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Higher wages are generally thought to increase human capital production, particularly in the developing world. We introduce a simple model of human capital production in which investments and time allocation differ by age. Using data on test scores and schooling from rural India, we show that higher wages increase human capital investment in early life (in utero to age 2) but decrease human capital from age 5 to 16. Children switch out of school into productive work when rainfall is higher. The opportunity cost of schooling, even for fairly young children, is an important factor in determining overall human capital investment.

In a phase 3, placebo-controlled study, lenvatinib was associated with a significant increase in progression-free survival (18.3 months vs. 3.6 months). Toxic effects with lenvatinib were substantial and included hypertension, diarrhea, and unexplained death. The 10-year survival rate among patients with differentiated thyroid cancer that is refractory to radioiodine (iodine-131) therapy is 10% from the time of detection of metastasis. 1 – 3 Although treatment options have historically been limited, efforts have first targeted vascular endothelial growth factor (VEGF) and its receptor (VEGFR), since this signaling network has been associated with the aggressiveness and metastasis of thyroid cancer. 4 – 6 However, other molecular pathways of tumor growth and maintenance beyond VEGF-driven angiogenesis contribute to the pathogenesis of thyroid cancer, including BRAF, NRAS, HRAS, RET/PTC, fibroblast growth factor receptor (FGFR), and platelet-derived growth factor receptor (PDGFR). 7 – 16 Because . . .

Despite rapid initial uptake, COVID-19 vaccinations in the United States stalled within a few months of widespread rollout in 2021. In response, many state and local governments, employers and health systems used public health messaging, financial incentives and creative scheduling tools to increase vaccine uptake. Although these approaches drew on evidence from influenza and other vaccination efforts, they were largely untested in the context of SARS-CoV-2. In mid-2021, months after vaccines were widely available, we evaluated vaccination intentions and vaccine uptake using a randomized control trial. To do this, we recruited unvaccinated members of a Medicaid managed care plan in California (n = 2,701) and randomly assigned them to different public health messages, $10 or $50 financial incentives for vaccination, a simple vaccination appointment scheduler, or control. While messages increased vaccination intentions, none of the interventions increased vaccination rates. Estimates for financial incentives rule out even relatively small increases in vaccination rates. Small financial incentives and other behavioral nudges do not meaningfully increase COVID-19 vaccination rates amongst the vaccine hesitant.

Sex markets play a key role in the transmission of sexually transmitted infections (STI) and HIV/AIDS in developing countries. While individuals should substitute away from risky sex as STI prevalence rises, female sex workers draw a premium for engaging in unprotected sex, mitigating their propensity to use condoms. We provide the first evidence of a positive premium for non-condom sex in developing country male sex markets. Testing whether this is a compensating differential for disease risk, we find that a one percentage point increase in the STI rate increases the premium 28 percent. Market forces may curb the self-limiting effect of STI epidemics.

Tumour mutational burden (TMB) has been retrospectively correlated with response to immune checkpoint blockade. We prospectively explored the association of high tissue TMB (tTMB-high) with outcomes in ten tumour-type-specific cohorts from the phase 2 KEYNOTE-158 study, which assessed the anti-PD-1 monoclonal antibody pembrolizumab in patients with selected, previously treated, advanced solid tumours. In the multi-cohort, open-label, non-randomised, phase 2 KEYNOTE-158 study, patients were enrolled from 81 academic facilities and community-based institutions across 21 countries in Africa, the Americas, Asia, and Europe. Eligible patients were aged 18 years or older, had a histologically or cytologically confirmed advanced (ie, unresectable or metastatic, or both) incurable solid tumour (eligible tumour types were anal, biliary, cervical, endometrial, mesothelioma, neuroendocrine, salivary, small-cell lung, thyroid, and vulvar), progression on or intolerance to one or more lines of standard therapy, had measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) assessed by independent central radiological review, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, adequate organ function, and a tumour sample for biomarker analysis. Participants were given pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. Tissue TMB (tTMB) was assessed in formalin-fixed paraffin-embedded tumour samples using the FoundationOne CDx assay (Foundation Medicine, Cambridge, MA, USA). The prespecified definition of tTMB-high status was at least 10 mutations per megabase. The primary endpoint was the proportion of patients with an objective response (complete or partial response) as per Response Evaluation Criteria in Solid Tumours (version 1.1) by independent central review. This prespecified analysis assessed the association between antitumour activity and tTMB in treated patients with evaluable tTMB data. Efficacy was assessed in all participants who received at least one dose of pembrolizumab, had evaluable tTMB data, and were enrolled at least 26 weeks before data cutoff (June 27, 2019), and safety was assessed in all participants who received at least one dose of pembrolizumab and had tTMB-high status. KEYNOTE-158 is registered at ClinicalTrials.gov, NCT02628067, and is ongoing. Between Jan 15, 2016, and June 25, 2019, 1073 patients were enrolled. 1066 participants were treated as of data cutoff (June 27, 2019), of whom 805 (76%) were evaluable for TMB, and 105 (13%) of 805 had tTMB-high status and were assessed for safety. 1050 (98%) of 1066 patients enrolled by at least 26 weeks before data cutoff, of whom 790 (75%) were evaluable for TMB and included in efficacy analyses. 102 (13%) of these 790 patients had tTMB-high status (≥10 mutations per megabase), and 688 (87%) patients had non-tTMB-high status (<10 mutations per megabase). Median study follow-up was 37·1 months (IQR 35·0–38·3). Objective responses were observed in 30 (29%; 95% CI 21–39) of 102 patients in the tTMB-high group and 43 (6%; 5–8) of 688 in the non-tTMB-high group. 11 (10%) of 105 patients had treatment-related serious adverse events. 16 (15%) participants had a grade 3–5 treatment-related adverse event, of which colitis was the only such adverse event that occurred in more than one patient (n=2). One patient had fatal pneumonia that was assessed by the investigator to be treatment related. tTMB-high status identifies a subgroup of patients who could have a robust tumour response to pembrolizumab monotherapy. tTMB could be a novel and useful predictive biomarker for response to pembrolizumab monotherapy in patients with previously treated recurrent or metastatic advanced solid tumours. Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.

In India, an increasing number of women are choosing to remain single, which means they are likely to become Solo Agers. This study investigates the perceptions of single women in Mumbai about the concepts of women Solo Agers and Solo Aging, their potential of becoming Solo Agers, and the issues and challenges that women Solo Agers may face in India. And it proposes ways to address them.

A randomized study involving 410 patients with advanced pancreatic neuroendocrine tumors showed that everolimus, as compared with placebo, more than doubled the median progression-free survival (11 months vs. 4.6 months). Most of the adverse events were grade 1 or 2 in severity. The incidence and prevalence of pancreatic neuroendocrine tumors are increasing 1 – 3 ; these tumors represent approximately 1.3% of all cases of pancreatic cancer in incidence and 10% of cases in prevalence. 1 – 3 Pancreatic neuroendocrine tumors are frequently diagnosed at a late stage, with approximately 65% of patients presenting with unresectable or metastatic disease; as a result, these patients have a poor prognosis. The median survival time for patients with distant metastatic disease is 24 months, 2 and limited treatment options are available for this population. Streptozocin is the only approved therapy for pancreatic neuroendocrine tumors in the United States; however, the . . .

Peptide receptor radionucleotide therapy (PRRT) with 177 Lu-dotatate is widely used for the treatment of patients with neuroendocrine tumors (NETs). We analyzed data from 104 patients with NETs treated with 177 Lu -dotatate at a US academic center between December 2017 and October 2020 to better understand patterns of long-term efficacy, safety, and toxicity in the real-world setting. 177 Lu-dotatate (200 mCi) was administered every eight weeks for four doses. The most common sites of primary disease were small intestine NETs (n = 49, 47%), pancreatic NETs (n = 32, 31%), and lung NETs (n = 7, 7%). Twenty-seven percent had Ki-67 <3%, 49% had Ki-67 between 3–20%, and 13.5% had Ki-67 >20%. The cohort had been pretreated with a median of two prior lines of treatment. Forty percent had received prior liver-directed treatment. Seventy-four percent of patients completed all four doses of treatment. The objective response rate was 18%. The median time-to-treatment failure/death was significantly longer for small-bowel NETs when compared to pancreatic NETs (37.3 months vs. 13.2 months, p = 0.001). In a multivariate model, Ki-67, primary site, and liver tumor burden ≥50% were found to independently predict time-to-treatment failure/death. Around 40% of patients experienced adverse events of ≥grade 3 severity. Treatment-related adverse events leading to discontinuation of therapy happened in 10% of patients. Preexisting mesenteric/peritoneal disease was present in 33 patients; seven of these patients developed bowel-related toxicities including two grade 5 events. We also report two cases of delayed-onset minimal change nephrotic syndrome, which occurred 14 and 27 months after the last dose of PRRT. Lastly, we describe six patients who developed rapid tumor progression in the liver leading to terminal liver failure within 7.3 months from the start of PRRT, and identify potential risk factors associated with this occurrence, which will need further study.

Anaplastic thyroid cancer is a rare and aggressive cancer with no standard radiotherapy-based local treatment. Based on data suggesting synergy between pazopanib and paclitaxel in anaplastic thyroid cancer, NRG Oncology did a double-blind, placebo-controlled, randomised phase 2 clinical trial comparing concurrent paclitaxel and intensity-modulated radiotherapy (IMRT) with the addition of pazopanib or placebo with the aim of improving overall survival in this patient population. Eligible patients were aged 18 years or older with a pathological diagnosis of anaplastic thyroid cancer, any TNM stage, Zubrod performance status of 0–2, no recent haemoptysis or bleeding, and no brain metastases. Patients were enrolled from 34 centres in the USA. Initially, a run-in was done to establish safety. In the randomised phase 2 trial, patients in the experimental group (pazopanib) received 2–3 weeks of weekly paclitaxel (80 mg/m2) intravenously and daily pazopanib suspension 400 mg orally followed by concurrent weekly paclitaxel (50 mg/m2), daily pazopanib (300 mg), and IMRT 66 Gy given in 33 daily fractions (2 Gy fractions). In the control group (placebo), pazopanib was replaced by matching placebo. Patients were randomly assigned (1:1) to the two treatment groups by permuted block randomisation by NRG Oncology with stratification by metastatic disease. All investigators, patients, and funders of the study were masked to group allocation. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with Clinicaltrials.gov, NCT01236547, and is complete. The safety run-showed the final dosing regimen to be safe based on two out of nine participants having adverse events of predefined concern. Between June 23, 2014, and Dec 30, 2016, 89 patients were enrolled to the phase 2 trial, of whom 71 were eligible (36 in the pazopanib group and 35 in the placebo group; 34 [48%] males and 37 [52%] females). At the final analysis (data cutoff March 9, 2020), with a median follow-up of 2·9 years (IQR 0·002–4·0), 61 patients had died. Overall survival was not significantly improved with pazopanib versus placebo, with a median overall survival of 5·7 months (95% CI 4·0–12·8) in the pazopanib group versus 7·3 months (4·3–10·6) in the placebo group (hazard ratio 0·86, 95% CI 0·52–1·43; one-sided log-rank p=0·28). 1-year overall survival was 37·1% (95% CI 21·1–53·2) in the pazopanib group and 29·0% (13·2–44·8) in the placebo group. The incidence of grade 3–5 adverse events did not differ significantly between the treatment groups (pazopanib 88·9% [32 of 36 patients] and placebo 85·3% [29 of 34 patients]; p=0·73). The most common clinically significant grade 3–4 adverse events in the 70 eligible treated patients (36 in the pazopanib group and 34 in the placebo group) were dysphagia (13 [36%] vs 10 [29%]), radiation dermatitis (8 [22%] vs 13 [38%]), increased alanine aminotransferase (12 [33%] vs none), increased aspartate aminotransferase (eight [22%] vs none), and oral mucositis (five [14%] vs eight [24%]). Treatment-related serious adverse events were reported for 16 (44%) patients on pazopanib and 12 (35%) patients on placebo. The most common serious adverse events were dehydration and thromboembolic event (three [8%] each) in patients on pazopanib and oral mucositis (three [8%]) in those on placebo. There was one treatment-related death in each group (sepsis in the pazopanib group and pneumonitis in the placebo group). To our knowledge, this study is the largest randomised anaplastic thyroid cancer study that has completed accrual showing feasibility in a multicenter NCI National Clinical Trials Network setting. Although no significant improvement in overall survival was recorded in the pazopanib group, the treatment combination was shown to be feasible and safe, and hypothesis-generating data that might warrant further investigation were generated. National Cancer Institute and Novartis.

Systemic treatment of metastatic adrenocortical carcinoma (ACC) remains limited to chemotherapy and mitotane. Preliminary evidence suggesting that antitumor immune responses can be elicited in ACC has fostered interest in checkpoint inhibitors such as anti-PD-1 nivolumab. The primary endpoint was objective response rate according to the response evaluation criteria in solid tumors. Secondary endpoints were progression-free survival (PFS), overall survival, and safety. Single-arm, multicenter, phase 2 clinical trial with two-stage design. Comprehensive cancer center. Ten adult patients with metastatic ACC previously treated with platinum-based chemotherapy and/or mitotane as well as patients who declined front-line chemotherapy. Nivolumab (240 mg) IV every 2 weeks. Ten patients with metastatic ACC were enrolled between March and December 2016. The median number of doses of nivolumab administered was two. Three patients only received one treatment [one died of disease progression, one discontinued due to adverse events (AEs), one withdrew after beginning treatment]. The median PFS was 1.8 months. The median follow-up was 4.5 months (range, 0.1 to 25.6 months). Two patients had stable disease for a duration of 48 and 11 weeks, respectively. One patient had an unconfirmed partial response but discontinued the study due to an AE. Most AEs were grade 1/2. The most common grade 3/4 treatment-related AEs were aspartate aminotransferase and alanine aminotransferase elevations, mucositis, and odynophagia. Nivolumab demonstrated modest antitumor activity in patients with advanced ACC. The nivolumab safety profile was consistent with previous clinical experience without any unexpected AEs in this population.