Cardiac resynchronization therapy restores optimal atrioventricular mechanical timing in heart failure patients with ventricular conduction delay

AbstractObjectivesWe characterized the relationship between systolic ventricular function and left ventricular (LV) end-diastolic pressure (LVEDP) in patients with heart failure (HF) and baseline asynchrony during ventricular stimulation.BackgroundThe role of preload in the systolic performance improvement that can be obtained in HF patients with LV stimulation is uncertain.MethodsWe measured the maximum rate of increase of LV pressure, LVEDP, aortic pulse pressure (PP) and the atrioventricular mechanical latency (AVL) between left atrial systole and LV pressure onset in 39 patients with HF. Two subgroups were identified: “responder” if PP improved, or “nonresponder.”ResultsMaximum hemodynamic improvement occurred at an atrioventricular (AV) delay that did not decrease LVEDP. Left ventricular and biventricular (BV) stimulation increased systolic hemodynamics significantly, despite no significant increase in LVEDP. All parameters decreased when the LVEDP was decreased by shorter AV delay. Left ventricular and BV stimulation provided better hemodynamics than right ventricular (RV) stimulation. For the nonresponder subgroup, systolic hemodynamics only worsened during AV delay shortening. For the responder subgroup, optimum PP was achieved when AVL was near zero.ConclusionsRestoration of optimal left atrial-ventricular mechanical timing partly contributes to the hemodynamic improvements observed in this patient subgroup. However, preload alone cannot explain the differences seen between RV and BV stimulation and the contradictory PP decreases even at maximal preload in the nonresponder subgroup. These results may be explained by a site-dependent mechanism such as the degree of ventricular synchrony. Caution should be taken in these patients when optimizing AV delays using echocardiography techniques that focus on LV inflow

Women's risk of death beyond 42 days post partum: a pooled analysis of longitudinal Health and Demographic Surveillance System data in sub-Saharan Africa.

BACKGROUND: WHO's standard definitions of pregnancy-related and maternal deaths only include deaths that occur within 42 days of delivery, termination, or abortion, with major implications for post-partum care and maternal mortality surveillance. We therefore estimated post-partum survival from childbirth up to 1 year post partum to evaluate the empirical justification for the 42-day post-partum threshold. METHODS: We used prospective, longitudinal Health and Demographic Surveillance System (HDSS) data from 30 sites across 12 sub-Saharan African countries to estimate women's risk of death from childbirth until 1 year post partum from all causes. Observations were included if the childbirth occurred from 1991 onwards in the HDSS site and maternal age was 10-54 years. We calculated person-years as the time between childbirth and next birth, outmigration, death, or the end of the first year post partum, whichever occurred first. For six post-partum risk intervals (0-1 days, 2-6 days, 7-13 days, 14-41 days, 42-122 days, and 4-11 months), we calculated the adjusted rate ratios of death relative to a baseline risk of 12-17 months post partum. FINDINGS: Between Jan 1, 1991, and Feb 24, 2020, 647 104 births occurred in the HDSS sites, contributing to 602 170 person-years of exposure time and 1967 deaths within 1 year of delivery. After adjustment for confounding, mortality was 38·82 (95% CI 33·21-45·29) times higher than baseline on days 0-1 after childbirth, 4·97 (3·94-6·21) times higher for days 2-6, 3·35 (2·64-4·20) times higher for days 7-13, and 2·06 (1·74-2·44) times higher for days 14-41. From 42 days to 4 months post partum, mortality was still 1·20 (1·03-1·39) times higher (ie, a 20% higher risk), but deaths in this interval would be excluded from measurement of pregnancy-related mortality. Extending the WHO 42-day post-partum threshold up to 4 months would increase the post-partum pregnancy-related mortality ratio by 40%. INTERPRETATION: This multicountry study has implications for measurement and clinical practice. It makes the case for WHO to extend the 42-day post-partum threshold to capture the full duration of risk of pregnancy-related deaths. There is a need for a new indicator to track late pregnancy-related deaths that occur beyond 42 days, which are otherwise excluded from global maternal health surveillance efforts. Our results also emphasise the need for international agencies to disaggregate estimates by antepartum, intrapartum, postpartum, and extended post-partum periods. Additionally, the schedule and content of postnatal care packages should reflect the extended duration of post-partum risk. FUNDING: The UK Economic and Social Research Council

Evaluating pregnancy reporting in Siaya Health and Demographic Surveillance System through record linkage with ANC clinics

IntroductionHealth and Demographic Surveillance Systems (HDSS) are important sources of population health data in sub-Saharan Africa, but the recording of pregnancies, pregnancy outcomes, and early mortality is often incomplete. ObjectiveThis study assessed HDSS pregnancy reporting completeness and identified predictors of unreported pregnancies that likely ended in adverse outcomes. MethodsThe analysis utilized individually-linked HDSS and antenatal care (ANC) data from Siaya, Kenya for pregnancies in 2018-2020. We cross-checked ANC records with HDSS pregnancy registrations and outcomes. Pregnancies observed in the ANC that were missing reports in the HDSS despite a data collection round following the expected delivery date were identified as likely adverse outcomes, and we investigated the characteristics of such individuals. Clinical data were used to investigate the timing of HDSS pregnancy registration relative to care seeking and gestational age, and examine misclassification of miscarriages and stillbirths. ResultsFrom an analytical sample of 2,475 pregnancies observed in the ANC registers, 46% had pregnancy registrations in the HDSS, and 89% had retrospectively reported pregnancy outcomes. 1% of registered pregnancies were missing outcomes, compared to 10% of those lacking registration. Registered pregnancies had higher rates of stillbirth and perinatal mortality than those lacking registration. In 77% of cases, women accessed ANC prior to registering the pregnancy in the HDSS. Half of reported miscarriages were misclassified stillbirths. We identified 141 unreported pregnancies that likely ended in adverse outcomes. Such cases were more common among those who visited ANC clinics during the first trimester, made fewer overall visits, were HIV-positive, and outside of formal union. ConclusionsRecord linkage with ANC clinics revealed pregnancy underreporting in HDSS, resulting in biased measurement of perinatal mortality. Integrating records of ANC usage into routine data collection can augment HDSS pregnancy surveillance and improve monitoring of adverse pregnancy outcomes and early mortality.</jats:p

Evaluating pregnancy reporting in Siaya Health and Demographic Surveillance System through record linkage with ANC clinics.

INTRODUCTION: Health and Demographic Surveillance Systems (HDSS) are important sources of population health data in sub-Saharan Africa, but the recording of pregnancies, pregnancy outcomes, and early mortality is often incomplete. OBJECTIVE: This study assessed HDSS pregnancy reporting completeness and identified predictors of unreported pregnancies that likely ended in adverse outcomes. METHODS: The analysis utilized individually-linked HDSS and antenatal care (ANC) data from Siaya, Kenya for pregnancies in 2018-2020. We cross-checked ANC records with HDSS pregnancy registrations and outcomes. Pregnancies observed in the ANC that were missing reports in the HDSS despite a data collection round following the expected delivery date were identified as likely adverse outcomes, and we investigated the characteristics of such individuals. Clinical data were used to investigate the timing of HDSS pregnancy registration relative to care seeking and gestational age, and examine misclassification of miscarriages and stillbirths. RESULTS: From an analytical sample of 2,475 pregnancies observed in the ANC registers, 46% had pregnancy registrations in the HDSS, and 89% had retrospectively reported pregnancy outcomes. 1% of registered pregnancies were missing outcomes, compared to 10% of those lacking registration. Registered pregnancies had higher rates of stillbirth and perinatal mortality than those lacking registration. In 77% of cases, women accessed ANC prior to registering the pregnancy in the HDSS. Half of reported miscarriages were misclassified stillbirths. We identified 141 unreported pregnancies that likely ended in adverse outcomes. Such cases were more common among those who visited ANC clinics during the first trimester, made fewer overall visits, were HIV-positive, and outside of formal union. CONCLUSIONS: Record linkage with ANC clinics revealed pregnancy underreporting in HDSS, resulting in biased measurement of perinatal mortality. Integrating records of ANC usage into routine data collection can augment HDSS pregnancy surveillance and improve monitoring of adverse pregnancy outcomes and early mortality

Combination of chemotherapy and PD-1 blockade induces T cell responses to tumor non-mutated neoantigens

Here, we developed an unbiased, functional target-discovery platform to identify immunogenic proteins from primary non-small cell lung cancer (NSCLC) cells that had been induced to apoptosis by cisplatin (CDDP) treatment in vitro, as compared with their live counterparts. Among the multitude of proteins identified, some of them were represented as fragmented proteins in apoptotic tumor cells, and acted as non-mutated neoantigens (NM-neoAgs). Indeed, only the fragmented proteins elicited effective multi-specific CD4+ and CD8+ T cell responses, upon a chemotherapy protocol including CDDP. Importantly, these responses further increased upon anti-PD-1 therapy, and correlated with patients’ survival and decreased PD-1 expression. Cross-presentation assays showed that NM-neoAgs were unveiled in apoptotic tumor cells as the result of caspase-dependent proteolytic activity of cellular proteins. Our study demonstrates that apoptotic tumor cells generate a repertoire of immunogenic NM-neoAgs that could be potentially used for developing effective T cell-based immunotherapy across multiple cancer patients

Divergent age patterns of under-5 mortality in south Asia and sub-Saharan Africa: a modelling study.

BACKGROUND: Understanding the age pattern of under-5 mortality is essential for identifying the most vulnerable ages and underlying causes of death, and for assessing why the decline in child mortality is slower in some countries and subnational areas than others. The aim of this study is to detect age patterns of under-5 mortality that are specific to low-income and middle-income countries (LMICs). METHODS: In this modelling study, we used data from 277 Demographic and Health Surveys (DHSs), 58 Health and Demographic Surveillance Systems (HDSSs), two cohort studies, and two sample-registration systems. From these sources, we collected child date of birth and date of death (or age at death) from LMICs between 1966 and 2020. We computed 22 deaths rates from each survey with the following age breakdowns: 0, 7, 14, 21, and 28 days; 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, and 21 months; and 2, 3, 4, and 5 years. We assessed how probabilities of dying estimated for the 22 age groups deviated from predictions generated by a vital registration model that reflects the historical mortality of 25 high-income countries. FINDINGS: We calculated mortality rates of 81 LMICs between 1966 and 2020. In contrast with the other regions of the world, we found that under-5 mortality in south Asia and sub-Saharan Africa was characterised by increased mortality at both ends of the age range (ie, younger than 28 days and older than 6 months) at a given level of mortality. Observed mortality in these regions was up to 2 times higher than predicted by the vital registration model for the younger-than-28 days age bracket, and up to 10 times higher than predicted for the older-than-6 months age bracket. This age pattern of under-5 mortality is significant in 17 countries in south Asia and sub-Saharan Africa. Excess mortality in children older than 6 months without excess mortality in children younger than 28 days was found in 38 countries. In south Asia, results were consistent across data sources. In sub-Saharan Africa, excess mortality in children younger than 28 days was found mostly in DHSs; the majority of HDSSs did not show this excess mortality. We have attributed this difference in data sources mainly to omissions of early deaths in HDSSs. INTERPRETATION: In countries with age patterns of under-5 mortality that diverge from predictions, evidence-based public health interventions should focus on the causes of excess of mortality; notably, the effect of fetal growth restriction and infectious diseases. The age pattern of under-5 mortality will be instrumental in assessing progress towards the decline of under-5 mortality and the Sustainable Development Goals. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health

Biological Treatment and the Potential Risk of Adverse Postoperative Outcome in Patients With Inflammatory Bowel Disease: An Open-Source Expert Panel Review of the Current Literature and Future Perspectives

Abstract Background There is widespread concern that treatment with biologic agents may be associated with suboptimal postoperative outcome after surgery for inflammatory bowel diseases (IBD). Aim We aimed to search and analyze the literature regarding the potential association of biologic treatment on adverse postoperative outcome in patients with IBD. We used the subject as a case in point for surgical research. The aim was not to conduct a new systematic review. Method This is an updated narrative review written in a collaborative method by authors invited through Twitter via the following hashtags (#OpenSourceResearch and #SoMe4Surgery). The manuscript was presented as slides on Twitter to allow discussion of each section of the paper sequentially. A Google document was created, which was shared across social media, and comments and edits were verified by the primary author to ensure accuracy and consistency. Results Forty-one collaborators responded to the invitation, and a total of 106 studies were identified that investigated the potential association of preoperative biological treatment on postoperative outcome in patients with IBD. Most of these studies were retrospective observational cohorts: 3 were prospective, 4 experimental, and 3 population-based studies. These studies were previously analyzed in 10 systematic/narrative reviews and 14 meta-analyses. Type of biologic agents, dose, drug concentration, antidrug antibodies, interval between last dose, and types of surgery varied widely among the studies. Adjustment for confounders and bias control ranged from good to very poor. Only 10 studies reported postoperative outcome according to Clavien–Dindo classification. Conclusion Although a large number of studies investigated the potential effect of biological treatment on postoperative outcomes, many reported divergent results. There is a need for randomized controlled trials. Future studies should focus on the avoiding the weakness of prior studies we identified. Seeking collaborators and sharing information via Twitter was integral to widening the contributors/authors and peer review for this article and was an effective method of collaboration