[Larynx preservation: recommendations for decision-making in T3 laryngeal cancer patients]. / Organerhalt: Entscheidungskriterien für Patienten mit T3-Larynxkarzinom.

BACKGROUND: By today's standard, the optimal treatment of every individual tumor patient is discussed and determined in an interdisciplinary tumor board. According to the new S3 guidelines, larger volume T3 laryngeal cancers which are no longer safely resectable with larynx-sparing surgery are ideal candidates for a larynx preservation approach using primary chemoradiation (pCRT). So far, no clear criteria have been defined under what circumstances primary radiotherapy alone (pRT) might be acceptable in case chemotherapy (CT) is prohibited or in what cases, even in T3, upfront total laryngectomy with risk-adapted adjuvant treatment (TL±a[C]RT) should be recommended. METHOD: The literature was searched for parameters chosen as criteria for an inclusion in the surgical rather than the conservative arm in non-randomized LP studies or which proved to be significant prognostic markers after conservative treatment. Development of a counselling tool for therapeutic decision making. RESULTS: Significant prognostic markers were tumor volume (< 3.5 ccm/< 6 ccm vs. 6-12 ccm vs. > 12 ccm), presence and kind of vocal cord fixation (none vs. Succo I/II vs. Succo III/IV), extent of cartilage infiltration (none vs. minimal vs. multiple/gross), nodal status (N0­1 vs. N2-3), and laryngeal dysfunction (pretreatment necessity of feeding tube or tracheostomy). CONCLUSION: For T3 laryngeal cancers, pRT could be acceptable when the tumor volume is < 3.5 ccm for glottic and < 6 ccm for supraglottic tumors and there are no further risk factors. pCRT can be regarded as the standard for LP for tumors between 6 ccm and 12 ccm, vocal cord fixation Succo pattern I/II, only minimal cartilage infiltration and a high nodal burden. For tumor > 12 ccm, vocal cord fixation Succo pattern III/IV, gross or multiple cartilage infiltration or clinically relevant laryngeal dysfunction, upfront TL±a[C]RT should be considered.

[Larynx preservation up to T4 laryngeal cancer?] / Larynxorganerhalt bis zum T4­Larynxkarzinom?

Could primary chemoradiotherapy (pCRT) possibly be viewed as an alternative standard therapy to upfront total laryngectomy (TL)? According to the new German S3 guideline, despite higher rates of local recurrence, there would be no survival disadvantage and salvage surgery would be a curative option. In several large database studies and case series, statistically significant survival disadvantages of more than 30% between pCRT and TL have been reported for T4 laryngeal cancer. According to the literature, the success rate of salvage TL for T4 laryngeal cancer is only about 25-50%. Larynx preservation (LP) studies which could qualify the recommendation of pCRT as an alternative standard therapy to TL in T4 carcinomas should 1) evaluate T4a cancers within the T4 category; 2) perform subgroup analysis of laryngeal and hypopharyngeal cancers; 3) be sufficiently highly powered; 4) provide long-term outcomes of at least 5 years; 5) with oncological and 6) functional outcomes (duration of the need for tracheostomy and/or feeding tube dependency; necessity and success of salvage laryngectomies). 7) Specification of the criteria of the respective T4 classification (invasion through the outer cortex of the cartilage, or infiltration of which extralaryngeal structures) and 8) evaluation of pretreatment laryngeal function (at least: tracheostomy, feeding tube dependency). Collection of all the aforementioned data of T4 patients treated with pCRT in a large prospective observational cohort study in German-speaking countries is suggested. In case of rejection of TL by T4 laryngeal cancer patients, differentiation between primary spontaneous reluctance and a definitive, carefully considered decision is important. This distinction should be achieved by sensitive discussions. Not only oncological but also functional outcome probabilities should be included in the overall decision-making process.

A retrospective observational study to evaluate the clinical outcomes and routine management of patients with chronic lymphocytic leukaemia treated with idelalisib and rituximab in the UK and Ireland (RETRO-idel).

Idelalisib (IDL) is an oral first-in-class phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor approved for chronic lymphocytic leukaemia (CLL) alongside rituximab (R) since 2014. However, little data exist on routine practice. The RETRO-idel was a protocol-led, retrospective study of 110 patients [n = 27 front-line (1L)] who received IDL-R. The primary end-point was clinical overall response rate (ORR). The median (range) follow-up of the whole cohort was 30·2 (0·1-51·9) months. The median (range) age was 72 (48-89) years. Tumour protein p53-disruption was common [100% 1L, 32·5% relapsed/refractory (R/R)]. The best ORR (intention-to-treat) was 88·2% (1L 96·3%, R/R 85·5%). Overall, the median event-free survival (mEFS) was 20·3 months and time-to-next treatment was 29·2 months. The mEFS for 1L patients was 18·7 months and R/R patients was 21·7 months. The 3-year overall survival was 56·1% (95% confidence interval 45·7-65·3). IDL was discontinued in 87·3% (n = 96). More patients discontinued due to adverse events in the front-line setting (1L 63·0% vs. R/R 44·6%) and due to progressive disease in R/R patients (20·5% vs. 3·7% in 1L). Lower respiratory tract infection/pneumonia were reported in 34·5% (Grade ≥3, 19·1%), diarrhoea in 30·9% (Grade ≥3, 6·4%), and colitis in 9·1% (Grade ≥3, 5·5%). Overall, these data describe clear efficacy for IDL-R in routine practice. No new safety signals were identified, although careful management of known toxicities is required.

Evolution of Hepatitis C Virus Treatment During the Era of Sofosbuvir-Based Therapies: A Real-World Experience in France.

BACKGROUND: Treatment of hepatitis C virus (HCV) has been dramatically improved with the introduction of direct-acting antiviral agents (DAAs). Universal access to pangenotypic DAAs was provided in France from 2017, expanding the type of patients treated. Real-world studies are important to confirm effectiveness and safety in clinical practice, particularly in vulnerable populations. AIMS: To assess real-world effectiveness and safety of sofosbuvir-based therapy in adults with chronic HCV infection before and after universal access to DAAs in France. METHODS: This multicenter, non-interventional, prospective study assessed the effectiveness, safety, patient-reported outcomes and adherence with sofosbuvir-based regimens from October 2015 to July 2016 (Period 1: sofosbuvir-based therapy excluding sofosbuvir/velpatasvir) and from October 2017 to July 2018 (Period 2: pangenotypic sofosbuvir/velpatasvir-based therapy). RESULTS: Baseline data were documented for 1029 patients. Overall, 797 (77%) had sustained virologic response data available ≥ 9 weeks after treatment completion. Per protocol response was high (97%) irrespective of age, alcohol consumption, recreational drug use, or HIV/HCV coinfection. Adverse events occurred in approximately 25% of patients with the majority experiencing Grade 1 or 2 events. Sofosbuvir-based regimens improved health-related quality of life from baseline to end of treatment in patients with data at all timepoints. Overall, 99% of patients reported total or almost total adherence to therapy. CONCLUSIONS: Sofosbuvir-based therapy, including pangenotypic sofosbuvir/velpatasvir, is effective for the treatment of HCV in real-world clinical practice. This is an important step towards HCV elimination.

Laryngeal Cancer Risks in Workers Exposed to Lung Carcinogens: Exposure-Effect Analyses Using a Quantitative Job Exposure Matrix.

INTRODUCTION: Various established occupational lung carcinogens are also suspected risk factors for laryngeal cancer. However, individual studies are often inadequate in size to investigate this relatively rare outcome. Other limitations include imprecise exposure assessment and inadequate adjustment for confounders. METHODS: This study applied a quantitative job exposure matrix (SYN-JEM) for four established occupational lung carcinogens to five case-control studies within the International Head and Neck Cancer Epidemiology Consortium. We used occupational histories for 2256 laryngeal cancer cases and 7857 controls recruited from 1989 to 2007. We assigned quantitative exposure levels for asbestos, respirable crystalline silica, chromium-VI, and chromium-VI and nickel combined (to address highly correlated exposures) via SYN-JEM. We assessed effects of occupational exposure on cancer risk for males (asbestos, respirable crystalline silica, chromium-VI, and chromium-VI and nickel combined) and females (asbestos and respirable crystalline silica), adjusting for age, study, tobacco smoking, alcohol consumption, and asbestos exposure where relevant. RESULTS: Among females, odds ratios (ORs) were increased for ever versus never exposed. Among males, P values for linear trend were <0.05 for estimated cumulative exposure (all agents) and <0.05 for exposure duration (respirable crystalline silica, chromium-VI, and chromium-VI and nickel combined); strongest associations were for asbestos at >90th percentile cumulative exposure (OR = 1.3, 95% confidence interval [CI] = 1.0, 1.6), respirable crystalline silica at 30+ years duration (OR = 1.4, 95% CI = 1.2, 1.7) and 75th-90th percentile cumulative exposure (OR = 1.4, 95% CI = 1.1, 1.8), chromium-VI at >75th percentile cumulative exposure (OR = 1.9, 95% CI = 1.2, 3.0), and chromium-VI and nickel combined at 20-29 years duration (OR = 1.5, 95% CI = 1.1, 2.2). CONCLUSIONS: These findings support hypotheses of causal links between four lung carcinogens (asbestos, respirable crystalline silica, chromium-VI, and nickel) and laryngeal cancer.

Global real-world evidence of sofosbuvir/velpatasvir as simple, effective HCV treatment: Analysis of 5552 patients from 12 cohorts.

BACKGROUND AND AIMS: Achieving sustained virological response (SVR; cure) in hepatitis C patients using a simple regimen is key to making elimination by 2030 possible. In the largest real-world analysis to date, the effectiveness of pangenotypic, panfibrotic, single-tablet, sofosbuvir/velpatasvir (SOF/VEL) once-daily for 12 weeks was assessed in 12 clinical real-world cohorts from various geographical areas, settings and treatment practices. Factors affecting risk of not achieving SVR were assessed. METHODS: Adults treated with SOF/VEL 400/100 mg, without ribavirin, were included. All HCV patients reaching Week 12 or 24 post-treatment were assessed for SVR12/24. Factors associated with not achieving SVR12/24 for virological reasons were evaluated using logistic regression analysis. RESULTS: Overall, 5552 patients were included: 13.3% treatment-experienced; 20.7% compensated cirrhotic; 30.2% genotype 1; 29.5% genotype 2; 32.9% genotype 3; 4.7% genotype 4; 3.7% HIV coinfection; 13.4% current/former intravenous drug use. Of the 5196 patients evaluated for effectiveness, 98.9% achieved SVR12/24. High SVR12/24 rates occurred in all genotypes including genotype 3 (98.3%; 1649/1677) and in those with compensated cirrhosis (97.9; 1055/1078). Only 55 patients did not achieve SVR12/24 due to a virological reason; the only factor statistically significantly associated with an increased risk of not achieving SVR12/24 was compensated cirrhosis (P = .002). Overall, 6% (332/5552) of patients did not achieve SVR12/24 for non-virological reasons (67% lost to follow-up; 26.5% early treatment discontinuation). CONCLUSIONS: In this large cohort, representative of clinical practice, a simple 12-week regimen of SOF/VEL without ribavirin resulted in high SVR12/24 rates in diverse patient populations, even among those with compensated cirrhosis.

A change in the study evaluation paradigm reveals that larynx preservation compromises survival in T4 laryngeal cancer patients.

BACKGROUND: Larynx preservation (LP) is recommended for up to low-volume T4 laryngeal cancer as an evidence-based treatment option that does not compromise survival. However, a reevaluation of the current literature raises questions regarding whether there is indeed reliable evidence to support larynx preservation for T4 tumor patients. METHODS: In an observational cohort study of 810 laryngeal cancer patients, we evaluated the outcomes of all T4 tumor patients treated with primary chemo-radiotherapy (CRT) or primary radiotherapy alone (RT) compared with upfront total laryngectomy followed by adjuvant (chemo)radiotherapy (TL + a[C]RT). Additionally, we reevaluated the studies that form the evidence base for the recommendation of LP for patients with up to T4 tumors (Pfister et al., J Clin Oncol 24:3693-704, 2006). RESULTS: The evaluation of all 288 stage III and IV patients together did not show a significant difference in overall survival (OS) between CRT-LP and TL + a(C)RT (hazard ratio (HR) 1.23; 95% confidence interval (CI): 0.82-1.86; p = 0.31) using a multivariate proportional hazard model. However, a subgroup analysis of T4 tumor patients alone (N = 107; 13.9%) revealed significantly worse OS after CRT compared with TL + a(C)RT (HR 2.0; 95% CI: 1.04-3.7; p = 0.0369). A reevaluation of the subgroup of T4 patients in the 5 LP studies that led to the ASCO clinical practice guidelines revealed that only 21-45 T4 patients had differential data on survival outcome. These data, however, showed a markedly worse outcome for T4 patients after LP. CONCLUSIONS: T4 laryngeal cancer patients who reject TL as a treatment option should be informed that their chance of organ preservation with primary conservative treatment is likely to result in a significantly worse outcome in terms of OS. Significant loss of survival in T4 patients after LP is also confirmed in recent literature.

Strengthening capacity to research the social determinants of health in low- and middle-income countries: lessons from the INTREC programme.

BACKGROUND: The INDEPTH Training & Research Centres of Excellence (INTREC) collaboration developed a training programme to strengthen social determinants of health (SDH) research in low- and middle-income countries (LMICs). It was piloted among health- and demographic researchers from 9 countries in Africa and Asia. The programme followed a blended learning approach and was split into three consecutive teaching blocks over a 12-month period: 1) an online course of 7 video lectures and assignments on the theory of SDH research; 2) a 2-week qualitative and quantitative methods workshop; and 3) a 1-week data analysis workshop. This report aims to summarise the student evaluations of the pilot and to suggest key lessons for future approaches to strengthen SDH research capacity in LMICs. METHODS: Semi-structured interviews and questionnaires with 24 students from 9 countries in Africa and Asia were used to evaluate each teaching block. Information was collected about the students' motivation and interest in studying SDH, any challenges they faced during the consecutive teaching blocks, and suggestions they had for future courses on SDH. RESULTS: Of the 24 students who began the programme, 13 (54%) completed all training activities. The students recognised the need for such a course and its potential to improve their skills as health researchers. The main challenges with the online course were time management, prior knowledge and skills required to participate in the course, and the need to get feedback from teaching staff throughout the learning process. All students found the face-to-face workshops to be of high quality and value for their work, because they offered an opportunity to clarify SDH concepts taught during the online course and to gain practical research skills. After the final teaching block, students felt they had improved their data analysis skills and were better able to develop research proposals, scientific manuscripts, and policy briefs. CONCLUSIONS: The INTREC programme has trained a promising cadre of health researchers who live and work in LMICs, which is an essential component of efforts to identify and reduce national and local level health inequities. Time management and technological issues were the greatest challenges, which can inform future attempts to strengthen research capacity on SDH.

Estimating and explaining the effect of education and income on head and neck cancer risk: INHANCE consortium pooled analysis of 31 case-control studies from 27 countries.

Low socioeconomic status has been reported to be associated with head and neck cancer risk. However, previous studies have been too small to examine the associations by cancer subsite, age, sex, global region and calendar time and to explain the association in terms of behavioral risk factors. Individual participant data of 23,964 cases with head and neck cancer and 31,954 controls from 31 studies in 27 countries pooled with random effects models. Overall, low education was associated with an increased risk of head and neck cancer (OR = 2.50; 95% CI = 2.02 - 3.09). Overall one-third of the increased risk was not explained by differences in the distribution of cigarette smoking and alcohol behaviors; and it remained elevated among never users of tobacco and nondrinkers (OR = 1.61; 95% CI = 1.13 - 2.31). More of the estimated education effect was not explained by cigarette smoking and alcohol behaviors: in women than in men, in older than younger groups, in the oropharynx than in other sites, in South/Central America than in Europe/North America and was strongest in countries with greater income inequality. Similar findings were observed for the estimated effect of low versus high household income. The lowest levels of income and educational attainment were associated with more than 2-fold increased risk of head and neck cancer, which is not entirely explained by differences in the distributions of behavioral risk factors for these cancers and which varies across cancer sites, sexes, countries and country income inequality levels.

Association of history of allergies and influenza-like infections with laryngeal cancer in a case-control study.

Prior studies suggest that history of allergy and infections early in life might be inversely associated with cancer. We explored the association between allergies, recent influenza infections and laryngeal cancer risk. We used data from a case-control study which included 229 cases of laryngeal cancer and 769 population controls matched for age and sex. History of a physician-diagnosed allergy, influenza-like infections in the past 5 years, smoking, alcohol consumption and occupational exposure to carcinogens were self-reported. Allergies were classified into two groups (Type I and Type IV), according to the underlying immunologic mechanism. Conditional logistic regression models were fitted using laryngeal cancer as the outcome, adjusting for smoking, alcohol consumption and occupational exposure and stratified for age and sex. Having any allergy was not associated significantly with laryngeal cancer. Although Type I and Type IV allergies were non-significantly associated with laryngeal cancer, Type IV allergies showed a strong inverse association after adjusting for smoking and alcohol (OR 0.50, 95 % CI 0.22-1.2). Participants who reported at least one influenza-like infection during the past 5 years were significantly less likely to have laryngeal cancer (OR 0.57, 95 % CI 0.39-0.81). After considering fever (≥38.5 °C) as a criterion for influenza infection, the association between influenza infection and laryngeal cancer was even stronger (OR 0.29, 95 % CI 0.13-0.63). We found no significant association between any allergy and laryngeal cancer, some indication of an inverse association between Type IV allergy and laryngeal cancer, whereas recent influenza infections were inversely associated with laryngeal cancer risk.

Training needs for research in health inequities among health and demographic researchers from eight African and Asian countries.

BACKGROUND: To support equity focussed public health policy in low and middle income countries, more evidence and analysis of the social determinants of health inequalities is needed. This requires specific know how among researchers. The INDEPTH Training and Research Centres of Excellence (INTREC) collaboration will develop and provide training on the social determinants of health approach for health researchers from the International Network for the Demographic Evaluation of Populations and Their Health in Low- and Middle-Income Countries (INDEPTH) in Africa and Asia. To identify learning needs among the potential target group, this qualitative study explored what INDEPTH researchers from Ghana, Tanzania, South Africa, Kenya, Indonesia, India, Vietnam, and Bangladesh feel that they want to learn to be able to conduct research on the causes of health inequalities in their country. METHODS: Using an inductive method, online concept-mapping, participants were asked to generate statements in response to the question what background knowledge they would need to conduct research on the causes of health inequalities in their country, to sort those statements into thematic groups, and to rate them in terms of how important it would be for the INTREC program to offer instruction on each of the statements. Statistical techniques were used to structure statements into a thematic cluster map and average importance ratings of statements/clusters were calculated. RESULTS: Of the 150 invited researchers, 82 participated in the study: 54 from Africa; 28 from Asia. Participants generated 59 statements and sorted them into 6 broader thematic clusters: "assessing health inequalities"; "research design and methods"; "research and policy"; "demography and health inequalities"; "social determinants of health" and "interventions". African participants assigned the highest importance to further training on methods for assessing health inequalities. Asian participants assigned the highest importance to training on research and policy. CONCLUSION: The identified thematic clusters and statements provide a detailed understanding of what INDEPTH researchers want to learn in order to be able to conduct research on the social determinants of health inequalities. This offers a framework for developing capacity building programs in this emerging field of public health research.

Occupation and educational inequalities in laryngeal cancer: the use of a job index.

BACKGROUND: Previous studies tried to assess the association between socioeconomic status and laryngeal cancer. Alcohol and tobacco consumption explain already a large part of the social inequalities. Occupational exposures might explain a part of the remaining but the components and pathways of the socioeconomic contribution have yet to be fully disentangled. The aim of this study was to evaluate the role of occupation using different occupational indices, differentiating between physical, psycho-social and toxic exposures and trying to summarize the occupational burden into one variable. METHODS: A population-based case-control study conducted in Germany in 1998-2000 included 208 male cases and 702 controls. Information on occupational history, smoking, alcohol consumption and education was collected with face-to-face interviews. A recently developed job-classification index was used to account for the occupational burden. A sub-index focussed on jobs involving potentially carcinogenic agents (CAI) for the upper aero digestive tract. RESULTS: When adjusted for smoking and alcohol consumption, higher odds ratios (ORs) were found for lower education. This OR decreased after further adjustment using the physical and psycho-social job indices (OR = 3.2, 95%-CI: 1.5-6.8), similar to the OR using the sub-index CAI (OR = 3.0, 95%-CI: 1.4-6.5). CONCLUSIONS: The use of an easily applicable control variable, simply constructed on standard occupational job classifications, provides the possibility to differentiate between educational and occupational contributions. Such an index might indirectly reflect the effect of carcinogenic agents, which are not collected in many studies.

Virological failure and drug resistance in patients on antiretroviral therapy after treatment interruption in Lilongwe, Malawi.

BACKGROUND: Since 2004, Malawi has rapidly scaled up access to antiretroviral therapy (ART) in the national program following a public health approach with limited laboratory monitoring. We examined virological outcomes in patients with treatment interruption at 2 clinics of the Lighthouse Trust, Lilongwe, Malawi. METHODS: We evaluated patients who resumed first-line ART after having at least 1 treatment interruption documented in the electronic data system in 2008-2009. Viral load (VL) was analyzed at least 2 months after resumption of ART. For VL ≥1000 copies/mL, drug-resistance genotype was characterized using the Stanford database. RESULTS: Between June and November 2009, we enrolled 133 patients (58.7% female) with a mean age of 38.4 years. Mean duration of ART prior to treatment interruption was 14.3 months. After a minimum of 2 months following ART resumption, VL was undetectable in 81 (60.9%) patients, was 400-1000 copies/mL in 12 (9.0%) patients, and was ≥1000 copies/mL in 40 (30.1%) patients. Genotyping and drug-resistance testing were successfully performed for 36 of 40 patients, all carrying human immunodeficiency virus type 1 subtype C. Relevant mutations affecting nonnucleoside reverse transcriptase inhibitors were found in 32 of 133 (24.1%) patients and combined with relevant nucleoside reverse transcriptase mutations in 27 of 133 (20.3%) patients. CONCLUSIONS: Virological failure combined with drug resistance after resumption of first-line ART occurred in 24.1% of the patients with treatment interruption, requiring a switch to protease inhibitor-based second-line therapy. Patients with treatment interruption should receive VL assessment after resumption of ART to detect treatment failure and to reduce development and spread of drug resistance.

Diet and the risk of head and neck cancer: a pooled analysis in the INHANCE consortium.

We investigated the association between diet and head and neck cancer (HNC) risk using data from the International Head and Neck Cancer Epidemiology (INHANCE) consortium. The INHANCE pooled data included 22 case-control studies with 14,520 cases and 22,737 controls. Center-specific quartiles among the controls were used for food groups, and frequencies per week were used for single food items. A dietary pattern score combining high fruit and vegetable intake and low red meat intake was created. Odds ratios (OR) and 95% confidence intervals (CI) for the dietary items on the risk of HNC were estimated with a two-stage random-effects logistic regression model. An inverse association was observed for higher-frequency intake of fruit (4th vs. 1st quartile OR = 0.52, 95% CI = 0.43-0.62, p (trend) < 0.01) and vegetables (OR = 0.66, 95% CI = 0.49-0.90, p (trend) = 0.01). Intake of red meat (OR = 1.40, 95% CI = 1.13-1.74, p (trend) = 0.13) and processed meat (OR = 1.37, 95% CI = 1.14-1.65, p (trend) < 0.01) was positively associated with HNC risk. Higher dietary pattern scores, reflecting high fruit/vegetable and low red meat intake, were associated with reduced HNC risk (per score increment OR = 0.90, 95% CI = 0.84-0.97).

Cause of death distribution with InterVA and physician coding in a rural area of Burkina Faso.

OBJECTIVES: To compare the cause of death distribution using the Physician Coded Verbal Autopsy approach versus the Interpreting Verbal Autopsy model, based on information from a French verbal autopsy questionnaire, in rural north-western Burkina Faso. METHODS: Data from 5649 verbal autopsy questionnaires reviewed by local physicians at the Nouna Health and Demographic Surveillance Site between 1998 and 2007 were considered for analyses. Information from VA interviews was extracted to create a set of standard indicators needed to run the Interpreting Verbal Autopsy model. Cause-specific mortality fractions were used to compare Physician Coded Verbal Autopsy and Interpreting Verbal Autopsy results. RESULTS: At the population level, 62.5% of causes of death using the Interpreting Verbal Autopsy model corresponded with those determined by two or three physicians. Although seven of the 10 main causes of death were present in both approaches, the comparison of percentages of single causes of death shows discrepancies, dominated by higher malaria rates found in the Physician Coded Verbal Autopsy approach. CONCLUSION: Our results confirm that national mortality statistics, which are partly based on verbal autopsies, must be carefully interpreted. Difficulties in determining malaria as cause of death in holoendemic malaria regions might result in higher discrepancies than those in non-endemic areas. As neither Physician Coded Verbal Autopsy nor Interpreting Verbal Autopsy results represent a gold standard, uncertainty levels with either procedure are high.

Long-term effects of malaria prevention with insecticide-treated mosquito nets on morbidity and mortality in African children: randomised controlled trial.

OBJECTIVE: The objective is to investigate the effect of malaria control with insecticide-treated mosquito nets (ITNs) regarding possible higher mortality in children protected during early infancy, due to interference with immunity development, and to assess long-term effects on malaria prevalence and morbidity. METHODS: Between 2000 and 2002, a birth cohort was enrolled in 41 villages of a malaria holoendemic area in north-western Burkina Faso. All neonates (n = 3387) were individually randomised to ITN protection from birth (group A) vs. ITN protection from age 6 months (group B). Primary outcome was all-cause mortality. In 2009, a survey took place in six sentinel villages, and in 2010, a census was conducted in all study villages. RESULTS: After a median follow-up time of 8.3 years, 443/3387 (13.1%) children had migrated out of the area and 484/2944 (16.4%) had died, mostly at home. Long-term compliance with ITN protection was good. There were no differences in mortality between study groups (248 deaths in group A, 236 deaths in group B; rate ratio 1.05, 95% CI: 0.889-1.237, P = 0.574). The survey conducted briefly after the rainy season in 2009 showed that more than 80% of study children carried asexual malaria parasites and up to 20% had clinical malaria. CONCLUSION: Insecticide-treated mosquito net protection in early infancy is not a risk factor for mortality. Individual ITN protection does not sufficiently reduce malaria prevalence in high-transmission areas. Achieving universal ITN coverage remains a major challenge for malaria prevention in Africa.

Exploring the role narrative free-text plays in discrepancies between physician coding and the InterVA regarding determination of malaria as cause of death, in a malaria holo-endemic region.

BACKGROUND: In countries where tracking mortality and clinical cause of death are not routinely undertaken, gathering verbal autopsies (VA) is the principal method of estimating cause of death. The most common method for determining probable cause of death from the VA interview is Physician-Certified Verbal Autopsy (PCVA). A recent alternative method to interpret Verbal Autopsy (InterVA) is a computer model using a Bayesian approach to derive posterior probabilities for causes of death, given an a priori distribution at population level and a set of interview-based indicators. The model uses the same input information as PCVA, with the exception of narrative text information, which physicians can consult but which were not inputted into the model. Comparing the results of physician coding with the model, large differences could be due to difficulties in diagnosing malaria, especially in holo-endemic regions. Thus, the aim of the study was to explore whether physicians' access to electronically unavailable narrative text helps to explain the large discrepancy in malaria cause-specific mortality fractions (CSMFs) in physician coding versus the model. METHODS: Free-texts of electronically available records (N = 5,649) were summarised and incorporated into the InterVA version 3 (InterVA-3) for three sub-groups: (i) a 10%-representative subsample (N = 493) (ii) records diagnosed as malaria by physicians and not by the model (N = 1035), and (iii) records diagnosed by the model as malaria, but not by physicians (N = 332). CSMF results before and after free-text incorporation were compared. RESULTS: There were changes of between 5.5-10.2% between models before and after free-text incorporation. No impact on malaria CSMFs was seen in the representative sub-sample, but the proportion of malaria as cause of death increased in the physician sub-sample (2.7%) and saw a large decrease in the InterVA subsample (9.9%). Information on 13/106 indicators appeared at least once in the free-texts that had not been matched to any item in the structured, electronically available portion of the Nouna questionnaire. DISCUSSION: Free-texts are helpful in gathering information not adequately captured in VA questionnaires, though access to free-text does not explain differences in physician and model determination of malaria as cause of death.

Results of a Prospective Non-Interventional Post-Authorization Safety Study of Idelalisib in Germany.

BACKGROUND: In pivotal studies, idelalisib demonstrated remarkable efficacy and manageable tolerability in patients with chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL). This prospective, multicenter, non-interventional post-authorization study assessed the characteristics, clinical management, and outcome of CLL and FL patients receiving idelalisib in routine clinical practice in Germany. PATIENTS: Observational study in CLL and FL patients treated with idelalisib between September 2015 and December 2020. RESULTS: A total of 147 patients with CLL and FL were included with a median age of 75 and 71 years, respectively. More than 80% of patients presented with comorbidity and many CLL patients with documented high-risk genetic features, including del(17p)/TP53 mutation or unmutated IGHV. The median progression-free survival (PFS) and overall survival (OS) were not reached in the CLL cohort irrespective of del(17p)/TP53 or unmutated IGHV. The estimated 6-month PFS and OS rates in CLL were 82% and 92%. The estimated 6-month PFS and OS rates for FL were 32.2% and 77.2%. Overall response rates in the CLL and FL cohorts were 70.4% and 36.4%, with the presence of high-risk genetics having no negative impact. No unexpected adverse events were observed. Most frequently reported adverse drug reactions (ADRs) were diarrhea, nausea, pneumonia, rash, and fatigue. CONCLUSION: This real-world study shows that idelalisib is an effective therapy for CLL and FL, regardless of age and high-risk genetic features, consistent with results from previous clinical trials. Collected safety data and the pattern of ADRs reflect those from previous studies.

Risk of hepatocellular carcinoma in treatment-naïve chronic hepatitis B patients receiving tenofovir disoproxil fumarate versus entecavir in the United States.

BACKGROUND: Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are the first-line treatment agents for chronic hepatitis B virus (HBV). Recently, whether the degree to which the risk of hepatocellular carcinoma (HCC) may be reduced by ETV vs TDF has been debated. We compared the incidence of HCC among treatment-naïve patients receiving TDF vs ETV in the United States. METHODS: From a large administrative medical claims database of commercially insured patients, we identified 166,933 adults with a diagnosis of chronic hepatitis B and a minimum of 12 months of prior enrolment, of whom 3934 and 6127 initiated ETV and TDF respectively. Fine-Gray hazard regression models incorporating treatment propensity scores (PS) were used to estimate the risk of HCC incidence associated with TDF vs ETV; variables considered for adjustment included demographic characteristics, concomitant medication use and baseline comorbidities, as well as competing events including liver transplantation and medication changes. RESULTS: After PS weighting, the TDF and ETV groups were well-matched. During the follow-up, 90 patients developed HCC, including 50 receiving ETV and 40 receiving TDF, giving rise to crude incidence rates of 0.62 per 100 person-years (PY) and 0.30 per 100 PY respectively. In PS-weighted, multivariable analysis, TDF was associated with a subdistribution hazard ratio for HCC of 0.58 (95% confidence interval [CI]: 0.38-0.89) compared to ETV. Results were similar when patients ≥40 years and men and women were analysed separately. CONCLUSION: Among commercially insured, treatment-naïve patients with chronic hepatitis B in the United States, treatment with TDF was associated with significantly lower risk of HCC than ETV.

Sofosbuvir and risk of estimated glomerular filtration rate decline or end-stage renal disease in patients with renal impairment.

BACKGROUND: Sofosbuvir, a prodrug nucleoside inhibitor of hepatitis C virus, has a predominant circulating metabolite that is renally eliminated. Whether sofosbuvir is associated with chronic kidney disease (CKD) progression is not well understood. METHODS: We performed a retrospective analysis of patients with estimated glomerular filtration rate (eGFR) 30-89 mL/min/1.73 m2 treated with sofosbuvir in 76 Phase 2/3 registrational trials. We evaluated eGFR at each study visit. Separately, we performed a retrospective analysis of an administrative claims database (IQVIA PharMetrics Plus™) to compare the risk of incident end-stage renal disease (ESRD) associated with the use of sofosbuvir or non-sofosbuvir regimens among patients with CKD using propensity score methods. Exposure, CKD status and outcomes were determined using diagnosis and medication claim codes. Cox proportional hazards methods were used to estimate ESRD risk. RESULTS: Among 4642 trial participants with baseline stage 2 CKD (eGFR 60-89 ml/min/1.73 m2 ) and 682 trial participants with stage 3 CKD (eGFR 30-59 ml/min/1.73 m2 ) mean (SD) eGFR improved from baseline to 4 weeks post-treatment (+0.7 [9.3] and +2.6 [8.8] ml/min/1.73 m2 , respectively; p < 0.001 each). In the second analysis, among 2042 patients with CKD receiving sofosbuvir-based regimens compared to 431 receiving non-sofosbuvir-based regimens, after adjusting for baseline covariates and weighting based on treatment propensity scores, there was no significant difference in risk of ESRD (adjusted HR = 0.85, 95% CI: 0.51-1.42). CONCLUSIONS: Clinical trial participants with CKD did not experience worsening eGFR during sofosbuvir-based treatment, and sofosbuvir was not associated with an increased risk of ESRD in patients with CKD in a nationally-representative administrative claims database.