Miracle-dz/UniFAR-FTUs huggingface dataset:
Nivolumab plus ipilimumab in advanced melanoma.

BACKGROUND In patients with melanoma, ipilimumab (an antibody against cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4]) prolongs overall survival, and nivolumab (an antibody against the programmed death 1 [PD-1] receptor) produced durable tumor regression in a phase 1 trial. On the basis of their distinct immunologic mechanisms of action and supportive preclinical data, we conducted a phase 1 trial of nivolumab combined with ipilimumab in patients with advanced melanoma. METHODS We administered intravenous doses of nivolumab and ipilimumab in patients every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses (concurrent regimen). The combined treatment was subsequently administered every 12 weeks for up to 8 doses. In a sequenced regimen, patients previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses. RESULTS A total of 53 patients received concurrent therapy with nivolumab and ipilimumab, and 33 received sequenced treatment. The objective-response rate (according to modified World Health Organization criteria) for all patients in the concurrent-regimen group was 40%. Evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease for ≥24 weeks) was observed in 65% of patients. At the maximum doses that were associated with an acceptable level of adverse events (nivolumab at a dose of 1 mg per kilogram of body weight and ipilimumab at a dose of 3 mg per kilogram), 53% of patients had an objective response, all with tumor reduction of 80% or more. Grade 3 or 4 adverse events related to therapy occurred in 53% of patients in the concurrent-regimen group but were qualitatively similar to previous experience with monotherapy and were generally reversible. Among patients in the sequenced-regimen group, 18% had grade 3 or 4 adverse events related to therapy and the objective-response rate was 20%. CONCLUSIONS Concurrent therapy with nivolumab and ipilimumab had a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy, with rapid and deep tumor regression in a substantial proportion of patients. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; ClinicalTrials.gov number, NCT01024231.).
Soldier‐biased gene expression in a subterranean termite implies functional specialization of the defensive caste

In a termite colony, reproduction is typically monopolized by a small number of sexuals that are supported by reproductively altruistic soldiers and workers. We expect caste differentiation to be associated with clear‐cut differences in gene expression, and for these differences to reflect caste function and development. Here, we use RNA‐Sequencing to compare the gene expression profiles of sexual nymphs and two non‐reproductive helper castes (i.e., workers and soldiers) of the Eastern subterranean termite Reticulitermes flavipes. We found that of n = 93 genes that are strictly expressed as a function of caste, a majority (78%) show a soldier‐specific pattern. This conspicuous soldier‐bias in genome‐wide expression suggests that this defensively specialized caste is functionally well‐differentiated from both the reproductive and the other non‐reproductive caste of this species, despite a shared developmental program with workers. Gene ontology analysis supports the notion of functional specialization by soldiers, as soldier‐biased gene sets are enriched for novel biological processes. Whether this pattern reflects ancient or more recent bouts of selection for caste novelty at the gene‐regulatory level is not known, but because soldiers are sterile and thus have no direct fitness, any selection for novelty must have been mediated indirectly, through reproducing relatives.
Combined angiotensin inhibition for the treatment of diabetic nephropathy.

BACKGROUND Combination therapy with angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria; however, its safety and effect on the progression of kidney disease are uncertain. Methods We provided losartan (at a dose of 100 mg per day) to patients with type 2 diabetes, a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0 to 89.9 ml per minute per 1.73 m(2) of body-surface area and then randomly assigned them to receive lisinopril (at a dose of 10 to 40 mg per day) or placebo. The primary end point was the first occurrence of a change in the estimated GFR (a decline of ≥ 30 ml per minute per 1.73 m(2) if the initial estimated GFR was ≥ 60 ml per minute per 1.73 m(2) or a decline of ≥ 50% if the initial estimated GFR was <60 ml per minute per 1.73 m(2)), end-stage renal disease (ESRD), or death. The secondary renal end point was the first occurrence of a decline in the estimated GFR or ESRD. Safety outcomes included mortality, hyperkalemia, and acute kidney injury. Results The study was stopped early owing to safety concerns. Among 1448 randomly assigned patients with a median follow-up of 2.2 years, there were 152 primary end-point events in the monotherapy group and 132 in the combination-therapy group (hazard ratio with combination therapy, 0.88; 95% confidence interval [CI], 0.70 to 1.12; P=0.30). A trend toward a benefit from combination therapy with respect to the secondary end point (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P=0.10) decreased with time (P=0.02 for nonproportionality). There was no benefit with respect to mortality (hazard ratio for death, 1.04; 95% CI, 0.73 to 1.49; P=0.75) or cardiovascular events. Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years, vs. 2.6 events per 100 person-years with monotherapy; P<0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, P<0.001). Conclusions Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. (Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; VA NEPHRON-D ClinicalTrials.gov number, NCT00555217.).
Improving and sustaining quality of child health care through IMCI training and supervision: experience from rural Bangladesh.

BACKGROUND The Integrated Management of Childhood Illness (IMCI) strategy includes guidelines for the management of sick children at first-level facilities. These guidelines intend to improve quality of care by ensuring a complete assessment of the child's health and by providing algorithms that combine presenting symptoms into a set of illness classifications for management by IMCI-trained service providers at first-level facilities. OBJECTIVES To investigate the sustainability of improvements in under-five case management by two cadres of first-level government service providers with different levels of pre-service training following implementation of IMCI training and supportive supervision. METHODS Twenty first-level health facilities in the rural sub-district of Matlab in Bangladesh were randomly assigned to IMCI intervention or comparison groups. Health workers in IMCI facilities received training in case management and monthly supportive supervision that involved observations of case management and reinforcement of skills by trained physicians. Health workers in comparison facilities were supervised according to Government of Bangladesh standards. Health facility surveys involving observations of case management were carried out at baseline (2000) and at two points (2003 and 2005) after implementation of IMCI in intervention facilities. FINDINGS Improvement in the management of sick under-five children by IMCI trained service providers with only 18 months of pre-service training was equivalent to that of service providers with 4 years of pre-service training. The improvements in quality of care were sustained over a 2-year period across both cadres of providers in intervention facilities. CONCLUSION IMCI training coupled with regular supervision can sustain improvements in the quality of child health care in first-level health facilities, even among workers with minimal pre-service training. These findings can guide government policy makers and provide further evidence to support the scale-up of regular supervision and task shifting the management of sick under-five children to lower-level service providers.
Beyond our control?: Pre-tertiary bridging program students' perceptions of factors that affect their progress with study

The general purpose of the research study reported here was to gather students’ perceptions of factors which influenced their progress with Tertiary Preparation Program (TPP) studies at the University of Southern Queensland. A considerable body of research has been published on factors that affect the progression of undergraduate students. No similar studies with pre-tertiary bridging program students have been found in the literature. The main methodology employed in the study was analysis of data gathered by the use of a self-report questionnaire. Construction of the questionnaire was based on the outcomes of a study, undertaken by the author and a colleague in 2004-5, of factors which influence undergraduate student progression. The questionnaire was delivered to all students enrolled in the core course TPP7120 in a sample of semesters in a sample of years from 2006 to 2009. The results of the study reported here indicate that factors perceived by students to have most strongly influenced them to discontinue their studies were those relating to personal circumstances that were beyond the control of the course teaching team or the University. Factors which were perceived by students to have most strongly influenced them to continue included factors related to personal volition, social/family support, institutional support, and the quality of the teaching-learning experience. Based on the results of the study, suggestions are made as to how retention rates in pre-tertiary bridging programs could be increased
CPAP, weight loss, or both for obstructive sleep apnea.

BACKGROUND Obesity and obstructive sleep apnea tend to coexist and are associated with inflammation, insulin resistance, dyslipidemia, and high blood pressure, but their causal relation to these abnormalities is unclear. METHODS We randomly assigned 181 patients with obesity, moderate-to-severe obstructive sleep apnea, and serum levels of C-reactive protein (CRP) greater than 1.0 mg per liter to receive treatment with continuous positive airway pressure (CPAP), a weight-loss intervention, or CPAP plus a weight-loss intervention for 24 weeks. We assessed the incremental effect of the combined interventions over each one alone on the CRP level (the primary end point), insulin sensitivity, lipid levels, and blood pressure. RESULTS Among the 146 participants for whom there were follow-up data, those assigned to weight loss only and those assigned to the combined interventions had reductions in CRP levels, insulin resistance, and serum triglyceride levels. None of these changes were observed in the group receiving CPAP alone. Blood pressure was reduced in all three groups. No significant incremental effect on CRP levels was found for the combined interventions as compared with either weight loss or CPAP alone. Reductions in insulin resistance and serum triglyceride levels were greater in the combined-intervention group than in the group receiving CPAP only, but there were no significant differences in these values between the combined-intervention group and the weight-loss group. In per-protocol analyses, which included 90 participants who met prespecified criteria for adherence, the combined interventions resulted in a larger reduction in systolic blood pressure and mean arterial pressure than did either CPAP or weight loss alone. CONCLUSIONS In adults with obesity and obstructive sleep apnea, CPAP combined with a weight-loss intervention did not reduce CRP levels more than either intervention alone. In secondary analyses, weight loss provided an incremental reduction in insulin resistance and serum triglyceride levels when combined with CPAP. In addition, adherence to a regimen of weight loss and CPAP may result in incremental reductions in blood pressure as compared with either intervention alone. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT0371293 .).
The Four Major Education GI Bills: A Historical Study of the Shifting National Purposes and Accompanying Changes in Economic Value to Veterans

Benefits for soldiers follow the formation of ancient and present day armies raised for the purpose of extending the national or state will. Veterans' benefits for defenders of the U.S. emerged during the American colonial period. College benefits began after WWII with the GI Bill of Rights. This study examines the variations in purpose for nationally established educational benefits for veterans and the singular value to the veterans of these 5educational benefits. The study begins with an overview of the history of veterans' benefits. Primary emphasis is then placed on the educational portion of the World War II Servicemen's Readjustment Act and the current educational benefit, the Montgomery GI Bill. As the purpose of awarding educational benefits changed from World War II to the latest U.S. war, the Gulf War of 1990-1991, the economic value to the individual veteran also changed. The WWII GI Bill featured an educational provision intended to keep returning veterans out of the changing economy whereas current GI Bills is intended as a recruiting incentive for an all-volunteer force. Correspondingly, the economic value to the individual veteran has changed. Data supporting this study were extracted from historical documents in primary and secondary scholarly studies and writings, government documents, national newspapers and periodicals, Veterans Administration publications, service newspapers, and anecdotal writings. The study offers conclusions regarding the shifting purposes and economic value and recommends changes to current and future GI Bills. The conclusions of this study are: (a) the purpose of the Montgomery GI Bill is to serve as a recruitment tool for the armed force, whereas the WWII GI Bill emphasized concern over the return of millions of veterans to a changing wartime economy unable to offer full employment and, (b) the present GI Bill funds less than 50% of the costs for a 4-year degree while the first GI Bill fully funded a college degree, including tuition and living expenses.
Effects of root canal preparation, various filling techniques and retreatment after filling on vertical root fracture and crack formation.

AIM To investigate the incidence of cracks in root dentin after rotary instrumentation and filling with cold lateral condensation (CL), single-cone obturation (SC), and warm vertical compaction (WV) and retreatment of each filling system. METHODOLOGY One-hundred sixty mandibular incisors were selected. Twenty teeth were left unprepared and served as a control, and the remaining 140 teeth were instrumented. Twenty teeth were assigned to an only prepared group. The remaining 120 teeth were assigned to three root canal filling groups and three retreatment groups (n = 20), as follows: CL, WV, SC, and retreatment of each filling system. All the roots were sectioned perpendicular to the long axis at 2, 4, 6, and 8 mm from the apex, and the sections were then observed under a stereomicroscope. The absence/presence of cracks and vertical root fractures were recorded, and the data were analyzed with a Pearson's chi-square test (P = 0.05). RESULTS No complete vertical root fractures were observed in the unprepared and only prepared groups. However, vertical fractures were observed in the filling and retreatment groups. There were significantly more cracks in the retreatment after WV group than the other groups, with the exception of the retreatment after SC, WV, and CL resulted in significantly more cracks than the only prepared and SC. CONCLUSIONS The filling techniques (except SC) caused more cracks than preparation only. The SC caused fewer cracks compared to the other filling techniques. The retreatment following the different filling techniques (except CL) caused more cracks than the original fillings.
The experience of purchaser-provider split in the implementation of family physician and rural health insurance in Iran: an institutional approach.

BACKGROUND The Iranian health system, under the banner of family physician (FP) programme, has undergone substantial reforms to change utilization of health services, improve quality of care and enhance affordability. The national implementation of FP initiated in 2005 in parallel with rural health insurance (RHI) in rural areas and cities of <20 000 populations in Iran. The implementation of FP was the first national attempt to split the purchaser and provider of the primary health-care services in Iran. Using an adapted institutional approach, this article aims to explore the process of purchaser-provider split (PPS) during the implementation of FP and RHI reforms, and its consequences for the health system in Iran. METHODS We conducted 71 face-to-face interviews and three focus group discussions at national, provincial and local levels with policy makers, managers, researchers, health-care practitioners and representatives of the public. Interviews and focus groups were digitally recorded and transcribed verbatim. Data collection was supplemented by the review of relevant documents at all three levels. We analysed the data using an inductive-deductive framework analysis approach. RESULTS Views towards PPS and its consequences on the implementation of FP were diverse. Some participants identified the PPS as an essential reform for undertaking the parallel implementation of FP and RHI. Others wondered whether the split has been beneficial as expected and asked for more scrutiny. CONCLUSIONS The implementation of FP and RHI in Iran demonstrated the mixed effects of PPS on health system performance. Our research revealed that PPS did not succeed in changing the status quo, became a reason for fighting, misunderstanding, lack of co-operation and failure of the fragile partnership between the purchaser and provider. We advocate careful contextual preparation prior to large-scale application of PPS during nationwide implementation of FP in Iran as well as other settings.
Recent Clinical Advancement of the Effects of Parathyroid Analogues on Fracture Healing in Humans: A Review of Literature

Problem statement: Numerous animal studies have shown that administration of Parathyroid Hormone (PTH) or a related analogue promotes callus formation and bone union. However, there has yet to be sufficient evidence in human subjects to justify the use of PTH or related analogues in promoting fracture healing. The purpose of this paper is to (1) review all literature involving the use of PTH analogues in humans (2) compare the clinical efficacy of PTH analogues to conventional management of fracture healing and (3) evaluate the safety profile and potential side-effects of PTH analogues administered in humans. Approach: We conducted a systematic review of multiple databases analysing papers within the last 10 years. All studies involving the use of PTH analogues in humans were included. All animal studies were excluded. Appropriate statistics regarding patients age, gender, site of fracture, teriparatide treatment regime, clinical outcomes and imaging outcomes were extracted, analysed and summarized. Results: A total of 10 observational studies and 2 randomized controlled trials were evaluated in this study. With administration of teriparatide (PTH1-34), the mean time to 100% disappearance of fracture site pain was 3.1 months ±0.7 months. Delayed or non-union fractures achieved bony bridging in 4.3 months. For new fractures treated non-surgically, there have been reports of shorter time to cortical bridging in the treatment group (7.4 weeks, n = 34, p = 0.006) as compared to the control group (9.1 weeks, n = 34). Lastly, a total of 8 out of 254 patients (3.1%) experienced mild side effect from teriparatide administration. Conclusion: Teriparatide shows promise to be a viable option for the treatment of fractures. Although initial studies do prove encouraging, greater evidence is needed to evaluate the optimal dosing regimen and the patient and fracture types that would achieve the best response.
Tofacitinib versus methotrexate in rheumatoid arthritis.

BACKGROUND Methotrexate is the most frequently used first-line antirheumatic drug. We report the findings of a phase 3 study of monotherapy with tofacitinib, an oral Janus kinase inhibitor, as compared with methotrexate monotherapy in patients with rheumatoid arthritis who had not previously received methotrexate or therapeutic doses of methotrexate. METHODS We randomly assigned 958 patients to receive 5 mg or 10 mg of tofacitinib twice daily or methotrexate at a dose that was incrementally increased to 20 mg per week over 8 weeks; 956 patients received a study drug. The coprimary end points at month 6 were the mean change from baseline in the van der Heijde modified total Sharp score (which ranges from 0 to 448, with higher scores indicating greater structural joint damage) and the proportion of patients with an American College of Rheumatology (ACR) 70 response (≥70% reduction in the number of both tender and swollen joints and ≥70% improvement in three of five other criteria: the patient's assessment of pain, level of disability, C-reactive protein level or erythrocyte sedimentation rate, global assessment of disease by the patient, and global assessment of disease by the physician). RESULTS Mean changes in the modified total Sharp score from baseline to month 6 were significantly smaller in the tofacitinib groups than in the methotrexate group, but changes were modest in all three groups (0.2 points in the 5-mg tofacitinib group and <0.1 point in the 10-mg tofacitinib group, as compared with 0.8 points in the methotrexate group [P<0.001 for both comparisons]). Among the patients receiving tofacitinib, 25.5% in the 5-mg group and 37.7% in the 10-mg group had an ACR 70 response at month 6, as compared with 12.0% of patients in the methotrexate group (P<0.001 for both comparisons). Herpes zoster developed in 31 of 770 patients who received tofacitinib (4.0%) and in 2 of 186 patients who received methotrexate (1.1%). Confirmed cases of cancer (including three cases of lymphoma) developed in 5 patients who received tofacitinib and in 1 patient who received methotrexate. Tofacitinib was associated with increases in creatinine levels and in low-density and high-density lipoprotein cholesterol levels. CONCLUSIONS In patients who had not previously received methotrexate or therapeutic doses of methotrexate, tofacitinib monotherapy was superior to methotrexate in reducing signs and symptoms of rheumatoid arthritis and inhibiting the progression of structural joint damage. The benefits of tofacitinib need to be considered in the context of the risks of adverse events. (Funded by Pfizer; ORAL Start ClinicalTrials.gov number, NCT01039688.).