Summary Background China has a quarter of all patients with multidrug-resistant tuberculosis (MDRTB) worldwide, but less than 5% are in quality treatment programmes. In a before-and-after study we ...aimed to assess the effect of a comprehensive programme to provide universal access to diagnosis, treatment, and follow-up for MDRTB in four Chinese cities (population 18 million). Methods We designated city-level hospitals in each city to diagnose and treat MDRTB. All patients with smear-positive pulmonary tuberculosis diagnosed in Center for Disease Control (CDC) clinics and hospitals were tested for MDRTB with molecular and conventional drug susceptibility tests. Patients were treated with a 24 month treatment package for MDRTB based on WHO guidelines. Outpatients were referred to the CDC for directly observed therapy. We capped total treatment package cost at US$4644. Insurance reimbursement and project subsidies limited patients' expenses to 10% of charges for services within the package. We compared data from a 12 month programme period (2011) to those from a retrospective survey of all patients with MDRTB diagnosed in the same cities during a baseline period (2006–09). Findings 243 patients were diagnosed with MDRTB or rifampicin-resistant tuberculosis during the 12 month programme period compared with 92 patients (equivalent to 24 per year) during the baseline period. 172 (71%) of 243 individuals were enrolled in the programme. Time from specimen collection for resistance testing to treatment initiation decreased by 90% (from median 139 days IQR 69–207 to 14 days 10–21), the proportion of patients who started on appropriate drug regimen increased 2·7 times (from nine 35% of 26 patients treated to 166 97% of 172), and follow-up by the CDC after initial hospitalisation increased 24 times (from one 4% of 23 patients to 163 99% of 164 patients). 6 months after starting treatment, the proportion of patients remaining on treatment increased ten times (from two 8% of 26 patients to 137 80% of 172), and 116 (67%) of 172 patients in the programme period had negative cultures or clinical–radiographic improvement. Patients' expenses for hospital admission after MDRTB diagnosis decreased by 78% (from $796 to $174), reducing the ratio of patients' expenses to annual household income from 17·6% to 3·5% (p<0·0001 for all comparisons between baseline and programme periods). However, 36 (15%) patients did not start or had to discontinue treatment in the programme period because of financial difficulties. Interpretation This comprehensive programme substantially increased access to diagnosis, quality treatment, and affordable treatment for MDRTB. The programme could help China to achieve universal access to MDRTB care but greater financial risk protection for patients is needed. Funding Bill & Melinda Gates Foundation.
Summary Background China scaled up a tuberculosis control programme (based on the directly observed treatment, short-course DOTS strategy) to cover half the population during the 1990s, and to the ...entire population after 2000. We assessed the effect of the programme. Methods In this longitudinal analysis, we compared data from three national tuberculosis prevalence surveys done in 1990, 2000, and 2010. The 2010 survey screened 252 940 eligible individuals aged 15 years and older at 176 investigation points, chosen by stratified random sampling from all 31 mainland provinces. All individuals had chest radiographs taken. Those with abnormal radiographs, persistent cough, or both, were classified as having suspected tuberculosis. Tuberculosis was diagnosed by chest radiograph, sputum-smear microscopy, and culture. Trained staff interviewed each patient with tuberculosis. The 1990 and 2000 surveys were reanalysed and compared with the 2010 survey. Findings From 1990 to 2010, the prevalence of smear-positive tuberculosis decreased from 170 cases (95% CI 166–174) to 59 cases (49–72) per 100 000 population. During the 1990s, smear-positive prevalence fell only in the provinces with the DOTS programme; after 2000, prevalence decreased in all provinces. The percentage reduction in smear-positive prevalence was greater for the decade after 2000 than the decade before (57% vs 19%; p<0·0001). 70% of the total reduction in smear-positive prevalence (78 of 111 cases per 100 000 population) occurred after 2000. Of these cases, 68 (87%) were in known cases—ie, cases diagnosed with tuberculosis before the survey. Of the known cases, the proportion treated by the public health system (using the DOTS strategy) increased from 59 (15%) of 370 cases in 2000 to 79 (66%) of 123 cases in 2010, contributing to reduced proportions of treatment default (from 163 43% of 370 cases to 35 22% of 123 cases) and retreatment cases (from 312 84% of 374 cases to 48 31% of 137 cases; both p<0·0001). Interpretation In 20 years, China more than halved its tuberculosis prevalence. Marked improvement in tuberculosis treatment, driven by a major shift in treatment from hospitals to the public health centres (that implemented the DOTS strategy) was largely responsible for this epidemiological effect. Funding Chinese Ministry of Health.
Summary Background The post-2015 End TB Strategy sets global targets of reducing tuberculosis incidence by 50% and mortality by 75% by 2025. We aimed to assess resource requirements and ...cost-effectiveness of strategies to achieve these targets in China, India, and South Africa. Methods We examined intervention scenarios developed in consultation with country stakeholders, which scaled up existing interventions to high but feasible coverage by 2025. Nine independent modelling groups collaborated to estimate policy outcomes, and we estimated the cost of each scenario by synthesising service use estimates, empirical cost data, and expert opinion on implementation strategies. We estimated health effects (ie, disability-adjusted life-years averted) and resource implications for 2016–35, including patient-incurred costs. To assess resource requirements and cost-effectiveness, we compared scenarios with a base case representing continued current practice. Findings Incremental tuberculosis service costs differed by scenario and country, and in some cases they more than doubled existing funding needs. In general, expansion of tuberculosis services substantially reduced patient-incurred costs and, in India and China, produced net cost savings for most interventions under a societal perspective. In all three countries, expansion of access to care produced substantial health gains. Compared with current practice and conventional cost-effectiveness thresholds, most intervention approaches seemed highly cost-effective. Interpretation Expansion of tuberculosis services seems cost-effective for high-burden countries and could generate substantial health and economic benefits for patients, although substantial new funding would be required. Further work to determine the optimal intervention mix for each country is necessary. Funding Bill & Melinda Gates Foundation.
Summary Background The post-2015 End TB Strategy proposes targets of 50% reduction in tuberculosis incidence and 75% reduction in mortality from tuberculosis by 2025. We aimed to assess whether these ...targets are feasible in three high-burden countries with contrasting epidemiology and previous programmatic achievements. Methods 11 independently developed mathematical models of tuberculosis transmission projected the epidemiological impact of currently available tuberculosis interventions for prevention, diagnosis, and treatment in China, India, and South Africa. Models were calibrated with data on tuberculosis incidence and mortality in 2012. Representatives from national tuberculosis programmes and the advocacy community provided distinct country-specific intervention scenarios, which included screening for symptoms, active case finding, and preventive therapy. Findings Aggressive scale-up of any single intervention scenario could not achieve the post-2015 End TB Strategy targets in any country. However, the models projected that, in the South Africa national tuberculosis programme scenario, a combination of continuous isoniazid preventive therapy for individuals on antiretroviral therapy, expanded facility-based screening for symptoms of tuberculosis at health centres, and improved tuberculosis care could achieve a 55% reduction in incidence (range 31–62%) and a 72% reduction in mortality (range 64–82%) compared with 2015 levels. For India, and particularly for China, full scale-up of all interventions in tuberculosis-programme performance fell short of the 2025 targets, despite preventing a cumulative 3·4 million cases. The advocacy scenarios illustrated the high impact of detecting and treating latent tuberculosis. Interpretation Major reductions in tuberculosis burden seem possible with current interventions. However, additional interventions, adapted to country-specific tuberculosis epidemiology and health systems, are needed to reach the post-2015 End TB Strategy targets at country level. Funding Bill and Melinda Gates Foundation
Summary Background Pixantrone dimaleate (pixantrone)—a novel aza-anthracenedione—was synthesised to reduce anthracycline-related cardiotoxicity without compromising antitumour efficacy. We aimed to ...assess the efficacy and safety of pixantrone versus an investigator's choice of a single-agent therapy in heavily pretreated patients with relapsed or refractory aggressive non-Hodgkin lymphoma. Methods In this phase 3, multicentre, open-label, randomised trial at 66 hospitals in Europe, India, Russia, South America, the UK, and the USA, patients with histologically confirmed aggressive non-Hodgkin lymphoma who had relapsed after two or more previous chemotherapy regimens were randomly assigned (1:1) by an interactive voice response system to treatment with pixantrone dimaleate (85 mg/m2 intravenously on days 1, 8, and 15 of a 28-day cycle, for up to six cycles) or to a comparator (vinorelbine, oxaliplatin, ifosfamide, etoposide, mitoxantrone, or gemcitabine) given at prespecified standard doses and schedules. Patients were stratified by region, International Prognostic Index score, and previous stem-cell transplantation. Patients and investigators were not masked to treatment assignment; however, an independent assessment panel was masked. The primary endpoint was the proportion of patients with a complete or unconfirmed complete response in the intention-to-treat (ITT) population at the end of treatment. Primary analyses of efficacy were based on the independent assessment panel's data review. The study is registered at ClinicalTrials.gov , number NCT00088530. Findings The ITT population comprised 70 patients randomly assigned to the pixantrone group and 70 to the comparator. Five patients (two in the pixantrone group and three in the comparator group) dropped out before receiving their study drug. 14 patients (20·0% 95% CI 11·4–31·3) who received pixantrone achieved a complete or unconfirmed complete response at end of treatment compared with four patients (5·7% 1·6–14·0) in the comparator group (p = 0·021). The most common grade 3 or 4 adverse events in patients given pixantrone were uncomplicated, non-cumulative neutropenia (28 41·2% of 68 patients vs 13 19·4% of 67 patients in the comparator group), leucopenia (16 23·5% vs five 7·5%), and thrombocytopenia (eight 11·8% vs seven 10·4%). Interpretation Pixantrone, given as a single-agent salvage therapy in heavily pretreated patients with relapsed or refractory aggressive non-Hodgkin lymphoma, is efficacious and tolerable. It could be a treatment option for patients whose aggressive non-Hodgkin lymphoma has failed to respond to at least two previous chemotherapy regimens. Funding Cell Therapeutics, Inc.
It has been known for years that the same genetic defects drive breast cancer formation, yet, the onset of breast cancer in different individuals among the same population differs greatly in their ...life spans with unknown mechanisms.
We used a MMTV-PyMT mouse model with different genetic backgrounds (FVB/NJ vs. C57BL/6J) to generate different cancer onset phenotypes, then profiled and analyzed the gene expression of three tumor stages in both Fvb.B6 and Fvb mice to explore the underlying mechanisms.
We found that in contrast with the FVB/N-Tg (MMTV-PyMT) 634Mul mice (Fvb mice), mammary tumor initiation was significantly delayed and tumor progression was significantly suppressed in the Fvb.B6 mice (generated by crossing FVB/NJ with C57BL/6J mice). Transcriptome sequencing and analysis revealed that the differentially expressed genes were enriched in immune-related pathways. Flow cytometry analysis showed a higher proportion of matured dendritic cells in the Fvb.B6 mice. The plasma levels of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) were significantly reduced in the Fvb.B6 mice. IL-6 also impaired the maturation of bone marrow dendritic cells (BMDCs) of the Fvb mice in vitro.
All these findings suggest that immunity levels (characterized by a reduced IL-6 level and intact DC maturation in Fvb.B6 mice) are the key factors affecting tumor onset in a murine mammary cancer model.
OBJECTIVES: To describe patterns of cognitive deficits and activities of daily living (ADLs) in older people with diabetes mellitus.
DESIGN: Cross‐sectional, population‐based study.
SETTING: Three ...homecare agency areas in Boston, Massachusetts.
PARTICIPANTS: Two hundred ninety‐one homebound people aged 60 and older; 40% with diabetes mellitus.
MEASUREMENTS: Demographic data; evidence of diabetes mellitus and other diseases; Mini‐Mental State Examination and tests of memory and executive function; ADLs.
RESULTS: Executive and visuospatial functions were more impaired in individuals with diabetes mellitus than in those without, as assessed using Block Design (mean score±standard deviation 17.1±8.6 vs 20.5±9.6, P=.003) and Trails B (median seconds to accomplish the task: 255 vs 201, P=.03). For memory, word retention score was lower in those with diabetes mellitus than without (39.1±28.9 vs 48.0±29.7, P=.01), but the other memory tests did not show a difference between these two subgroups. More individuals with diabetes mellitus suffered from depressive symptoms than those without (55% vs 42%, P=.03). The ADL scores of those with diabetes mellitus were higher than those without.
CONCLUSION: The pattern of cognitive deficits in people with diabetes mellitus suggests frontal‐subcortical dysfunction, as seen in microvascular disease of the brain. The impairment in ADLs may be associated with this executive dysfunction, which cerebral microvascular disease in diabetes mellitus may cause.
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