9 patients tested, we could document heavy chain clonality in any given patient; however, no restriction of gene usage among patients was observed in the variable regions of these chains. In the case of light chains, in 14 out of 17 patients we could document not only clonality but also restriction of light chain variable gene usage to IgVL1-40 or IgVL1-44. Our goal is to understand the relevance of this restricted expression of light chain variable region, and its effect on the communication between plasma cells and the neighboring stromal cells that might provide more insight into the disease pathology. To this end, we are generating viral vector constructs that will harbor the germline or mutant versions of IgVλ1-40 and IgVλ1-44 genes and introduced into pre-established malignant plasma cell lines (i.e. myeloma cell lines). We will assay the effects of this over expression in terms of alterations in the expression of cytokines such as VEGF and TNF, and on plasma cell-stromal cell interaction (in a co-culture system). Results from these assays will be discussed.

Restless legs syndrome (RLS) is a common sleep‐related movement disorder characterised by an uncomfortable urge to move the legs that occurs during periods of inactivity. Although there have been many case reports on antipsychotic‐induced RLS, ziprasidone has never been reported as a cause of RLS. We present a case of a female patient with schizophrenia who presented with symptoms of RLS following the administration of high doses of ziprasidone added to quetiapine and valproate. The patient’s symptoms of RLS occurred following the administration and titration of ziprasidone to 160 mg, and were relieved upon reducing the dose to 120 mg/day. Other potential causative medications and differential diagnoses that could have caused similar symptoms were excluded. Clinicians should be aware of the potential for ziprasidone‐induced RLS. Dopamine and serotonin interaction could be the mechanism underlying ziprasidone‐induced RLS.