Clinical and non-clinical markers of prognosis in heart failure

Heart failure (HF) is a major cause of morbidity and mortality, and the prevalence of HF is only increasing globally. The rise in prevalence is primarily attributed to a combination of increasing survival especially in patients in industrialized countries and increasing incidence in low- and middle-income countries (mostly in a younger population). The clinical course of HF varies from patient to patient. For some, an initial diagnosis of HF is soon followed by multiple hospitalisations deeply impacting their quality of life, others have a fairly indolent course and some die soon after a diagnosis of HF is made. The treatment for many also depends on various factors including the phenotype of HF, the aetiology of HF and other co-existent chronic conditions to name a few. There are patients with HF who may not be candidates for intensive invasive procedures but would on the other hand benefit from supportive care and palliative care advice with treatment being directed towards preservation of quality of life. Physicians are therefore often faced with the question of the prognosis their patients with HF face. Accurate assessment of prognosis is therefore important in shared decision making for patients with HF. However, assessment of prognosis is not straightforward. Reliance on a clinician’s acumen or single prognostic markers such as left ventricular ejection fraction (LVEF) and New York heart association (NYHA) class can be inaccurate and is not advised. Therefore, multivariable models were turned to in order to paint a more accurate picture of a patient’s prognosis by incorporating different individual markers known to be associated with clinical outcomes in HF. Multiple prognostic models have consequently been developed for assessment of prognosis in HF. However, uptake of these in clinical practice remain low. Many factors contribute including issues with reproducibility of prognostic ability in different populations, unavailability of variables and complexity of statistical methodologies. The evolving risk of different outcomes due to pharmacological and non-pharmacological advances in HF is another influencing factor. I consequently conducted a systemic analysis of the literature of prognostic models in HF – focusing primarily on a single phenotype of HF – HF with reduced ejection fraction (HFrEF). I identified several variables common to most models, with LVEF, sex, age, NYHA class being some of the most frequently featured. Inclusion of more contemporary prognostic markers such as NT-proBNP and non-clinical markers such as region, race/ethnicity and socioeconomic status was however very less frequent or absent altogether. Given this background, the aim of this thesis was to explore a select set of clinical and non-clinical markers, some of which have featured in previous models to review their prognostic importance along with a few which have not been featured in risk models in the past. The analyses presented were conducted in three contemporary clinical trial datasets in HFrEF – ATMOSPHERE, PARADIGM-HF and DAPA-HF. I used a variety of statistical measures to assess the association between 3 commonly used markers – LVEF, sex & chronic obstructive pulmonary disease (COPD) and 4 uncommonly/previously unused markers – geography & ethnicity, income inequality and frailty – and common clinical outcomes examined in HF. Different outcomes were tested – including cardiovascular, non-cardiovascular & all-cause death and first & recurrent HF, cardiovascular & all-cause hospitalisations. Cox regression was used to study the association between LVEF and COPD with various clinical outcomes. I used competing risk regression to study the other markers of prognosis and their association with clinical outcomes. In the DAPA-HF cohort, each 5% decrease in LVEF was associated with a 20% higher risk of HF hospitalisation (95% CI 1.13 – 1.27) and a 20% higher risk of cardiovascular death (95% CI 1.13 – 1.28). The risks of the same outcomes in those with COPD was 78% (95% CI 1.44 – 2.20) and 28% (95% CI 1.00 – 1.63) respectively. The rest of the analyses were carried out in a pooled cohort of the ATMOSPHERE and PARADIGM-HF trials. Women had a 19% lower risk of HF hospitalisation (95% CI 0.74 – 0.90) and 26% lower risk of cardiovascular death (95% CI 0.67 – 0.81). Among the Asian countries, the highest and lowest risk of hospitalisation for HF was seen in patients belonging to Taiwan (1.88; 95% CI 1.46 – 2.42) and India (0.44; 95% CI 0.36 – 0.54) respectively. In the same patients living in the Philippines had the highest risk of cardiovascular death (sHR 1.87; 95% CI 1.36 – 2.57) and the lowest risk of the same outcome was seen in those living in Japan (subdistribution hazard ratio (sHR) 0.68; 95% CI 0.46 – 0.98). When levels of income inequality were examined, patients lining in countries with the greatest inequality had a 57% higher risk of hospitalisation for HF (95% CI 1.36 – 1.81) and the risk of cardiovascular death was 50% greater (95% CI 1.29 – 1.74) compared to patients living in countries with the lowest income inequality. Using an acceptable method, I found that 69% of the population in ATMOSPHERE and PARADIGM-HF were frail. In the same population, the frailest patients carried a 89% higher risk of HF hospitalisation (95% CI 1.69 – 2.11) and the sHR for cardiovascular death was 2.14 (95% CI 1.92 – 2.38). All the above listed associations were statistically significant. In conclusion, I found that a select set of traditionally featured markers in prognostic models in HF remained strong predictors of hospitalisation and mortality in contemporary set of HF populations. In addition, several non-clinical and clinical markers that have infrequently featured in previous prognostic markers also carry significant value in measuring risk of clinical outcomes in HF. The inclusion of such markers may improve the predictive ability and clinical applicability of prognostic models in HF in the future

Clinical and Epidemiological Profiles of Severe Malaria in Children from Delhi, India

Plasmodium vivax is traditionally known to cause benign tertian malaria, although recent reports suggest that P. vivax can also cause severe life-threatening disease analogous to severe infection due to P. falciparum. There are limited published data on the clinical and epidemiological profiles of children suffering from ‘severe malaria’ in an urban setting of India. To assess the clinical and epidemiological profiles of children with severe malaria, a prospective study was carried out during June 2008–December 2008 in the Department of Pediatrics, Guru Teg Bahadur Hospital, a tertiary hospital located in East Delhi, India. Data on children aged ≤12 years, diagnosed with severe malaria, were analyzed for their demographic, clinical and laboratory parameters. All patients were categorized and treated as per the guidelines of the World Health Organization. In total, 1,680 children were screened for malaria at the paediatric outpatient and casualty facilities of the hospital. Thirty-eight children tested positive for malaria on peripheral smear examination (2.26% slide positivity rate). Of these, 27 (71%) were admitted and categorized as severe malaria as per the definition of the WHO while another 11 (29%) received treatment on outpatient basis. Most (24/27; 88.8%) cases of severe malaria (n=27) were infected with P. vivax. Among the cases of severe malaria caused by Plasmodium vivax (n=24), 12 (50%) presented with altered sensorium (cerebral malaria), seven (29.1%) had severe anaemia (haemoglobin <5 g/dL), and 17 (70.8%) had thrombocytopaenia, of which two had spontaneous bleeding (epistaxis). Cases of severe vivax malaria are clinically indistinguishable from severe falciparum malaria. Our study demonstrated that majority (88.8%) of severe malaria cases in children from Delhi and adjoining districts of Uttar Pradesh were due to P. vivax-associated infection. P. vivax should, thus, be regarded as an important causative agent for severe malaria in children

Sacubitril/valsartan in Asian patients with heart failure with reduced ejection fraction

The Prospective comparison of Angiotensin Receptor-neprilysin inhibitor (ARNI) with Angiotensin converting enzyme inhibitor (ACEI) to Determine Impact on Global Mortality and morbidity in Heart Failure (HF) trial (PARADIGM-HF) showed that adding a neprilysin inhibitor (sacubitril) to a renin-angiotensin system blocker (and other standard therapy) reduced morbidity and mortality in ambulatory patients with chronic HF with reduced ejection fraction (HFrEF). In PARADIGM-HF, valsartan combined with sacubitril (a so-called ARNI) was superior to the current gold standard of an ACEI, specifically enalapril, reducing the risk of the primary composite outcome of cardiovascular (CV) death or first HF hospitalization by 20% and all-cause death by 16%. Following the results of PARADIGM-HF, sacubitril/valsartan was approved by American and European regulatory authorities for the treatment of HFrEF. The burden of HF in Asia is substantial, both due to the huge population of the region and as a result of increasing CV risk factors and disease. Both the prevalence and mortality associated with HF are high in Asia. In the following review, we discuss the development of sacubitril/valsartan, the prototype ARNI, and the available evidence for its efficacy and safety in Asian patients with HFrEF

Effect of antenatal exercises on pulmonary functions and labour outcome in uncomplicated primigravida women: a randomized controlled study

Background: Physical fitness could influence pulmonary functions, labour and neonatal outcomes in pregnancy. The present study was undertaken to evaluate the effect of antenatal exercises on pulmonary functions and labour outcomes.Methods: Study included 122 uncomplicated primigravida in age group of 18-35 years at 24th - 28th week of gestation were randomly allocated into study and control groups. Antenatal exercises were performed by study group for a minimum of 3 days a week for 20 minute duration till their delivery. Pulmonary function tests (PFTs) were done for all subjects at 24th week of gestation and after 36th week of gestation.Results: A significant improvement in FEV1, FVC, FEF25-75%, MEF50%, MIF50% and MVV between 24 &amp; 36 weeks was observed in the study group after exercises. In study group 85.24% patients had spontaneous onset of labour, 14.8% patients had induction of labour as compared to 75.4% and 24.6% respectively in control group, however statistically insignificant. In the study group 41.67% patients did not require augmentation compared to 22.95% in the control group. In study group 13.11% patients had meconium stained liquor which was significantly less in comparison to 41% patients in the control group. Mean duration of first, second and third stage of labour was shorter in study group than control group. In study group 96.72% had normal and none had instrumental vaginal delivery compared to 88.52% and 6.6% from control group respectively. Caesarean section rate was 3.3% in study group and 4.9% in control group. APGAR score was normal in all the neonates. Fetal weight gain, birth weight, birth length and head circumference was significantly higher and NICU stay was significantly lesser in study group compared to control group.Conclusions: Antenatal exercises lead to improvement of pulmonary functions and hence labour and neonatal outcomes

Clinical and Epidemiological Profiles of Severe Malaria in Children from Delhi, India

Plasmodium vivax is traditionally known to cause benign tertian malaria, although recent reports suggest that P. vivax can also cause severe life-threatening disease analogous to severe infection due to P. falciparum . There are limited published data on the clinical and epidemiological profiles of children suffering from \u2018severe malaria\u2019 in an urban setting of India. To assess the clinical and epidemiological profiles of children with severe malaria, a prospective study was carried out during June 2008\u2013December 2008 in the Department of Pediatrics, Guru Teg Bahadur Hospital, a tertiary hospital located in East Delhi, India. Data on children aged 6412 years, diagnosed with severe malaria, were analyzed for their demographic, clinical and laboratory parameters. All patients were categorized and treated as per the guidelines of the World Health Organization. In total, 1,680 children were screened for malaria at the paediatric outpatient and casualty facilities of the hospital. Thirty-eight children tested positive for malaria on peripheral smear examination (2.26% slide positivity rate). Of these, 27 (71%) were admitted and categorized as severe malaria as per the definition of the WHO while another 11 (29%) received treatment on outpatient basis. Most (24/27; 88.8%) cases of severe malaria (n=27) were infected with P. vivax. Among the cases of severe malaria caused by Plasmodium vivax (n=24), 12 (50%) presented with altered sensorium (cerebral malaria), seven (29.1%) had severe anaemia (haemoglobin &lt;5 g/dL), and 17 (70.8%) had thrombocytopaenia, of which two had spontaneous bleeding (epistaxis). Cases of severe vivax malaria are clinically indistinguishable from severe falciparum malaria. Our study demonstrated that majority (88.8%) of severe malaria cases in children from Delhi and adjoining districts of Uttar Pradesh were due to P. vivax-associated infection. P. vivax should, thus, be regarded as an important causative agent for severe malaria in children

Estimation of Gestational Age, Using Neonatal Anthropometry: A Cross-sectional Study in India

Prematurity is a significant contributor to neonatal mortality in India. Conventionally, assessment of gestational age of newborns is based on New Ballard Technique, for which a paediatric specialist is needed. Anthropometry of the newborn, especially birthweight, has been used in the past to predict the gestational age of the neonate in peripheral health facilities where a trained paediatrician is often not available. We aimed to determine if neonatal anthropometric parameters, viz. birthweight, crown heel-length, head-circumference, mid-upper arm-circumference, lower segment-length, foot-length, umbilical nipple distance, calf-circumference, intermammary distance, and hand-length, can reliably predict the gestational age. The study also aimed to derive an equation for the same. We also assessed if these neonatal anthropometric parameters had a better prediction of gestational age when used in combination compared to individual parameters. We evaluated 1,000 newborns in a cross-sectional study conducted in Guru Teg Bahadur Hospital in Delhi. Detailed anthropometric estimation of the neonates was done within 48 hours after birth, using standard techniques. Gestational age was estimated using New Ballard Scoring. Out of 1,250 consecutive neonates, 1,000 were included in the study. Of them, 800 randomly-selected newborns were used in devising the model, and the remaining 200 newborns were used in validating the final model. Quadratic regression analysis using stepwise selection was used in building the predictive model. Birthweight (R=0.72), head-circumference (R=0.60), and mid-upper arm-circumference (R=0.67) were found highly correlated with gestation. The final equation to assess gestational age was as follows: Gestational age (weeks)=5.437 7W\u20130.781 7W2+2.815 7HC\u20130.041 7HC2+0.285 7MUAC\u201322.745 where W=Weight, HC=Head-circumference and MUAC=Mid-upper arm-circumference; Adjusted R=0.76. On validation, the predictability of this equation is 46% (\ub11 week), 75.5% (\ub12 weeks), and 91.5% (\ub13 weeks). This mathematical model may be used in identifying preterm neonates

NewsPanda: Media Monitoring for Timely Conservation Action

Non-governmental organizations for environmental conservation have a significant interest in monitoring conservation-related media and getting timely updates about infrastructure construction projects as they may cause massive impact to key conservation areas. Such monitoring, however, is difficult and time-consuming. We introduce NewsPanda, a toolkit which automatically detects and analyzes online articles related to environmental conservation and infrastructure construction. We fine-tune a BERT-based model using active learning methods and noise correction algorithms to identify articles that are relevant to conservation and infrastructure construction. For the identified articles, we perform further analysis, extracting keywords and finding potentially related sources. NewsPanda has been successfully deployed by the World Wide Fund for Nature teams in the UK, India, and Nepal since February 2022. It currently monitors over 80,000 websites and 1,074 conservation sites across India and Nepal, saving more than 30 hours of human efforts weekly. We have now scaled it up to cover 60,000 conservation sites globally.Comment: Accepted to IAAI-23: 35th Annual Conference on Innovative Applications of Artificial Intelligence. Winner of IAAI Deployed Application Award. Code at https://github.com/NewsPanda-WWF-CMU/weekly-pipelin

Income inequality and outcomes in heart failure: a global between-country analysis

Objectives: This study examined the relationship between income inequality and heart failure outcomes. Background: The income inequality hypothesis postulates that population health is influenced by income distribution within a society, with greater inequality associated with worse outcomes. Methods: This study analyzed heart failure outcomes in 2 large trials conducted in 54 countries. Countries were divided by tertiles of Gini coefficients (where 0% represented absolute income equality and 100% represented absolute income inequality), and heart failure outcomes were adjusted for standard prognostic variables, country per capita income, education index, hospital bed density, and health worker density. Results: Of the 15,126 patients studied, 5,320 patients lived in Gini coefficient tertile 1 countries (coefficient: &lt;33%), 6,124 patients lived in tertile 2 countries (33% to 41%), and 3,772 patients lived in tertile 3 countries (&gt;41%). Patients in tertile 3 were younger than tertile 1 patients, were more often women, and had less comorbidity and several indicators of less severe heart failure, yet the tertile 3-to-1 hazard ratios (HRs) for the primary composite outcome of cardiovascular death or heart failure hospitalization were 1.57 (95% confidence interval [CI]: 1.38 to 1.79) and 1.48 for all-cause death (95% CI: 1.29 to 1.71) after adjustment for recognized prognostic variables. After additional adjustments were made for per capita income, education index, hospital bed density, and health worker density, these HRs were 1.46 (95% CI: 1.25 to 1.70) and 1.30 (95% CI: 1.10 to 1.53), respectively. Conclusions: Greater income inequality was associated with worse heart failure outcomes, with an impact similar to those of major comorbidities. Better understanding of the societal and personal bases of these findings may suggest approaches to improve heart failure outcomes

The prevalence and importance of frailty in heart failure with reduced ejection fraction – an analysis of PARADIGM-HF and ATMOSPHERE

Aims: Frailty, characterized by loss of homeostatic reserves and increased vulnerability to physiological decompensation, results from an aggregation of insults across multiple organ systems. Frailty can be quantified by counting the number of ‘health deficits’ across a range of domains. We assessed the frequency of, and outcomes related to, frailty in patients with heart failure and reduced ejection fraction (HFrEF). Methods and results: Using a cumulative deficits approach, we constructed a 42‐item frailty index (FI) and applied it to identify frail patients enrolled in two HFrEF trials (PARADIGM‐HF and ATMOSPHERE). In keeping with previous studies, patients with FI ≤0.210 were classified as non‐frail and those with higher scores were divided into two categories using score increments of 0.100. Clinical outcomes were examined, adjusting for prognostic variables. Among 13 625 participants, mean (± standard deviation) FI was 0.250 (0.10) and 8383 patients (63%) were frail (FI &gt;0.210). The frailest patients were older and had more symptoms and signs of heart failure. Women were frailer than men. All outcomes were worse in the frailest, with high rates of all‐cause death or all‐cause hospitalization: 40.7 (39.1–42.4) vs. 22.1 (21.2–23.0) per 100 person‐years in the non‐frail; adjusted hazard ratio 1.63 (1.53–1.75) (P &lt; 0.001). The rate of all‐cause hospitalizations, taking account of recurrences, was 61.5 (59.8–63.1) vs. 31.2 (30.3–32.2) per 100 person‐years (incidence rate ratio 1.76; 1.62–1.90; P &lt; 0.001). Conclusion: Frailty is highly prevalent in HFrEF and associated with greater deterioration in quality of life and higher risk of hospitalization and death. Strategies to prevent and treat frailty are needed in HFrEF

Relationship between duration of heart failure, patient characteristics, outcomes, and effect of therapy in PARADIGM-HF

Aims: Little is known about patient characteristics, outcomes, and the effect of treatment in relation to duration of heart failure (HF). We have investigated these questions in PARADIGM-HF. The aim of the study was to compare patient characteristics, outcomes, and the effect of sacubitril/valsartan, compared with enalapril, in relation to time from HF diagnosis in PARADIGM-HF. Methods and results: HF duration was categorized as 0–1, &gt;1–2, &gt;2–5, and &gt;5 years. Outcomes were adjusted for prognostic variables, including N-terminal pro-brain natriuretic peptide (NT-proBNP). The primary endpoint was the composite of HF hospitalization or cardiovascular death. The number of patients in each group was as follows: 0–1 year, 2523 (30%); &gt;1–2 years, 1178 (14%); &gt;2–5 years, 2054 (24.5%); and &gt;5 years, 2644 (31.5%). Patients with longer-duration HF were older, more often male, and had worse New York Heart Association class and quality of life, more co-morbidity, and higher troponin-T but similar NT-proBNP levels. The primary outcome rate (per 100 person-years) increased with HF duration: 0–1 year, 8.4 [95% confidence interval (CI) 7.6–9.2]; &gt;1–2 years, 11.2 (10.0–12.7); &gt;2–5 years, 13.4 (12.4–14.6); and &gt;5 years, 14.2 (13.2–15.2); P &lt; 0.001. The hazard ratio was 1.26 (95% CI 1.07–1.48), 1.52 (1.33–1.74), and 1.53 (1.33–1.75), respectively, for &gt;1–2, &gt;2–5, and &gt;5 years, compared with 0–1 year. The benefit of sacubitril/valsartan was consistent across HF duration for all outcomes, with the primary endpoint hazard ratio 0.80 (95% CI 0.67–0.97) for 0–1 year and 0.73 (0.63–0.84) in the &gt;5 year group. For the primary outcome, the number needed to treat for &gt;5 years was 18, compared with 29 for 0–1 year. Conclusions: Patients with longer-duration HF had more co-morbidity, worse quality of life, and higher rates of HF hospitalization and death. The benefit of a neprilysin inhibitor was consistent, irrespective of HF duration. Switching to sacubitril/valsartan had substantial benefits, even in patients with long-standing HF