Establish Cause Of Death Research Articles

Warburg-Effect Driven Lactic Acidosis Is Associated with Early Death in Patients with Lymphoma

Introduction: Lactic acidosis is a medical emergency and in most cases results from an imbalance between tissue oxygenation and oxygen demand (Type A). However, Type B lactic acidosis occurs in the absence of a recognizable impairment in systemic oxygen delivery, and is most commonly associated with drug or toxin ingestion, sepsis, severe nutritional deficits such as thiamine, and less commonly, malignancy. The capacity of shifting glucose metabolism to anaerobic pathway despite the presence of adequate oxygen, enhancing the rate of glucose uptake, accelerated glycolysis and hence producing more lactate, is a well-defined phenomenon in malignant cell metabolism, and is called the Warburg Effect (WE) or aerobic glycolysis. A systemic rise in lactate and lactic acidosis has been reported in hematologic malignancies and less commonly in solid tumors, and is thought to occur as a consequence of both increased production of lactate- reflecting high malignancy burden, and impaired lactate turnover or elimination by liver or kidney. Few case reports or series have demonstrated a possible correlation between early death and elevated lactate in patients with hematologic malignancy (Table 1). We aimed to characterize the incidence and clinical impact of Warburg-driven lactic acidosis on outcome including early death. Methods: A retrospective study of patients admitted to the haemato-oncology department in a large tertiary medical center between the years 2013- 2022, that presented with elevated lactate levels during the first week of admission. Patients with hematologic diseases other than lymphoma were excluded. Of 40 patients reviewed, 21 patients were excluded because of underlying hematological malignancy other than lymphoma. Medical records were retrieved and reviewed for a recognizable cause for elevated lactate, or non (assigned as the WE group). Early-death was defined as death of any cause within 4 weeks of admission. Results: Nineteen patients had lymphoma and elevated lactate levels within the first week of admission. Of these, 12 patients fulfilled the criteria for WE and 7 patients had their high lactate attributed to other causes such as hemorrhagic shock (n=1), sepsis (n=5) and concomitant metformin use (n=1). Median age among patients with WE was 72.5 years (range 66-86) with 41.6% (n=5) males. All but one had aggressive lymphoma. Diffuse Large B cell Lymphoma was the most frequent type (n=9) followed by T cell Lymphoma (n=2) and follicular lymphoma (n=1). Most patients had advanced disease (Stage III-IV in 75%) and the median International Prognostic Index (IPI) of the patients was 4 (range 3-5). The median lactate level was 31.5 mg/dL (range 25-64; with upper limit of normal value-20 mg/dL). Two patients received thiamin therapy once WE was recognized. Early-death rate was 75% (9 patients) among patients with WE. The established cause of death in this population was: sepsis (n=3), DIC (n=1), uremia and multi organ failure (n=2) and respiratory failure due to lung infiltration by lymphoma (n=3). Both steroid and chemotherapy were initiated earlier in surviving patients as compared to those who died early (within 4 weeks of admission); in surviving patients, chemotherapy was initiated at a median of 3 days before first elevated lactate was detected (range (-)7-1), and steroids at median of 3 days before first elevated lactate was detected, while in those who died early, chemotherapy was initiated at median of 5 days after first elevated lactate was detected (range (-)2-18) and steroids at median 1 day after first elevated lactate (p=0.29 and 0.05 for steroids and chemo, respectively). (Table 2). Conclusion: Warburg driven lactic acidosis is a marker of ‘acute cancer’ in lymphoma patients and is associated with a very high mortality rate. Early recognition of this very high-risk clinical scenario is of utmost importance and should prompt immediate anti-lymphoma therapy that may improve outcome.

Validation studies of verbal autopsy methods: a systematic review

BackgroundVerbal autopsy (VA) has emerged as an increasingly popular technique to assign cause of death in parts of the world where the majority of deaths occur without proper medical certification. The purpose of this study was to examine the key characteristics of studies that have attempted to validate VA cause of death against an established cause of death.MethodsA systematic review was conducted by searching the MEDLINE, EMBASE, Cochrane-library, and Scopus electronic databases. Included studies contained 1) a VA component, 2) a validation component, and 3) original analysis or re-analysis. Characteristics of VA studies were extracted. A total of 527 studies were assessed, and 481 studies screened to give 66 studies selected for data extraction.ResultsSixty-six studies were included from multiple countries. Ten studies used an existing database. Sixteen studies used the World Health Organization VA questionnaire and 5 studies used the Population Health Metrics Research Consortium VA questionnaire. Physician certification was used in 36 studies and computer coded methods were used in 14 studies. Thirty-seven studies used high level comparator data with detailed laboratory investigations.ConclusionMost studies found VA to be an effective cause of death assignment method and compared VA cause of death to a high-quality established cause of death. Nonetheless, there were inconsistencies in the methodologies of the validation studies, and many used poor quality comparison cause of death data. Future VA validation studies should adhere to consistent methodological criteria so that policymakers can easily interpret the findings to select the most appropriate VA method.Prospero RegistrationCRD42020186886.

Quantitative assessment of placental morphology may identify specific causes of stillbirth.

BackgroundStillbirth is frequently the result of pathological processes involving the placenta. Understanding the significance of specific lesions is hindered by qualitative subjective evaluation. We hypothesised that quantitative assessment of placental morphology would identify alterations between different causes of stillbirth and that placental phenotype would be independent of post-mortem effects and differ between live births and stillbirths with the same condition.MethodsPlacental tissue was obtained from stillbirths with an established cause of death, those of unknown cause and live births. Image analysis was used to quantify different facets of placental structure including: syncytial nuclear aggregates (SNAs), proliferative cells, blood vessels, leukocytes and trophoblast area. These analyses were then applied to placental tissue from live births and stillbirths associated with fetal growth restriction (FGR), and to placental lobules before and after perfusion of the maternal side of the placental circulation to model post-mortem effects.ResultsDifferent causes of stillbirth, particularly FGR, cord accident and hypertension had altered placental morphology compared to healthy live births. FGR stillbirths had increased SNAs and trophoblast area and reduced proliferation and villous vascularity; 2 out of 10 stillbirths of unknown cause had similar placental morphology to FGR. Stillbirths with FGR had reduced vascularity, proliferation and trophoblast area compared to FGR live births. Ex vivo perfusion did not reproduce the morphological findings of stillbirth.ConclusionThese preliminary data suggest that addition of quantitative assessment of placental morphology may distinguish between different causes of stillbirth; these changes do not appear to be due to post-mortem effects. Applying quantitative assessment in addition to qualitative assessment might reduce the proportion of unexplained stillbirths.Electronic supplementary materialThe online version of this article (doi:10.1186/s12907-016-0023-y) contains supplementary material, which is available to authorized users.

Undetermined Manner of Death: An Autopsy Series.

A manner of death may be ruled undetermined by the forensic pathologist when there is insufficient information about the circumstances surrounding the death to make a ruling. The aim of our study was to retrospectively analyze a series of autopsy cases that were classified as undetermined manner of death after complete investigations. In all, 48 cases were examined. In 23 cases (48%), the cause of death was determined. The most frequent cause of death was toxic death (n=11). More than one manner of death was deemed conceivable for most cases (n=39). The most frequent and the most probable manner of death was accident (n=37). Homicide was not excluded in about 23% of the cases. Our study showed that the manner of death may remain undetermined despite an established cause of death, and even when two or more conceivable causes of death are considered. Our study pointed out that undetermined manner of death covers a wide range of situations and that homicide may be underestimated.

Early Mortality and Cardiorespiratory Failure in Patients with Fibrodysplasia Ossificans Progressiva

Fibrodysplasia ossificans progressiva, a rare genetic disorder of progressive extraskeletal ossification, is the most disabling form of heterotopic ossification in humans. However, little is known about the lifespan or causes of mortality in these patients. We undertook this study to determine the lifespan and causes of mortality in individuals who had fibrodysplasia ossificans progressiva. We reviewed comprehensive mortality reports from two large registries of patients with fibrodysplasia ossificans progressiva. Together, these registries comprise >90% of all known patients with this condition in the world. We noted the sex, dates of birth and death, and the cause of death for each individual. We verified the cause of death with extensive medical records, when available. We also collected date of birth, current age, and sex information for each living patient member of the International Fibrodysplasia Ossificans Progressiva Association. Sixty deaths (thirty male and thirty female patients) were reported in the fibrodysplasia ossificans progressiva community during a thirty-three-year-period. For all sixty patients, the median age at the time of death was forty years (range, three to seventy-seven years). Data were sufficient to establish the cause of death in forty-eight (80%) of the sixty individuals. The median age at the time of death for the forty-eight patients (twenty-four male and twenty-four female patients) with an established cause of death was also forty years. The median lifespan estimated from the 371 individuals in the international fibrodysplasia ossificans progressiva community who were alive and the sixty who had died was fifty-six years (95% confidence interval, fifty-one to sixty years). The most common causes of death in patients with fibrodysplasia ossificans progressiva were cardiorespiratory failure from thoracic insufficiency syndrome (54%; median age, forty-two years) and pneumonia (15%; median age, forty years). Fibrodysplasia ossificans progressiva is not only an extremely disabling disease but also a condition of considerably shortened lifespan. The most common cause of death in patients with fibrodysplasia ossificans progressiva is cardiorespiratory failure from thoracic insufficiency syndrome.

Timing and impact of infections in acute pancreatitis

Although infected necrosis is an established cause of death in acute pancreatitis, the impact of bacteraemia and pneumonia is less certain. This was a cohort study of 731 patients with a primary episode of acute pancreatitis in 2004-2007, including 296 patients involved in a randomized controlled trial to investigate the value of probiotic treatment in severe pancreatitis. Time of onset of bacteraemia, pneumonia, infected pancreatic necrosis, persistent organ failure and death were recorded. The initial infection in 173 patients was diagnosed a median of 8 (interquartile range 3-20) days after admission (infected necrosis, median day 26; bacteraemia/pneumonia, median day 7). Eighty per cent of 61 patients who died had an infection. In 154 patients with pancreatic parenchymal necrosis, bacteraemia was associated with increased risk of infected necrosis (65 versus 37.9 per cent; P = 0.002). In 98 patients with infected necrosis, bacteraemia was associated with higher mortality (40 versus 16 per cent; P = 0.014). In multivariable analysis, persistent organ failure (odds ratio (OR) 18.0), bacteraemia (OR 3.4) and age (OR 1.1) were associated with death. Infections occur early in acute pancreatitis, and have a significant impact on mortality, especially bacteraemia. Prophylactic strategies should focus on early intervention.