Immediate Cause Of Death Research Articles

Mortality due to ischemic stroke in Serbia after redistribution of the inaccurately coded deaths

Abstract Background Ischemic stroke is a major common cause of death not only in Serbia but worldwide. Mortality statistics commonly include ill-defined, impossible and insufficiently specified causes of death among the underlying causes of death (CoDs). In the activities of the Laboratory for Strengthening the Capacity and Performance of the Health System and Workforce for Health Equity, we examined mortality due to ischemic stroke either as well-defined underlying CoDs or garbage codes (GCs - including the ill-defined, unspecified or impossible CoDs) in Belgrade in 2015 and 2020. Methods Anonymous mortality data of the City Institute of Public Health Belgrade were analyzed, and the GCs were redistributed to ischemic stroke as underlying CoDs (ICD-10 codes I63-I63.9), based on the principles of the Global Burden of Disease study, using the three-step approach: 1) exploration and analysis of GCs; 2) modelling of the underlying, antecedent and immediate causes of death; 3) proportionate redistribution. Results 17% of the total of all deaths in Belgrade in 2015 and 20.9% in 2020 were GCs. Before the redistribution, the share of ischemic stroke as the well-coded CoDs of total mortality was 7.3% (1443/19641) in 2015 and 4.6% (1022/21957) in 2020. A total of GCs - 309 deaths in 2015 and 322 in 2020 were identified for redistribution to ischemic stroke. Based on the type of GCs, in 2015, a total of 139 cases were redistributed in type 1 GCs, 83 in type 2 GCs and 87 in type 3 GCs. In 2020, 141 cases were redistributed due to type 1 GCs, 62 type 2 GCs and 119 type 3 GCs. Conclusions This study underscores the significant proportion of all ischemic deaths in Belgrade that were coded with the GCs. After the redistribution, almost one-fifth of the ischemic strokes, previously known as GCs, were added, emphasizing the crucial role of accurate coding in understanding mortality patterns. Improving the coding of deaths is necessary to have reliable information for health policymaking. Key messages • One-fifth of the ischemic strokes in Belgrade were previously GCs. • Accurate coding is essential for understanding mortality patterns and developing valid health policies.

Clinical characteristics and analysis of related factors associated with early death in newly diagnosed patients with acute promyelocytic leukemia

ObjectiveThe objective of this study was to investigate the clinical characteristics and analysis of related factors associated with early death in newly diagnosed patients with acute promyelocytic leukemia (APL).MethodsThis retrospective study included patients who visited our hospital between January 2010 and August 2022 and were diagnosed with APL for the first time. We analyzed their clinical and laboratory characteristics and analysis of related factors associated with early death.ResultsA total of 269 patients with a primary diagnosis of APL were collected. The male to female ratio was 6:5, and the median age was 42 years (range 7–80). Among patients with initial APL diagnosis, there were 34 early deaths, resulting in an early mortality rate of 13%. The median time from diagnosis to death was 8.5 days (range 3–24). Comparative analysis of the clinical characteristics between patients who died early and those who did not, using a logistic regression model, revealed that age, white blood cell count (WBC) at initial diagnosis, and prolongation time of prothrombin time (PT) were independent risk factors for early death in patients with primary APL (P < 0.05). Comparing the clinical characteristics during hospitalization between the early death group and the non-early death group, it was observed that the daily mean of WBC during hospitalization was significantly higher in patients who died early than in those who did not (P < 0.001). Conversely, the daily mean of platelet count (PLT) was significantly lower in patients who died early compared to those who did not (P < 0.001). Furthermore, statistically significant differences were found in the mean daily infusion of PLT (P < 0.05), fibrinogen (Fib) (P < 0.05), and fresh frozen plasma (FFP) (P < 0.05) during hospitalization between patients who died early and those who did not. Specifically, the mean daily infusion of PLT and FFP was significantly higher in the early-death group than in the non-early-death group. Cerebral hemorrhage was identified as the immediate cause of death in 25 out of the 34 early-death patients (74%). The remaining causes of death included infection in 5 cases (15%), all of which were severe pulmonary infections, including 2 cases of combined differentiation syndrome, and abandonment of treatment in 4 patients (11%) at initial diagnosis.ConclusionIn patients with primary APL, age, WBC at initial diagnosis, and PT prolongation time were identified as independent risk factors for early death (P < 0.05). Laboratory findings regarding WBC and PLT during hospitalization, as well as the infusion of PLT, Fib, and FFP during hospitalization, were also statistically significant. Cerebral hemorrhage was found to be the main cause of early death in patients with primary APL.

Evaluation of Errors on Death Certificates.

Death certificates provide vital data for disease surveillance and health policy. However, errors are common globally, undermining data reliability. This study analyzed prevalence and types of errors in death certificates at a tertiary hospital in Nepal. A cross-sectional study reviewed all death certificates issued at Lumbini Medical College, Nepal from April 2020 to April 2022. Certificates were assessed for errors including improper sequencing, absent time intervals, abbreviations, illegible writing, and inaccurate immediate, antecedent, and underlying causes of death as per international guidelines. Errors were classified as major or minor. Of 139 certificates, none were error-free. The most common error was incorrectly or incompletely filling the immediate cause of death (77.7%). Other errors included absent time of death (17.3%), abbreviations (57.6%), illegible writing (22.3%), and omitting the hospital stamp/medical council registration number (8.6%). Based on international criteria, 76.3% had minor errors, 23% had both major and minor errors. This study found a high rate of errors in death certification at a tertiary hospital in Nepal, undermining data accuracy. Regular training and monitoring with feedback are recommended to improve certification practices. Accurate cause-of-death data is vital for healthcare policy and decision-making in Nepal.

Fatal Hemoperitoneum Secondary to a Spontaneous Splenic Vein Rupture.

Spontaneous hemoperitoneum is rare and is often labeled as idiopathic because the source of bleeding is never found. We report the case of a 35-year-old male who died of a splenic vein rupture. The decedent was a chronic alcoholic with a reported history of cirrhosis and medication noncompliance. Internal examination revealed pale visceral organs, marked hemoperitoneum, a fibrotic/nodular liver, esophageal varices, and a ruptured splenic vein. Pertinent microscopic findings include liver parenchyma with bridging fibrous septa, nodules of regenerating hepatocytes, and the presence of Mallory-Denk bodies. The immediate cause of death was determined to be splenic vein rupture with the underlying cause of death being chronic alcoholism. This case is reported to emphasize the importance of correlating past medical history with thorough vascular dissection in cases of spontaneous hemoperitoneum. In a patient with fatal hemoperitoneum and risk factors for splenic vein pathology (ie, cirrhosis, portal vein hypertension), a high suspicion should be kept for splenic vein rupture.

Fat embolism and COVID-19 infection: autopsy and post-mortem laboratory findings in SARS-CoV-2 positive patients.

The article is one of the very first autopsy reports worldwide, which associates COVID-19 infection and pulmonary fat embolism. To point to a crucial connection between a severe acute respiratory syndrome caused by coronavirus 2 (SARS-CoV-2) infection and pulmonary fat embolism as one of the possible major mechanisms of severe COVID-19 symptoms. Lung, brain and kidney tissues examination of 16 full human autopsy cases. All deceased suffered from COVID-19 infection, none of them was admitted to hospital prior to death, immediate causes of death vary. Autopsies accompanied by microbiological examination and histological examination using Oil Red O staining were performed. Consequently, we have implemented a control cohort consisting of 16 deceased with no presence of pulmonary infection and various immediate causes of death. Of the 16 autopsy cases, 11 (68.8%) were males and 5 (31.3%) females, with overall mean age 68.1 (39-86) years. Causes of death of studied subjects were natural, mostly from respiratory failure (in 12 cases, 75%). Cardiopulmonary resuscitation was performed in 7 cases (43.8%). None of dissected persons had larger signs of body trauma. Pulmonary fat embolism was found in 11 cases (68.8%), which generalised to kidneys in 8 patients (50% of all cases, 72.3% of cases with pulmonary fat embolism) and to brain tissue in 1 case. We demonstrated a reasonable relation between a COVID-19 disease and a variously severe fat embolism, severity of which does not directly correlate with body weight. Further investigation or even change of medical treatment needs to be considered in patients with COVID-19.

The discrepancy of antemortem clinical diagnosis and postmortem autopsy diagnosis of lung pathologies in under-five deaths and the reasons for discrepancies: a case series analysis

BackgroundDiagnostic autopsy is the most reliable approach to definitively ascertain the cause of death and evaluate the accuracy of antemortem clinical diagnoses. Identifying diagnostic discrepancies is vital to understanding common gaps in antemortem clinical diagnoses and modifying antemortem diagnostic approaches to increase the accuracy of clinical diagnosis. The objective of this study was to determine the frequency of diagnostic discrepancies between antemortem clinical diagnoses and postmortem autopsies on lung pathologies and to understand the reasons for diagnostic discrepancies among cases included in Child Health and Mortality Prevention Surveillance (CHAMPS) in Ethiopia.MethodsA clinical case series study of deaths among children under-five in the CHAMPS study at three sites in Ethiopia between October 2019 and April 2022 was conducted. The antemortem clinical diagnoses and postmortem pathological diagnoses of the lung were compared for each case. Two senior physicians assessed the findings for both agreement and disagreement. McNemar’s test was used to assess for statistically significant differences between antemortem and postmortem diagnoses.ResultsSeventy-five cases were included (73.3% male). Over half (54.7%) died between the 1st and 7th day of life. Sepsis (66.7%), pneumonia (6.7%), and meconium aspiration syndrome (5.0%) were the most common immediate causes of death. Half (52%) of cases were correctly diagnosed antemortem. The magnitude of diagnostic discrepancy was 35% (95% CI: 20-47%). The most common contributing factors to diagnostic discrepancy were gaps in knowledge (22/75, 35.5%) and problems in consultation and teamwork (22/75, 35.5%).ConclusionsMisdiagnoses were common among young children who died with positive lung pathology findings. In-service education initiatives and multidisciplinary collaboration are needed to mitigate high rates of diagnostic discrepancies among young children to potentially prevent future deaths.

RETROSPECTIVE ANALYSIS OF CLINICAL, EPIDEMIOLOGY AND PATHOMORPHOLOGICAL FEATURES OF MYOCARDIAL INFARCTION

The aim of this study is to conduct a retrospective analysis of the clinical, epidemiological, and pathomorphological features of myocardial infarction. Materials and methods: A retrospective analysis was conducted using data from medical records and autopsy results from the pathology department for the year 2023. Results. In 2023, the pathology department performed 182 autopsies, with 123 patients diagnosed with acute, repeated, or recurrent myocardial infarction (MI), accounting for 67.6% of all autopsies. The average age of the deceased was 74.4±0.9 years, with 81.3% being persons of incapacitated age. Women comprised the majority at 55.3% (T=2784.5; p=0.001). The highest proportion of MI-related deaths occurred in September, accounting for 12.2%. In the pathological diagnosis, myocardial infarction (MI) was the primary disease, with varying localization of the pathological process in the left ventricle. Transmural MI was detected in 95.9% of the deceased, while subendocardial MI was found in 4.1%. Acute MI developed against the background of a previously experienced MI in 43.9% of cases, and in 5.5% of cases, it was a repeated acute recurrent MI. Changes in the aorta, coronary vessels, and basal vessels of the brain were observed in 100.0% of the cases, with hypertensive disease detected in 95.9% of cases. Acute cardiopulmonary failure with the development of pulmonary edema was the immediate cause of death in 95.9% of cases. Macroscopic examination revealed hypertrophy of the left ventricle. The myocardium appeared reddish-brown and elastic, with white layers. Brown-gray infarct areas of different sizes were present in the left ventricular wall, while in cases of repeated acute myocardial infarction, the affected area was gray-white and hard to the touch. Microscopically, hypertrophy of cardiomyocytes of the left ventricle with perinuclear lipofuscinosis was observed in all deceased individuals. Sections of the infarct zone contained homogenized, anucleated, fragmented cardiomyocytes, dilated full blood vessels with small perivascular hemorrhages, and neutrophilic-macrophage infiltrates of varying intensity. Large centers of cardiosclerosis were detected in cases of repeated MI, while signs of angiogenesis with the formation of granulation tissue were observed in cases of recurrent MI. Conclusion. In 2023, 123 autopsies revealed a diagnosis of acute, repeated, or recurrent myocardial infarction (MI) in 67.6% of all cases. The average age of the deceased was 74.4±0.9 years, with 81.3% being individuals of incapacitated age. There was a predominance of women, accounting for 55.3% of cases. Acute MI developed against the background of a previously experienced one in 43.9% of the deceased, while repeated acute recurrent MI was detected in 5.5% of cases. Pathomorphological changes corresponded to the typical features of MI depending on its age.

Analysis of injuries in aircraft accident victims in 2002–2022 based on the resources of the Jagiellonian University Department of Forensic Medicine in Kraków = Analiza obrażeń ofiar katastrof lotniczych w latach 2002–2022 na podstawie danych pochodzących z materiałów Zakładu Medycyny Sądowej Uniwersytetu Jagiellońskiego w Krakowie

Aim: The study aimed to analyse the most common injuries of victims of aviation accidents and compare it with the most recent literature. Methods and materials: Retrospective analysis of autopsy protocols of aircraft crash victims from the Forensic Medicine Department from years 2002–2022. The case selection has been made by two independent researchers. After applying the exclusion criteria 27 cases were obtained. Further searched for features that the bodies of victims had in common. There were analysed sex, age, circumstances of the incident, injuries, presence of psychoactive substances (alcohol, drugs), and blood concentration of carboxyhemoglobin. Results: Among 27 cases we found 19 airplane crashes, 4 glider accidents, 3 motor glider accidents, and one helicopter crash. The 1 case had no information about the type of aircraft. The injuries that emerged in each of the victims were typical results of direct impact forces. The most common were rupture of the lungs 63.0 % (n = 17/27), heart 55.6% (n = 15/27), liver 51.9% (n = 14/27), aorta 40.7% (n = 11/27) and spleen 29.6% (n = 8/27). Common bone traumas included fractures of the ribs 77.8% (n = 21/27) upper limbs 77.8% (n = 21/27), skull 74.1% (n = 20/27), pelvis 59.3% (n = 16/27) and spine 51.9% (n = 14/27). Injuries of the cervical spine occurred in victims who violently tilted their heads back. Conclusions: In most cases, the immediate cause of death was extensive multi-organ injuries, followed by thermal burns or brain injuries. In almost half of the victims, the presence of carboxyhemoglobin in the blood indicates that they were alive during the crashes. Knowledge of injury patterns can improve aviation safety and guide in reconstructing the mechanisms and sequences of the accidents.

Profile of Deaths Due to COVID-19 in Three Zones of Ahmedabad City during the all Three Waves of Pandemic: A Record Based Study

Introduction: Mortality due to COVID- 19 was observed in India including Gujarat during the pandemic. Death audit of all the deaths among cases of COVID- 19 during the pandemic was carried out in Municipal Corporation area of a city of Gujarat in India. Objective: Present research was carried out to describe socio-demographic and clinical profile among deceased due to COVID-19. Method: Descriptive cross sectional record-based study was carried out. Case papers of 1078 deaths from three zones of municipal corporation were allotted for death audit to a tertiary care teaching hospital and the findings were described as proportions, mean, median, and associations were demonstrated through appropriated tests like Chi square test, t-test. Results: Mean age of deceased was 63.66+11.99 years. Male:Female ratio was 2.5:1.The median duration of stay of the deceased in the hospital was 7 (IQR: 3-12). The most commonly recorded immediate cause of death was Type 1 Respiratory failure 533 (49.44%). Proportion of comorbidities increased with increase in age and this was statistically highly significant. However, there was no gender-wise association of comorbidities. There was no association of SpO2 levels with age. However, SpO2 levels were significantly associated with fever, sore throat, breathlessness and ischaemic heart disease. Conclusion: Based on the findings of the study, individuals more than 60 years of age were identified as high risk group, Emphasis on early referral and proper management of comorbidities is required to decrease the mortality.

Analysis of cases of suicide by self-immolation in the post-mortem material of the Department of Forensic Medicine in Cracow.

Analysis of self-immolation cases and distribution of the resulting burns and their degree. The study included 16 cases from the Department of Forensic Medicine, Jagiellonian University Medical College in Cracow from 2000-2022 in which the cause of death was self-immolation. Based on the analysis of photographs and autopsy reports, drawings were made showing the exact distribution and nature of the injuries, moreover, the approximate percentage of body surface area affected was determined as well as the frequency of involvement of specific areas of the body, and the presence of previous diseases and mental disorders including previous suicide attempts. 81% of victims were male. Two age groups were predominant among the cases analyzed, namely, individuals around the age of 20, and those between 50 and 60 years of age. 44% of the deceased had burns exceeding 80% of total body surface. The most frequently involved body areas were the extremities and chest as well as head and neck. Fourth-degree burns were most prevalent on the head and neck, third-degree burns prevailed on the upper and lower extremities, second-degree burns were mostly found on the chest, and first-degree burns - on the lower extremities. There were no cases of fourth-degree burns of the buttocks. 38% of the subjects had a history of substance abuse, 56% suffered from mental illnesses, whereas 31% attempted suicide in the past. The distribution of burns in self-immolation cases is inhomogeneous. The most frequently affected area was the head, neck, chest and extremities, most likely due to victims dousing themselves with a flammable substance from the top of the head through the chest. In all cases, the immediate cause of death was burn disease, regardless of the size of the body surface area affected by the burns. The majority of victims had a history of mental illness, substance abuse or suicide attempts.

Diabetes mellitus as a cause of premature death in small areas of Spain by socioeconomic level from 2016 to 2020: A multiple-cause approach

ObjectiveThis study aimed to assess premature mortality due to Diabetes in small areas of Spain between 2016 and 2020, and its relationship with socioeconomic level and the immediate cause of death. As a secondary objective, we evaluated the effect of the Covid 19 pandemic. MethodsThis was an ecological study of premature mortality due to Diabetes from 2016 to 2020, with a focus on small areas. All deaths in people under 75 years of age due to Diabetes as the underlying cause were included ResultsThe final sample comprised 7382 premature deaths in 5967 census tracts. Women living in census tracts with an high level of deprivation(RR=2.40) were at a significantly higher risk. Mortality from Diabetes increased with deprivation, especially people aged 0–54(RR=2.40). People with an immediate cause of death related to a circulatory disease, living in census tracts with an high level of deprivation(RR=3.86) was associated with a significantly greater risk of death with underlying Diabetes. When a disease of the circulatory system was recorded as the immediate cause of death, being 65–74 years (RR=71.01) was associated with a significantly higher risk of premature mortality. ConclusionsLiving in geographic areas with higher levels of socioeconomic deprivation is associated with a higher risk of premature death from Diabetes in Spain. This relationship has a greater impact on women, people under 54 years, and people at risk of death caused directly by diseases of the circulatory system. Premature mortality due to diabetes saw a modest increase in 2020.

Determinants of Mortality of Patients Admitted to the Intensive Care Unit at Debre Berhan Comprehensive Specialized Hospital: A Retrospective Cohort Study.

The provision of intensive care services is advancing globally. However, in resource-limited settings, it is lagging far behind and intensive care unit mortality is still higher due to various reasons. This study aimed to assess determinants of mortality among medical patients admitted to the intensive care unit. A five-year facility-based retrospective Cohort Study was conducted. A total of 546 medical patients admitted to the intensive care unit from March 2017 to February 2022 were included. Document review using a structured questionnaire was implemented to collect data. Data entered into Epi Data were analyzed by STATA and summarized using frequency tables and graphs. Binary and multivariate logistic regression analyses were performed to identify determinants of mortality. The overall mortality was 35.9%. Approximately half of the deaths were attributed to septic shock, congestive heart failure, severe community-acquired pneumonia, and stroke. The most common immediate cause of death was cardio-respiratory arrest. Source of admission, GCS level at admission, duration of ICU stay, treatment with inotropes, septic shock, and retroviral infection status were found to have a statistically significant association with ICU mortality. This study revealed a significantly higher mortality rate among patients admitted to the intensive care unit. Early identification and admission of patients to the intensive care unit are important factors that could decrease mortality. Patient selection is essential since some patients with a high likelihood of mortality might not benefit from intensive care unit admission in an area with high resource limitations.

Diseases of the nervous system as the underlying cause of death

To identify the leading causes of death in the adult population from the class of diseases of the nervous system (DNS, class G) according to medical death certificates (MDC) and to discuss the problems of their assessment. The source of information was the electronic database of the Main Department of the Civil Registry Office of the Moscow Region. All cases of class G deaths were selected (total 10.739), an analysis was carried out according to underlying cause of death (UCD) codes and the immediate cause of death. In 2022, mortality from diseases included in the DNS amounted to 130.7 per 100 000 of the population over 18 years old (100.3 among men, 191.0 among women). The average age of men is 74.3±14.1, women - 83.5±9.9 years (p<0.0001) due to the younger age of death of men from «G31.2 Degeneration of the nervous system caused by alcohol» and a higher contribution of this cause to male mortality; 82.5% of deaths were for codes G90-G99 («Other disorders of the nervous system»); 15.5% were neurodegenerative diseases (G10-G32). Sixty-six percent of all UCD in both women and men accounted for «unspecified encephalopathy» (G93.4), in 2nd place (10.5%) was «cerebral cyst» (G93.0). In 45 cases, code G93.6 (cerebral edema) was mistakenly used as UCD. Differences in the structure of causes of death at home, in hospital and elsewhere are statistically significant (p<0.00001). In 58.3%, cerebral edema and herniation were indicated as the immediate cause of death (G93.6 and G93.5). Nosologically unfounded, insufficiently well-defined UCD were established in most cases of death from DNS, In 0.5% of the total number of deaths from DNS, an erroneous presentation as UCD of transient disorders of cerebral circulation or cerebral edema was noted. The results indicate the need for an analysis of the causes of death based on a comparison of medical records and MDC.

Trends in cause-specific mortality among persons with Alzheimer's disease in South Carolina: 2014 to 2019.

Inconsistencies of reports contributes to the underreporting of Alzheimer's disease (AD) on death certificates. Whether underreporting exists within South Carolina has not been studied. We conducted a prospective, population-based study on a cohort of persons (N = 78,534) previously diagnosed with AD and died between 2014-2019. We linked vital records with the South Carolina Alzheimer's Disease and Related Dementias Registry to investigate their cause of death and survival rates. Descriptive analyses calculated frequencies of demographic and health-related characteristics. Turnbull's method estimated the survival probabilities for different subgroups of patients. Hazard ratios were computed from the Cox proportional hazards model, adjusting for the following confounding variables of age at diagnosis, education level, gender, and race. The top immediate cause of death was Alzheimer's disease among all racial groups, except for Native American/American Indian. More females (60.3%) were affected by AD compared to males (39.7%). There is a 25% probability of survival, beyond 5 years, after AD diagnosis. Black/African American AD patients have the smallest risk of all-cause mortality across all racial/ethnic groups (HR 0.87; 95% CI, 0.85-0.89). Individuals with lower education had a lower likelihood of mortality. Although AD was not underreported in the state of South Carolina further research is needed to develop protocols around classification of deaths among those diagnosed with dementia and comorbidities, including cardiovascular disease, to ensure dementia is properly reported as we move to prevent and treat Alzheimer's disease by 2025 and beyond.

Chronic Lymphocytic Leukemia and Fatal Tissue Infiltration

Chronic lymphocytic leukemia (CLL) is typically characterized as an indolent process that is most often a comorbid condition rather than an immediate cause of death. While it is well-known that CLL can infiltrate tissues and manifest as small lymphocytic lymphoma, diffuse parenchymal infiltration with perforation and hemorrhage is most often associated with more aggressive lymphomas, such as diffuse large B-cell lymphoma. Here we present a series of three cases of CLL in which fatal hemorrhage (two spontaneous and one procedure-related) resulted from tissue compromise due to infiltration of organ parenchyma by the patient's known CLL. In the first case, the patient died of spontaneous duodenal perforation and hemorrhage associated with CLL. This patient also had heart failure related to myocardial infiltration and diffuse hepatic infiltration. A second patient died of spontaneous pulmonary hemorrhage associated with CLL. The final case involved fatal pulmonary hemorrhage during bronchoscopy in a patient with unsuspected bronchial involvement by CLL. At autopsy, all three cases showed histologic and immunohistochemical features of typical CLL. None of the cases showed evidence of Richter transformation, and none of the patients had clinically evident coagulopathy. The literature contains few reports of parenchymal infiltration by CLL with fatal perforation or hemorrhage. This pattern may represent an under-appreciated mechanism of CLL contribution to morbidity and mortality. Further characterization of how CLL invades tissue and ultimately leads to compromise in the integrity of that tissue may be of clinical significance. In addition, continued research into the prevalence of CLL-related organ compromise, risk assessment, and disease progression monitoring is warranted to improve patient outcomes and quality of life.

Safety and efficacy of gene replacement therapy for X-linked myotubular myopathy (ASPIRO): a multinational, open-label, dose-escalation trial

X-linked myotubular myopathy is a rare, life-threatening, congenital muscle disease observed mostly in males, which is caused by mutations in MTM1. No therapies are approved for this disease. We aimed to assess the safety and efficacy of resamirigene bilparvovec, which is an adeno-associated viral vector serotype 8 delivering human MTM1. ASPIRO is an open-label, dose-escalation trial at seven academic medical centres in Canada, France, Germany, and the USA. We included boys younger than 5 years with X-linked myotubular myopathy who required mechanical ventilator support. The trial was initially in two parts. Part 1 was planned as a safety and dose-escalation phase in which participants were randomly allocated (2:1) to either the first dose level (1·3 × 1014 vector genomes [vg]/kg bodyweight) of resamirigene bilparvovec or delayed treatment, then, for later participants, to either a higher dose (3·5 × 1014 vg/kg bodyweight) of resamirigene bilparvovec or delayed treatment. Part 2 was intended to confirm the dose selected in part 1. Resamirigene bilparvovec was administered as a single intravenous infusion. An untreated control group comprised boys who participated in a run-in study (INCEPTUS; NCT02704273) or those in the delayed treatment cohort who did not receive any dose. The primary efficacy outcome was the change from baseline to week 24 in hours of daily ventilator support. After three unexpected deaths, dosing at the higher dose was stopped and the two-part feature of the study design was eliminated. Because of changes to the study design during its implementation, analyses were done on an as-treated basis and are deemed exploratory. All treated and control participants were included in the safety analysis. The trial is registered with ClinicalTrials.gov, NCT03199469. Outcomes are reported as of Feb 28, 2022. ASPIRO is currently paused while deaths in dosed participants are investigated. Between Aug 3, 2017 and June 1, 2021, 30 participants were screened for eligibility, of whom 26 were enrolled; six were allocated to the lower dose, 13 to the higher dose, and seven to delayed treatment. Of the seven children whose treatment was delayed, four later received the higher dose (n=17 total in the higher dose cohort), one received the lower dose (n=7 total in the lower dose cohort), and two received no dose and joined the control group (n=14 total, including 12 children from INCEPTUS). Median age at dosing or enrolment was 12·1 months (IQR 10·0-30·9; range 9·5-49·7) in the lower dose cohort, 31·1 months (16·0-64·7; 6·8-72·7) in the higher dose cohort, and 18·7 months (10·1-31·5; 5·9-39·3) in the control cohort. Median follow-up was 46·1 months (IQR 41·0-49·5; range 2·1-54·7) for lower dose participants, 27·6 months (24·6-29·1; 3·4-41·0) for higher dose participants, and 28·3 months (9·7-46·9; 5·7-32·7) for control participants. At week 24, lower dose participants had an estimated 77·7 percentage point (95% CI 40·22 to 115·24) greater reduction in least squares mean hours per day of ventilator support from baseline versus controls (p=0·0002), and higher dose participants had a 22·8 percentage point (6·15 to 39·37) greater reduction from baseline versus controls (p=0·0077). One participant in the lower dose cohort and three in the higher dose cohort died; at the time of death, all children had cholestatic liver failure following gene therapy (immediate causes of death were sepsis; hepatopathy, severe immune dysfunction, and pseudomonal sepsis; gastrointestinal haemorrhage; and septic shock). Three individuals in the control group died (haemorrhage presumed related to hepatic peliosis; aspiration pneumonia; and cardiopulmonary failure). Most children with X-linked myotubular myopathy who received MTM1 gene replacement therapy had important improvements in ventilator dependence and motor function, with more than half of dosed participants achieving ventilator independence and some attaining the ability to walk independently. Investigations into the risk for underlying hepatobiliary disease in X-linked myotubular myopathy, and the need for monitoring of liver function before gene replacement therapy, are ongoing. Astellas Gene Therapies.

Clinical manifestations of damage to the cardiovascular system and predictors of poor prognosis of Takayasu arteritis in Kyrgyz patients

Damage to the cardiovascular system (CVS) in Takayasu arteritis (AT) is characterized by a wide range of clinical manifestations and an unfavorable prognosis of the disease. Objectives: determine the characteristics of clinical manifestations of damage to the CVS and predictors of unfavorable prognosis in Kyrgyz patients with АТ. Methods: The study included 135 patients with a reliable diagnosis of AT, verified according to the classification criteria of the American College of Rheumatology/The European Alliance of Rheumatology Associations (ACR/EULAR, American College of Rheumatology/European Alliance of Associations for Rheumatology). All patients underwent clinical and standard laboratory and instrumental examination. Results: CVC lesion was observed in 84.4% of patients with AT and was manifested mainly by secondary arterial hypertension (AH) and aortic regurgitation (AR) – 52.8% and 27.8% of cases, respectively. The main cause of secondary hypertension was renovascular hypertension (63.4%). Myocarditis (8.5%) and coronary syndrome (3.8%) were significantly less frequently diagnosed. Among the cardiovascular complications (CVc) that developed in 32.5% of patients, decompensated chronic heart failure (DCHF) (48.7%) and acute cerebrovascular accident (ACVA) were the most common (40,5%). The immediate cause of death in the observed cohort was DCHF (66.7%) due to severe AR (83.3%) and ischemic cardiomyopathy (16.7%). Predictors of the development of CVc were the V anatomical type of vascular lesion, high activity of the pathological process, severity of stenotic changes, serious clinical complications (CC) and severe AR (p&lt;0.05). Conclusion: 1. CVS lesion was observed in 84.4% of Kyrgyz patients with AT. 2. The most frequent variant of cardiovascular pathology was secondary hypertension (52.8%) caused by vasorenal (63.4%), coarctation (33%) and aortic (3.6%) changes. The second most common was pathology of the aortic valve (27.8%) with a predominance of minor AR (45.8%). 3. CVc was observed in one third of patients (32.5%) and in most cases were presented with DCHF (48.7%) and ACVA (40.5%). 4. Unfavorable factors associated with an increased risk of CVc in the observed patients were V anatomical type of vascular lesion, high activity, pronounced stenotic changes, severe CC and severe AR (p&lt;0.05).

Information on Death Certificates: Comparison Between Inpatient and Outpatient Sectors

The death of a person and the circumstances of death are documented on the death certificate in Germany. The path of the corpse to burial as well as the quality of the cause of death statistics are significantly influenced by the information in the official death certificate. The quality of the information in the death certificates has been repeatedly criticized. The aim of the present study was to identify typical sources of error in death certificates and to obtain information on whether qualitative differences exist between death certificates completed in the outpatient and inpatient sectors. A retrospective evaluation was performed of 218 death certificates of deaths examined by the Institute of Legal Medicine as part of a second postmortem examination prior to cremation. Of these, 118 death certificates were issued in the hospital and 100 death certificates were issued on an outpatient basis by the family physician or a physician on duty in the outpatient sector. All but one of the death certificates issued on an outpatient basis were legible. The information on the underlying disease was plausible. More than one-third of the epicrises had no significant findings or were not completed at all. The entry on the immediate causes of death in the designated field on the death certificate (Ia in the causal chain) were inadequate in one third of the cases. The error rate in the entries was higher in outpatient than in inpatient deaths. In the future, therefore, it will be necessary to prepare for the special situation of a post-mortem examination by means of further and advanced training events and to convey the importance of the diagnoses determined in the process, in order to eliminate these avoidable sources of error.

Determination of causes of adult deaths using minimally invasive tissue sampling in Gandaki province of Nepal: a multicenter hospital-based study

BackgroundMinimally Invasive Tissue Sampling (MITS) has been successfully used to establish the cause of death in low- and middle-income countries, mostly in stillbirths and neonates. The objective of this study was to determine the causes of death among adults using MITS in the Gandaki province of Nepal and to find out the contribution of MITS to identify the causes of death.MethodsA multicentric hospital-based pilot study was conducted to enroll 100 cases of adult deaths. The specimens of cerebrospinal fluid, blood, brain, lungs, and liver tissue were collected utilizing MITS. These specimens underwent standard histopathological, serological, and microbiological analyses. The findings from MITS, and if available, clinical records and forensic autopsy findings were compiled and the cause of death panel identified the causes of death. The final cause of death allocated to each case was based on the WHO International Medical Certificate of Death.ResultsAmong a total of 100 cases enrolled during the study period, infectious cause attributed to the immediate cause of death in 77 (77%), cardiovascular in 10 (10%), neurological in 8 (8%), malignancy in two (2%), and gastrointestinal and hepatobiliary cause in one (1%) case. The mean age of the cases was 50.8 ± 15.9 years and 76 (76%) were males. MITS established the cause of death in the causal chain of events in 81(81%) cases and identified the cause of death significantly more with infectious than non-infectious causes (p < 0.001).ConclusionsMITS was useful in establishing the cause of death in the majority of adult deaths and the most common cause was infectious disease. Our findings suggest that MITS can be a valuable and alternative tool for mortality surveillance in low-resource settings, where complete diagnostic autopsies are less accepted or less prioritized.

Two vicious circles associated with the aging of the immune system in the development of severe forms of COVID-19.

Background: The immune-inflammatory response is the basis of the pathophysiology of SARS-Cov-2 infection. In severe cases of COVID-19 uncontrolled systemic inflammatory response causes multiorgan dysfunction (MODS), as the most common immediate cause of death. Unfavorable outcome of the COVID-19 most often occurs in elderly patients. The aim of the study was to establish parameters with prognostic significance in severe cases of COVID-19 according to life years, laboratory markers of sepsis and MODS, as well as the number of peripheral CD4+ and CD8+T lymphocytes in 20 consecutively selected critically ill patients. Results: Eleven subjects were male, 9 female, mean age 73.45 ± 11.59, among which the oldest patient was 94 and the youngest 43years. All the patients met the sepsis and MODS criteria. Increased age and low CD4+ and CD8+T cell counts were identified as independent predictors of death. Only the two youngest patients (43 and 50years old) survived 28days, and they are the only ones with a CD4 lymphocyte count above 500 cells/mm3. Conclusion: Senescence of the immune system is mostly characterized by reduced regenerative capacity of adaptive immunity with diminished ability to respond to new antigens and a manifested proinflammatory phenotype. Additional reduction of protective capacity by further deterioration of T cell quantity and quality due to sepsis itself and mutual interaction of senescent T cells and vascular endothelial cells in the induction of cytokine storm represent two complementary vicious cycles in the development of sepsis-related multiorgan dysfunction.