Is Shift Work Sleep Disorder a Risk Factor for Metabolic Syndrome and Its Components? A Systematic Review of Cross-Sectional Studies.

Shift work sleep disorder is prevalent in night shift workers due to prolonged misalignment of the circadian rhythm. Night shift workers comprise a significant portion of the workforce and it is important to study the potential implications on their health. Studies have shown the association of metabolic syndrome (MetS) and the components, that is, obesity, dyslipidemia, hypertension, and insulin resistance, with shift workers. Nocturnal exposure to bright light can affect various physiological processes including melatonin secretion, which is a regulator in insulin synthesis. A systematic review was conducted to identify studies showing the association between shift work and MetS and/or its components, as well as to review the pathophysiology for further investigations. This review follows the guidelines as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist 2009. One thousand nine hundred ten records were identified from the PubMed database using both keywords and medical subject headings terms. After applying the inclusion/exclusion and eligibility criteria, 18 observational studies were included in the qualitative synthesis. Quality appraisal was conducted by two investigators independently using the Newcastle/Ottawa Scale, and 11 articles were finalized for the review after scoring 60% and above. Each study measured the different components of MetS and/or the presence of MetS. Statistically significant results were reported for the association between shift work and MetS, shift work and obesity, shift work and dyslipidemia, shift work and hypertension, and shift work and insulin resistance. This review identifies a need to emphasize treatment plans for shift workers to manage not only sleep disorders but other chronic diseases such as MetS, obesity, hypertension, dyslipidemia, and insulin resistance.

Decoding the Pathophysiology of Non-alcoholic Fatty Liver Disease Progressing to Non-alcoholic Steatohepatitis: A Systematic Review.

Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic manifestation of metabolic syndromes, and its roots are strongly associated with obesity and insulin resistance. The excess fat induces inflammatory pathways by tissue irritation and progresses to non-alcoholic steatohepatitis (NASH), fibrosis, and has emerged as the most frequent cause of hepatocellular cancer (HCC). This systematic review was structured per the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. The evidence was obtained from 13 research articles published in PubMed, Google Scholar, and Science Direct databases, including cross-sectional, case-control, prospective cohort studies, meta-analysis, and systematic reviews. The inclusion/exclusion criteria of free articles, published in English involving humans of mid-age in the last five years were applied. This review highlights findings in 7781 individuals, including non-NAFLD, NAFLD, and NASH positive individuals based on anthropometric measurement, blood samples, FibroScan, flow cytometry, and liver biopsy. The results underscored that the onset of inflammation set on the background of NAFLD starts NASH; the understanding and control of inflammation will help us design definitive biomarkers and treatment modalities. The complex pathogenesis and comparatively slow advancement but high morbidity have led investigators to understand the nuts and bolts for early management and prevention. Lipotoxicity and dysbiosis stimulate the immune system to generate cytokines and chemokines and decline in adipokines. The role of proteinase3 (PR3) and antitrypsin (ATT) ratio and biliverdin reductase (BVR) compel the exploration for non-invasive tests for definitive therapy.

Effectiveness of Manual Therapy and Acupuncture in Tension-Type Headache: A Systematic Review.

Tension-type headache is one of the most prevalent types of headache. The common presentation is a mild-to-moderate dull aching pain around the temporal region, like a tight band around the forehead, neck, shoulder, and sometimes behind eyes. It can occur at any age but most commonly in the adult female population. The exact underlying mechanism is not clear but muscle tension is one of the main causes, which can be due to stress and anxiety. There are several non-pharmacologic treatment options suggested for tension-type headaches, such as cognitive behavioral therapy, relaxation, biofeedback, acupuncture, exercise, manual therapy, and even some home remedies. This systematic review was performed to evaluate the effectiveness of acupuncture and manual therapy in tension-type headaches. The literature search was primarily done on PubMed. Eight articles involving 3846 participants showed evidence that acupuncture and manual therapy can be valuable non-pharmacological treatment options for tension-type headaches. Acupuncture was compared to routine care or sham intervention. Acupuncture was not found to be superior to physiotherapy, exercise, and massage therapy. Randomized controlled trials done in various countries showed manual therapy also significantly decreased headache intensity. Manual therapy has an efficacy that equals prophylactic medication and tricyclic antidepressants in treating tension-type headaches. The available data suggests that both acupuncture and manual therapy have beneficial effects on treating symptoms of tension-type headache. However, further clinical trials looking at long-term benefits and risks are needed.

Cesarean Section: A Potential and Forgotten Risk for Abdominal Wall Endometriosis.

Cesarean section endometriosis (CSE) can be caused by the iatrogenic deposition of endometrial cells, glands, and stroma during any time of the surgical procedure. It can be asymptomatic or, more frequently, resulting in chronic pain. Our article intends to provide more clinical information on CSE symptomatology, diagnosis, and preventive methods available in the literature, and discuss the malignancy transformation risk. We performed a systematic review based on the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. We included all types of study designs and selected only English articles from 2016 and forward. A total of 268 patients with abdominal wall endometriosis (AWE) were included in the final review; 260 women had CSE and eight women had endometriosis related to another gynecologic procedure. Attention for suggestive symptoms during anamnesis and the presence of abdominal nodules close to the cesarean scar should raise suspicions of scar endometriosis. In addition, abdominal ultrasonography (USG), computed tomography (CT), magnetic resonance imaging (MRI), and fine-needle aspiration (FNA) biopsy can be helpful to differentiate from other conditions such as incisional hernias, suture granulomas, or malignant tumors. However, the final diagnosis and treatment is still the complete excision of the tumor. Therefore, additional studies on pathophysiology would help with new preventive methods and less invasive therapeutic options.

Tubercular meningitis in children: Clinical, pathological, and radiological profile and factors associated with mortality.

CONTEXT: Childhood tuberculosis is a major public health problem in developing countries with tubercular meningitis being a serious complication with high mortality and morbidity. AIM: To study the clinicopathological as well as radiological profile of childhood tuberculous meningitis (TBM) cases. SETTINGS AND DESIGN: Prospective, observational study including children <14 years of age with TBM admitted in a tertiary care hospital from Western India. SUBJECTS AND METHODS: TBM was diagnosed based on predefined criteria. Glassgow coma scale (GCS) and intracranial pressure (ICP) was recorded. Staging was done as per British Medical Council Staging System. Mantoux test, chest X-ray, cerebrospinal fluid (CSF) examination, neuroimaging, and other investigations were done to confirm TB. STATISTICAL ANALYSIS USED: STATA software (version 9.0) was used for data analysis. Various risk factors were determined using Chi-square tests, and a P< 0.05 was considered significant. RESULTS: Forty-seven children were included, of which 11 (24.3%) died. Fever was the most common presenting symptom, and meningismus was the most common sign. Twenty-nine (62%) children presented with Stage III disease. Stage III disease, low GCS, and raised ICP were predictors of mortality. Findings on neuroimaging or CSF examination did not predict mortality. CONCLUSIONS: Childhood TBM presents with nonspecific clinical features. Stage III disease, low GCS, lack of Bacillus Calmette-Guérin vaccination at birth and raised ICP seem to the most important adverse prognostic factors.

Prognostic value of complete remission with superior platelet counts in acute myeloid leukemia.

BACKGROUND: Complete remission (CR) in acute myeloid leukemia (AML) is defined as having ≤5% leukemic blast cells in the bone marrow and return of normal hematopoiesis after the first induction cycle. There is a subset of patients, however, who achieve reduction of leukemic blast cells with a subnormal platelet count, designated as CR with incomplete platelet recovery (platelet count, ≤100,000/mcL; normal, 150,000-450,000/mcL), which is associated with inferior outcomes when compared with CR. Furthermore, there is another subset of patients with CR but superior platelet counts (≥400,000/mcL) whose prognostic significance is unclear. OBJECTIVE: To establish whether CR with superior platelet counts is associated with better outcomes and can be used as a separate entity for prognostication. METHODS: A retrospective chart review of 104 cases of AML was conducted. The highest platelet count during days 25-35 from initiation of induction chemotherapy (designated as day 30 platelet count) was documented. A multivariate analysis for other factors such as age, sex, risk categories, day 14+ plasma cell count (average plasma cell percentage at days 14-21), infections, allogeneic bone marrow transplant, and remission status was done. RESULTS: Day 30 platelet count was found to be an independent predictor of survival in AML. On the multivariate analysis, the subgroup with superior platelet counts (≥400,000/mcL) was found to be associated with better outcomes. LIMITATIONS: Results need to be validated in a larger cohort. CONCLUSIONS: CR with superior platelet recovery (≥400,000/mcL) is a unique subcategory in itself and has prognostic significance. This may help better assess response to chemotherapeutic agents and aid in further decision-making regarding treatment.

New developments in the treatment of chronic lymphocytic leukemia: role of obinutuzumab.

Obinutuzumab is a novel glycoengineered type II anti-CD20 monoclonal antibody with a higher affinity for CD20 epitope, enhanced antibody-dependent cellular cytotoxicity and direct cell death, leading to superior cytotoxicity compared with rituximab. The approval of obinutuzumab by US Food and Drug Administration was based on a pivotal, phase III, randomized trial of chlorambucil monotherapy (n=118), chlorambucil plus obinutuzumab (n=333), or chlorambucil plus rituximab (n=330) in previously untreated patients with CLL. Obinutuzumab was administered intravenously as 1,000 mg on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles. Obinutuzumab plus chlorambucil was associated with an overall response rate of 78% and a median progression-free survival of 26.7 months. Overall, obinutuzumab was fairly well tolerated in this pivotal study. The incidence of grade 3 or higher adverse events was infusion-related reactions (20%), neutropenia (33%), thrombocytopenia (10%), and infections (7%). Obinutuzumab in combination with chlorambucil is a safe and effective new treatment option for previously untreated elderly patients with CLL. It should become the new standard of care for these patients with significant co-morbidities who are not candidates for fludarabine-based therapy. Obinutuzumab combination therapy with several agents that inhibit kinases involved in the B-cell receptor signaling pathway, as well as many other agents utilized in the frontline and relapsed/refractory setting, is currently under investigation. As the results from these studies become available, the role of obinutuzumab is expected to expand to other settings.

Idelalisib: A Novel PI3Kδ Inhibitor for Chronic Lymphocytic Leukemia.

OBJECTIVE: To review and summarize data on idelalisib, which was approved by the Food and Drug Administration (FDA) in July 2014 for use in combination with rituximab for relapsed chronic lymphocytic leukemia (CLL). DATA SOURCES: A literature search using PubMed was conducted from January 2011 through May 2015 using the terms idelalisib, GS-101, CAL-101, PI3Kδ, and CLL. Data were also obtained through the FDA briefing documents, American Society of Clinical Oncology, and American Society of Hematology abstracts. STUDY SELECTION AND DATA EXTRACTION: The literature search was limited to human studies published in English. Priority was placed on trials of idelalisib in CLL. DATA SYNTHESIS: Idelalisib is a potent, first-in-class selective inhibitor of phosphatidylinositol-3-kinaseδ (PI3Kδ) approved by the FDA in July 2014 for the treatment of relapsed CLL, in combination with rituximab, in patients for whom rituximab monotherapy would be considered appropriate due to other comorbidities. PI3Kδ is hyperactivated in B-cell malignancies and plays a vital role in the B-cell receptor pathway, a key oncogenic driver in various B-cell malignancies, including CLL. Several phase I/II studies have demonstrated clinical activity of idelalisib in CLL, particularly in the setting of relapsed/refractory disease, with overall response rate ranging from 70% to 82%. The FDA approval was based on a phase III, randomized trial of rituximab monotherapy (n = 110) or idelalisib in combination with rituximab (n = 110) in heavily, pre-treated patients (median of 3 prior therapies) with relapsed CLL. Idelalisib was administered as 150 mg orally twice daily. Idelalisib plus rituximab was associated with an overall response rate of 81% and overall survival of 91% at 12 months. The median progression-free survival was not reached in the idelalisib arm at the time of the first interim analysis. The incidence of grade 3 or higher adverse events in the idelalisib plus rituximab arm was as follows: neutropenia (34%), thrombocytopenia (10%), anemia (5%), elevation in transaminases (5%), and diarrhea (4%). CONCLUSION: Idelalisib in combination with rituximab is a safe and effective new treatment option for patients with relapsed CLL, including those with poor prognostic factors. As the results from various ongoing studies become available, the role of idelalisib will likely continue to expand.

Breakthrough Therapy Designation: Bringing Innovation Swiftly to Patients.

In early 2012, the Breakthrough Therapy Act was introduced into the US House of Representatives and the Senate. The bills received bipartisan support and were included as an amendment to the Food and Drug Administration Safety and Innovation Act in the Prescription Drug User Fee Act V. On July 9, 2012, the breakthrough therapy designation was signed into law. As of June 13, 2014, a total of 48 products have been designated as breakthrough therapies by the Center for Drug Evaluation and Research, and 4 of those have received FDA new molecular entity approval.

Obinutuzumab: a novel anti-CD20 monoclonal antibody for previously untreated chronic lymphocytic leukemia.

OBJECTIVE: To review and summarize data on obinutuzumab, which was approved by the Food and Drug Administration (FDA) in November 2013 for use in combination with chlorambucil for previously untreated chronic lymphocytic leukemia (CLL). DATA SOURCES: A PubMed literature search (August 2002 to March 2014) was conducted using the terms obinutuzumab, GA101, anti-CD20 antibody, and CLL. Data were also obtained through the FDA briefing documents and American Society of Hematology abstracts. STUDY SELECTION AND DATA EXTRACTION: The literature search was limited to human studies published in English. Priority was placed on trials of obinutuzumab in previously untreated CLL. DATA SYNTHESIS: Obinutuzumab is a novel glycoengineered type II anti-CD20 monoclonal antibody, with a higher affinity for CD20 epitope, leading to superior cytotoxicity compared with rituximab. The FDA approval was based on a phase III, randomized trial of chlorambucil monotherapy (n = 118), chlorambucil plus obinutuzumab (n = 333), or rituximab (n =330) in previously untreated elderly CLL patients. Obinutuzumab was administered intravenously as 1000 mg on days 1, 8, and 15 of cycle 1 and day 1 for subsequent cycles. Median progression-free survival was 26.7 months in the chlorambucil plus obinutuzumab arm. The incidence of grade 3 or higher adverse events in the obinutuzumab plus chlorambucil arm was as follows: neutropenia (33%), infusion-related reactions (20%), thrombocytopenia (10%), and infections (7%). CONCLUSION: Obinutuzumab in combination with chlorambucil is a safe and effective new treatment option for previously untreated elderly CLL patients. It should become the new preferred therapy for these patients with significant comorbidities who are not candidates for fludarabine-based therapy.

Neonatal sepsis: high antibiotic resistance of the bacterial pathogens in a neonatal intensive care unit of a tertiary care hospital.

OBJECTIVE: To study the bacterial pathogens causing neonatal sepsis and their sensitivity pattern so that guidelines can be prepared for empirical antibiotic therapy. MATERIALS AND METHODS: We conducted a prospective analysis of all the cases admitted to the neonatal intensive care unit (NICU) of a tertiary care hospital and studied the culture and sensitivity pattern of organisms isolated. The neonates who presented with signs and symptoms of septicemia, with/without pneumonia and/or meningitis were studied and a detailed record of the maturity, age at onset, sex, birth weight (weight on admission for home deliveries), symptoms and signs along with the maternal risk factors was made. The cases with suspect sepsis were screened using various screening markers. Blood culture was done in all the cases, while cerebrospinal fluid was analysed only in those indicated. Sensitivity of the isolated organism was tested by Kirby Bauer disc diffusion techniques and various drug resistance mechanisms were studied. RESULT: Out of the 190 neonates (M:F=1.22:1) admitted to the NICU, 60 (31.57%) shows blood culture positive. Ninety-five percent cases were due to early onset septicemia. Thirty one neonates had Gram negative, twenty seven had Gram positive septicemia and two had candidial infection. Seventy percent Gram-positive isolates were resistant to penicillin. Ninety percent Gram negative isolates were resistant to gentamycin and ampicillin. Carbapenem resistance mechanisms such as ESBL. CONCLUSION: There is an increasing trend of antibiotic resistance to the commonly used and available drugs. Continuous surveillance for antibiotic susceptibility should be done to look for resistance pattern.