Tuberculosis (TB) remains a major cause of mortality in developing countries, and in these countries diabetes prevalence is increasing rapidly. Diabetes increases the risk of TB. Our aim was to ...assess the potential impact of diabetes as a risk factor for incident pulmonary tuberculosis, using India as an example.
We constructed an epidemiological model using data on tuberculosis incidence, diabetes prevalence, population structure, and relative risk of tuberculosis associated with diabetes. We evaluated the contribution made by diabetes to both tuberculosis incidence, and to the difference between tuberculosis incidence in urban and rural areas.
In India in 2000 there were an estimated 20.7 million adults with diabetes, and 900,000 incident adult cases of pulmonary tuberculosis. Our calculations suggest that diabetes accounts for 14.8% (uncertainty range 7.1% to 23.8%) of pulmonary tuberculosis and 20.2% (8.3% to 41.9%) of smear-positive (i.e. infectious) tuberculosis. We estimate that the increased diabetes prevalence in urban areas is associated with a 15.2% greater smear-positive tuberculosis incidence in urban than rural areas - over a fifth of the estimated total difference.
Diabetes makes a substantial contribution to the burden of incident tuberculosis in India, and the association is particularly strong for the infectious form of tuberculosis. The current diabetes epidemic may lead to a resurgence of tuberculosis in endemic regions, especially in urban areas. This potentially carries a risk of global spread with serious implications for tuberculosis control and the achievement of the United Nations Millennium Development Goals.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives: Tuberculosis (TB) remains a major global public health problem. In the past, a relationship between TB and diabetes mellitus (DM) was recognized, and its importance was acknowledged ...through joint treatment clinics. However, this is rarely highlighted in current research or control priorities. This paper aims to evaluate the evidence for an association between these two diseases.
Methods: A Medline literature search was undertaken, supplemented by checking references and contacting experts. We critically appraised studies that quantified the association between TB and DM, and were published after 1995. We assessed study quality according to criteria such as sample size, method of selection of cases and controls, losses to follow-up, quality and method of control of confounding, and summarized the results narratively and in tabular form.
Results: All studies identified statistically significant and clinically important associations, with the increase in risk or odds of TB varying between 1.5- and 7.8-fold for those with DM. Risk was highest at younger ages. Most studies had not measured and controlled adequately for potential major confounders.
Discussion: There is strong evidence for an association between TB and DM, which has potential public health implications. Further well-designed studies are needed to assess the magnitude precisely.
Current implantable left ventricular assist devices (LVAD) improve survival and function for patients with very late stage heart failure (HF) but may also offer benefit before inotrope dependence. ...Debate continues about selection of HF patients for LVAD therapy. We sought to determine what level of personal risk and disability HF patients thought would warrant LVAD therapy.
The study included 105 patients with symptomatic HF and an LV ejection fraction (EF) < 35% who were given a written paragraph about LVADs and asked about circumstances under which they would consider such a device. New York Heart Association (NYHA) functional class, time trade-off utility, and patient-assessed functional score were determined.
Participants (mean age, 58 years) had an LVEF of 21%. The median duration of HF was 5 years, and 65% had a primary prevention implantable cardioverter defibrillator. Presented with a scenario of bed-ridden HF, 81% stated they would definitely or probably want an LVAD; 50% would consider LVAD to prolong survival if HF survival were predicted to be < 1 year and 75% if < 6 months. Meanwhile, 44% would consider LVAD if they could only walk < 1 block and 64% if they could not dress without stopping. Anticipated thresholds did not differ by NYHA class, time trade-off, or functional score.
Patient thresholds for LVAD insertion parallel objective survival and functional data. HF patients would be receptive to referral for discussion of LVAD by the time expected mortality is within 6 to 12 months and activity remains limited to less than 1 block.
Clonal evolution is a key feature of cancer progression and relapse. We studied intratumoral heterogeneity in 149 chronic lymphocytic leukemia (CLL) cases by integrating whole-exome sequence and copy ...number to measure the fraction of cancer cells harboring each somatic mutation. We identified driver mutations as predominantly clonal (e.g., MYD88, trisomy 12, and del(13q)) or subclonal (e.g., SF3B1 and TP53), corresponding to earlier and later events in CLL evolution. We sampled leukemia cells from 18 patients at two time points. Ten of twelve CLL cases treated with chemotherapy (but only one of six without treatment) underwent clonal evolution, predominantly involving subclones with driver mutations (e.g., SF3B1 and TP53) that expanded over time. Furthermore, presence of a subclonal driver mutation was an independent risk factor for rapid disease progression. Our study thus uncovers patterns of clonal evolution in CLL, providing insights into its stepwise transformation, and links the presence of subclones with adverse clinical outcomes.
Display omitted
► Whole-exome analysis of clonal heterogeneity in 149 chronic lymphocytic leukemias ► Earlier and later mutations in the temporal evolution of CLL are identified ► Clonal evolution is commonly seen with treatment, typically in a branched pattern ► A subclonal driver in a pretreatment sample is associated with adverse outcome
The intratumoral heterogeneity in 149 chronic lymphocytic leukemia (CLL) cases was evaluated by whole-exome sequencing. The evolutionary patterns of distinct clones enabled a temporal ordering of mutations in CLL, revealed the association of clonal evolution with chemotherapy, and linked the presence of subclonal driver mutations with adverse clinical outcomes.
Intratumoral heterogeneity plays a critical role in tumor evolution. To define the contribution of DNA methylation to heterogeneity within tumors, we performed genome-scale bisulfite sequencing of ...104 primary chronic lymphocytic leukemias (CLLs). Compared with 26 normal B cell samples, CLLs consistently displayed higher intrasample variability of DNA methylation patterns across the genome, which appears to arise from stochastically disordered methylation in malignant cells. Transcriptome analysis of bulk and single CLL cells revealed that methylation disorder was linked to low-level expression. Disordered methylation was further associated with adverse clinical outcome. We therefore propose that disordered methylation plays a similar role to that of genetic instability, enhancing the ability of cancer cells to search for superior evolutionary trajectories.
Display omitted
•CLL harbors higher intrasample methylation variability compared with normal B cells•Higher intrasample variability arises from stochastically disordered methylation•Methylation disorder is associated with transcriptional variation•Methylation disorder affects genetic evolution and clinical outcome
Landau et al. perform bisulfite sequencing of primary chronic lymphocytic leukemias and find high levels of intrasample variability in DNA methylation patterns. Their findings suggest that disordered methylation plays a role similar to that of genetic instability in conferring adaptive advantage to cancer cells.
T-cell responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been described in recovered patients, and may be important for immunity following infection and vaccination as ...well as for the development of an adoptive immunotherapy for the treatment of immunocompromised individuals. In this report, we demonstrate that SARS-CoV-2–specific T cells can be expanded from convalescent donors and recognize immunodominant viral epitopes in conserved regions of membrane, spike, and nucleocapsid. Following in vitro expansion using a good manufacturing practice-compliant methodology (designed to allow the rapid translation of this novel SARS-CoV-2 T-cell therapy to the clinic), membrane, spike, and nucleocapsid peptides elicited interferon-γ production, in 27 (59%), 12 (26%), and 10 (22%) convalescent donors (respectively), as well as in 2 of 15 unexposed controls. We identified multiple polyfunctional CD4-restricted T-cell epitopes within a highly conserved region of membrane protein, which induced polyfunctional T-cell responses, which may be critical for the development of effective vaccine and T-cell therapies. Hence, our study shows that SARS-CoV-2 directed T-cell immunotherapy targeting structural proteins, most importantly membrane protein, should be feasible for the prevention or early treatment of SARS-CoV-2 infection in immunocompromised patients with blood disorders or after bone marrow transplantation to achieve antiviral control while mitigating uncontrolled inflammation.
•Coronavirus-specific polyfunctional T cells can be expanded from convalescent individuals for use for patients after bone marrow transplant.•SARS-CoV-2 T-cell products target structural viral proteins, including commonly recognized regions in the C terminus of membrane protein.
Display omitted
Nontypeable Haemophilus influenzae (NTHi) causes acute exacerbation of chronic obstructive pulmonary disease (AECOPD). IL-17A is central for neutrophilic inflammation and has been linked to COPD ...pathogenesis.
We investigated whether IL-17A is elevated in NTHi-associated AECOPD and required for NTHi-exacerbated pulmonary neutrophilia induced by cigarette smoke.
Experimental studies with cigarette smoke and NTHi infection were pursued in gene-targeted mice and using antibody intervention. IL-17A was measured in sputum collected from patients with COPD at baseline, during, and after AECOPD.
Exacerbated airway neutrophilia in cigarette smoke-exposed mice infected with NTHi was associated with an induction of IL-17A. In agreement, elevated IL-17A was observed in sputum collected during NTHi-associated AECOPD, compared with samples collected before or after the event. NTHi-exacerbated neutrophilia and induction of neutrophil chemoattractants over the background of cigarette smoke, as observed in wild-type mice, was absent in Il17a(-/-) mice and in mice treated with a neutralizing anti-IL-17A antibody. Further studies revealed that IL-1 receptor (R)1 signaling was required for IL-17A-dependent neutrophilia. Moreover, deficiency or therapeutic neutralization of IL-17A did not increase bacterial burden or delay bacterial clearance.
IL-17A is induced during NTHi-associated AECOPD. Functionally, IL-1R1-dependent IL-17A is required for NTHi-exacerbated pulmonary neutrophilia induced by cigarette smoke. Targeting IL-17A in AECOPD may thus be beneficial to reduce neutrophil recruitment to the airways.
Recent advances in cancer characterization have consistently revealed marked heterogeneity, impeding the completion of integrated molecular and clinical maps for each malignancy. Here, we focus on ...chronic lymphocytic leukemia (CLL), a B cell neoplasm with variable natural history that is conventionally categorized into two subtypes distinguished by extent of somatic mutations in the heavy-chain variable region of immunoglobulin genes (IGHV). To build the 'CLL map,' we integrated genomic, transcriptomic and epigenomic data from 1,148 patients. We identified 202 candidate genetic drivers of CLL (109 new) and refined the characterization of IGHV subtypes, which revealed distinct genomic landscapes and leukemogenic trajectories. Discovery of new gene expression subtypes further subcategorized this neoplasm and proved to be independent prognostic factors. Clinical outcomes were associated with a combination of genetic, epigenetic and gene expression features, further advancing our prognostic paradigm. Overall, this work reveals fresh insights into CLL oncogenesis and prognostication.
T-cell responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been described in recovered patients, and may be important for immunity following infection and vaccination as ...well as for the development of an adoptive immunotherapy for the treatment of immunocompromised individuals. In this report, we demonstrate that SARS-CoV-2-specific T cells can be expanded from convalescent donors and recognize immunodominant viral epitopes in conserved regions of membrane, spike, and nucleocapsid. Following in vitro expansion using a good manufacturing practice-compliant methodology (designed to allow the rapid translation of this novel SARS-CoV-2 T-cell therapy to the clinic), membrane, spike, and nucleocapsid peptides elicited interferon-γ production, in 27 (59%), 12 (26%), and 10 (22%) convalescent donors (respectively), as well as in 2 of 15 unexposed controls. We identified multiple polyfunctional CD4-restricted T-cell epitopes within a highly conserved region of membrane protein, which induced polyfunctional T-cell responses, which may be critical for the development of effective vaccine and T-cell therapies. Hence, our study shows that SARS-CoV-2 directed T-cell immunotherapy targeting structural proteins, most importantly membrane protein, should be feasible for the prevention or early treatment of SARS-CoV-2 infection in immunocompromised patients with blood disorders or after bone marrow transplantation to achieve antiviral control while mitigating uncontrolled inflammation.
PDF
