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Leprosy, a chronic infectious disease, leads to blood mineral imbalances: low levels of zinc, calcium, magnesium, and iron and high levels of copper. Interestingly, in late medieval Europe, minerals were used to treat leprosy. We investigated physiological responses to leprosy and possible evidence of treatment in dental tissues of leprosy sufferers from medieval Denmark and early 20th century Romania when multidrug therapy was not then yet invented. Using Synchrotron Fluorescence (SXRF) and laser ablation (LA-ICP-TOFMS), we show marked covariations in the zinc, calcium, and magnesium distributions, which are compatible with clinical studies but cannot be directly attributed to leprosy. Minerals used historically as a treatment for leprosy show no detectable intake (arsenic, mercury) or a diffuse distribution (lead) related to the daily consumption of contaminated water and food. Intense lead enrichments indicate acute incorporations, potentially through the administration of lead-enriched medication or the mobilization of lead from bone stores to the bloodstream during intense physiological stress related to leprosy. However, comparisons with a healthy control group are needed to ascertain these interpretations. The positive correlations and the patterns observed between lead and essential elements may indicate underlying pathophysiological conditions, demonstrating the potential of the two techniques for investigating diseases in past populations.

Background Buprenorphine is abused in several countries notwithstanding its benefits as an analgesic and as an opioid agonist treatment medication. Benzodiazepines and alcohol have previously been associated with buprenorphine toxicity. This study elucidates the role of emerging concomitant drugs in different groups of buprenorphine user deaths. Methods All cases in the Finnish national post-mortem toxicology database from 2016–2019 in which buprenorphine or norbuprenorphine was a laboratory finding in any post-mortem specimen and age at death of 15–64 years were investigated for cause and manner of death, concurrent drug and alcohol findings, age, and gender. Results There were 792 deaths with a buprenorphine finding, of which buprenorphine was implicated in poisoning without other opioids in 271 cases (34 %). In this group of buprenorphine poisoning deaths, concomitant benzodiazepines were found in 94 % (clonazepam 53 %), illicit drugs in 63 %, gabapentinoids in 50 % (pregabalin 41 %), alcohol in 41 %, antidepressants in 32 %, and antipsychotics in 28 % of cases; only three deaths showed no benzodiazepines, alcohol, or gabapentinoids. Polydrug use was common regardless of the cause of death. In the age group 15 to 24 years, concomitant use of benzodiazepines and illicit drugs, and buprenorphine poisoning were more prevalent than in the age group 25–64 years. Conclusions The unprecedentedly high concomitant use of benzodiazepines in buprenorphine user deaths obscures other possible pharmacological risk factors for buprenorphine poisoning that could be relevant for prevention. Higher mortality in the younger age group suggests particularly unsafe drug use patterns that should be addressed.

International audience; Cadmium (Cd) is a common environmental pollutant that threatens humans’ and animals’ health. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used drugs due to their wide therapeutic action; however, they have significant side effects. Since, under many circumstances, humans and animals may be co-exposed to Cd and NSAIDs, the current investigation was assigned to explore theintertwining relationship between Cd and NSAIDs. Four groups of male Wister rats were used: control group: rats received saline; Cd group: rats received cadmium (Cd, 2 mg/kg) orally; Px group: rats received a NSAID (piroxicam, Px, 7 mg/kg, i.p.); and Cd+Px group: rats received both Cd+Px. All treatments were given once a day for 28 consecutive days. Then, blood samples, stomach, liver, and kidney tissues were collected. The results indicated that Px provoked gastric ulcer indicated by high ulcer index, while Cd had no effect on the gastric mucosa. In addition, treatment with Cd or Px alone significantly induced liver and kidney injuries indicated by serum elevations of AST, ALT, ALP, ALB, total protein, creatinine, and urea along with histopathological alterations. Significant increases in malondialdehyde and reduction in GSH and CAT contents were reported along with up-regulated expression of Bax and Bcl-2 after Cd or Px exposure. However, when Cd and Px were given in a combination, Cd obviously potentiated the Px-inflicted cellular injury and death in the liver and kidney but not in the stomach when compared to their individual exposure. This study concluded that oxidative stress mechanisms were supposed to be the main modulator in promoting Cd and Px toxicities when given in combination.

Suicide is one of the most important public health problems. There was an association between suicide and several factors such as psychiatric diseases and psychological characteristics, somatic illness, cultural, socioeconomic, familial, occupational and individual risk factors. Also, high altitude and climatic factors including high temperature, cloudiness, more sunshine and low rainfalls were defined as some of these risk factors in the literature. In this study, we aimed to investigate correlation between suicide rates and altitudes of all cities in Turkey and between suicide rates and climatic factors including Rainfall Activity Index, Winter Mean Temperatures, Summer Mean Temperatures and Temperature Difference between January and July previously defined by several authors in the broad series in Turkey. In Turkey, 29865 suicidal deaths occurred in 10 years period between 2006 and 2015. Of them, 21020 (70.4%) were males and 8845 (29.6%) were females. In this study, we found that high altitude above 1500 m, winter median temperature lower than −10 °C and hard temperature changes above 25 °C between winter and summer of settlements were important factors that affected on female suicide rates appropriate to knowledge which defined in previous studies. In conclusion, we suggested that the associations among suicide rates with altitudes and climate should be studied in wider series obtained from different countries for reaching more reliable results. © 2018 Elsevier Ltd and Faculty of Forensic and Legal Medicine

Fragmentation of isolated populations increases the risk of inbreeding and loss of genetic diversity. The endemic Saimaa ringed seal (Pusa hispida saimensis) is one of the most endangered pinnipeds in the world with a population of only ~ 400 individuals. The current genetic diversity of this subspecies, isolated in Lake Saimaa in Finland for ca. 1000 generations, is alarmingly low. We performed whole-genome sequencing on Saimaa ringed seals (N = 30) and analyzed the level of homozygosity and genetic composition across the individual genomes. Our results show that the Saimaa ringed seal population has a high number of runs of homozygosity (RoH) compared with the neighboring Baltic ringed seal (Pusa hispida botnica) reference population (p

Background: Methanol poisoning is a serious medical, social and economic problem that may cause severe illness or death. After methanol ingestion, central nervous system depression, headache, dizziness, nausea, lack of coordination, and confusion begins. Once the initial symptoms have passed, a second set of symptoms arises, 10 to 30 hours after the initial exposure to methanol, including blurring or complete loss of vision and acidosis. Methanol poisoning by ingestion is a world-wide problem, and in some regions it is connected with high morbidity and mortality. The lethal dose of methanol in humans shows pronounced individual differences ranging from 15 to 500 ml. Methods: The records of the First Specialization Board of the Council of Forensic Medicine between 2002 and 2010 were reviewed retrospectively for all methyl alcohol poisoning cases. Results: There were 383 cases recorded. 360 (94%) of total fatalities were men and 23 (6%) were women. The age range was between 17 and 89. Although patients were conscious, cooperative, oriented at first, deteriorated general health state, metabolic acidosis and neurologic sequelae with severe electrocardiographic (ECG) changes were seen in progress of time. The laboratory findings and MRI imaging method were applied to assess progress and medical treatment. Unfortunately severe acidosis, central nervous system (CNS) sequelae and a lethal outcome occurred. The methyl alcohol blood concentrations ranged from 0 to 826 mg per 100 ml. The most common macroscopic and microscopic finding was lung edema, cerebral and cerebellar hemorrhage, ischemic changes in the brain and optic neuritis. Putaminal necrosis and hemorrhage, brainstem petechial hemorrhage, myocardial acute ischemic changes, thalamic and hypothalamic hemorrhage were detected rarely. Conclusions: This is the first study to report postmortem findings, clinical reports, crime scene reports and eye witness accounts to investigate methyl alcohol poisoning cases from medico-legal point of view in Turkey. Methanol poisoning by ingestion is a world-wide problem with high morbidity and mortality. For preventing methanol deaths, both awareness and public education must be increased. © 2017, Scientific Publishers of India. All rights reserved.

Oxycodone is a strong opioid drug commonly used to treat acute, cancer, and chronic non-malignant pain. In this study, all oxycodone-related medico-legal cases where death had occurred in a hospital or nursing home in Finland were investigated to determine the range of post-mortem (PM) oxycodone blood concentrations in a therapeutic setting. All toxicology cases in which oxycodone was detected in PM femoral blood during the 4-year period of 2016–2019 in Finland were retrieved from the national PM toxicology database. In this material, the 365 deceased hospital patient cases that met the study inclusion criteria were divided into four groups according to the cause and manner of death. The reference group of 121 fatal oxycodone poisoning cases comprised two groups: those with verified associated drug abuse and those without drug abuse. The median oxycodone concentration in PM blood was significantly higher in cancer patients (0.10 mg/L) than in patients with recent surgery (0.07 mg/L) or other disease (0.06 mg/L) (p p

Patients with hypercholesterolemia often have coronary microvascular dysfunction (CMD). Viral infections, such as the SARS-CoV-2 infection, may also result in CMD. Three non-randomized studies have shown significant beneficial effects of statins on CMD in non-infected patients. Similarly, in SARS-CoV-2 - infected patients one beneficial mechanism of action of statins may be the amelioration of endothelial dysfunction, which is a major driver of CMD. Apart from statins, lipoprotein apheresis and PCSK9 inhibitors can also improve or even reverse CMD. The potential reversal of CMD by using effective cholesterol-lowering medications during and after COVID-19 infection, especially in hypercholesterolemic COVID-19 patients, is important.

Informed consent is based on basic ethical principles that should be considered when conducting biomedical and behavioral research involving human subjects. These principles—respect, beneficence, and justice—form the foundations of informed consent which in itself is grounded on three fundamental elements: information, comprehension, and voluntary participation. While informed consent has focused on human subjects and research, the practice has been adopted willingly in the forensic science arena primarily to acquire reference samples from family members to assist in identifying missing persons. With advances in molecular biology technologies, data mining, and access to metadata, it is important to assess whether the past informed consent process and in particular associated risks are concomitant with these increased capabilities. Given the state-of-the-art, areas in which informed consent may need to be modified and augmented are as follows: reference samples from family members in missing persons or unidentified human remains cases; targeted analysis of an individual(s) during forensic genetic genealogy cases to reduce an investigative burden; donors who provide their samples for validation studies (to include population studies and entry into databases that would be applied to forensic statistical calculations) to support implementation of procedures and operations of the forensic laboratory; family members that may contribute samples or obtain genetic information from a molecular autopsy; and use of medical and other acquired samples that could be informative for identification purposes. The informed consent process should cover (1) purpose for collection of samples; (2) process to analyze the samples (to include type of data); (3) benefits (to donor, target, family, community, etc. as applicable); (4) risks (to donor, target, family, community, etc. as applicable); (5) access to data/reports by the donor; (6) sample disposition; (7) removal of data process (i.e., expungement); (8) process to ask questions/assessment of comprehension; (9) follow-up processes; and (10) voluntary, signed, and dated consent. Issues surrounding these topics are discussed with an emphasis on addressing risk factors. Addressing informed consent will allow human subjects to make decisions voluntarily and with autonomy as well as secure the use of samples for intended use.

This archive contains files with research data related to a publication "ISIMULATION OF SPACE WEATHERING ON ASTEROID SPECTRA THROUGH HYDROGEN ION IRRADIATION OF METEORITES" by Palamakumbure et al. You will find more content information in the README.txt file, The NASA Solar System Exploration Research Virtual Institute Center for Lunar and Asteroid Surface Science, and was conducted within institutional support RVO 67985831 of the Institute of Geology of the Czech Academy of Sciences.

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AimThe Saimaa ringed seal (Pusa hispida saimensis) is endemic to Lake Saimaa in Finland. The subspecies is thought to have originated when parts of the ringed seal population of the Baltic region were trapped in lakes emerging due to post-glacial bedrock rebound around 9,000 years ago. During the 20th century, the population experienced a drastic human-induced bottleneck. Today encompassing a little over 400 seals with extremely low genetic diversity, it is classified as endangered. Our main aim was to evaluate the role of the 20th century bottleneck in the erosion of genetic diversity in the Saimaa seal population. We also evaluated connections with other ringed seals from the Baltic Sea, Lake Ladoga, North America, Svalbard and the White Sea.LocationLake Saimaa, Finland, together with the Baltic Sea and the Arctic Ocean.MethodsWe sequenced sections of the mitochondrial control region from 60 up to 125 years old museum specimens of the Saimaa ringed seal. The generated dataset was combined with publicly available sequences. We studied how genetic variation has changed through time in this subspecies, and how it is phylogenetically related to other ringed seal populations.ResultsWe observed temporal fluctuations in haplotype frequencies and loss of haplotypes accompanied by a recent reduction in female effective population size. In apparent contrast with the traditionally held view of the Baltic origin of the population, the Saimaa ringed seal mtDNA variation shows also affinities to North American ringed seals.Main conclusionsOur results suggest that the Saimaa ringed seal has experienced recent genetic drift associated with small population size. The results further suggest that extant Baltic ringed seals do not represent well the ancestral population of the Saimaa ringed seal, which calls for re-evaluation of the deep history of this subspecies.

People with an evening (E)-type preference (ie, chronotype) experience musculoskeletal (MSK) pain and reduced health-related quality of life (HRQoL) more often than morning (M) types. Musculoskeletal pain is a well-established contributor to reduced HRQoL. This study aimed to evaluate whether eveningness amplifies the association between MSK pain and HRQoL in contrast to morningness. Questionnaire data on MSK pain dimensions (intensity, disability at work, number of pain sites [NPSs], and frequency), chronotype, covariates (sex, sufficiency of sleep duration, mental distress, and presence of coexisting diseases), and HRQoL (measured by 15D) were collected among 46-year-old individuals belonging to the Northern Finland Birth Cohort 1966 (N = 4257). Individuals without any MSK pain were excluded. General linear models were conducted to estimate the associations between chronotypes, MSK pain dimensions, and HRQoL. The interaction terms (chronotype x pain dimension) were tested in the models. There were 13% E-types and 43% M-types in the study sample. Each pain dimension and chronotype were related to HRQoL. In the sex-adjusted chronotype-specific models, the reduction in HRQoL in relation to pain appeared to be stronger among E-types than among M-types in respect to all pain dimensions. After adjustments, this was particularly seen in terms of NPS and pain frequency. Our findings suggest that eveningness intensifies the association between MSK pain and HRQoL, and, thus, they are indicative of E-types being more sensitive than M-types to the consequences of MSK pain. As such, MSK pain treatment and rehabilitation actions to improve HRQoL should be especially targeted at E-types.

Military pilots undergo rigorous selection compared with civilian professional pilots because of different operational requirements. There are no studies of military pilots’ subsequent civil aviation careers and fatal pilot aviation accidents. This study focuses on Vietnam War (VW) pilots and subsequent fatal aviation accidents in the U.S from 1965 to 2018. In total nine aviation accidents met the inclusion criteria and are described in detail, including the pilots’ previous civil aviation incidents. The VW pilots were healthy, had valid Medicals and continued to fly in demanding pilot positions after their military careers. Although the data are limited, this study suggests that previous military pilots may differ slightly from other pilots in their subsequent civil aviation careers. publishedVersion

Based on separate protective mechanisms related to lipid metabolism, viral cell entry and inflammation, fibrate treatment might be advantageous among patients who have been taking fibrates before SARS-CoV-2 infection and continue taking them during the infection. Based on published data on hospitalized COVID-19 patients, we recommend that the clinicians should ask their patients with metabolic syndrome who are already taking fibrates to continue fibrate treatment during the COVID-19 illness. This recommendation applies to both outpatients and hospitalized patients. However, results from the ongoing randomized controlled trials (RCTs) using fenofibrate treatment for the prevention or treatment of COVID-19 have yet to prove that fenofibrate is clinically significant for this indication. Non

Background Little is known on the landscape of viruses that have taken residence within our cells, nor on the interplay with the host imperative for their persistence. However, a lifetime of interactions conceivably have an imprint on our physiology and immune phenotype. Importantly, current metagenomics-insights on the healthy human virome are derived from bodily fluids, which are only a proxy of the true prevalence of human eukaryotic viruses within tissues. Most significantly, the virome’s systemic composition across the different organs of an individual has thus far remained uncharted. Results In this work, we revealed the genetic make-up of the eukaryotic human DNA virome in the body and showed that each organ (colon, liver, lung, heart, brain, kidney, skin, blood, hair) has unique viral compositions. By integration of quantitative (qPCR) and qualitative (hybrid-capture sequencing) analysis, we identified the DNAs of 17 viruses, primarily herpes-, parvo-, papilloma- and anello-viruses (>80% prevalence), typically persisting in low copies (mean 540 copies/ million cells). The within-sample diversities (a-diversity) were highest in the lung, liver, colon, and kidney. We assembled in total 70 viral genomes (>90% breadth coverage), distinct in each of the individuals, and identified high sequence homology across the organs. Moreover, we detected variations in virome composition and distribution in two individuals with underlying malignant conditions. Conclusions Our findings reveal unprecedented prevalences of viral DNAs in human organs. We showed that bodily fluids, although accessible to sampling, fail to deliver a comprehensive view of the numerous intracellular viruses colonizing our tissues. Our data demonstrate how a multi-organ approach is essential for analyzing differing virome compositions in various disease states. This atlas provides a fundamental ground for the studies of correlates to disease, and for the interpretation of next-generation sequencing data in clinical virology. Ultimately, our findings call for investigation of the crosstalk between human DNA viruses, the host, and other microbes, as it predictably has a significant impact on our health.

Heterozygous familial hypercholesterolemia (HeFH) patients are the prime example of subjects who are at high risk for both acute myocardial infarction (AMI) and ischemic stroke during, and post, SARS-CoV-2 infection. HeFH per se, if left untreated, results in premature clinical atherosclerosis often presenting in the fourth or fifth decade of life. The other concern in HeFH is endothelial dysfunction which is already evident from early childhood. In untreated HeFH patients, the severe hypercholesterolemia causes endothelial dysfunction from an early age, and as a result thereof, atherosclerotic lesions develop prematurely, particularly in the coronary arteries, and result in further endothelial dysfunction and inflammation in these critical segments of the arterial tree. As the pre-existing endothelial dysfunction in HeFH patients is most likely sensitive to further direct and indirect SARS-CoV-2 virus-dependent damage, we can infer that HeFH serves as an example of a comorbidity that predicts a poorer prognosis with COVID-19 infection. Indeed, a large US national database study showed that patients diagnosed with HeFH and SARS-CoV-2 infection had significantly increased Annualized Incidence Density Rates (AIDRs) of AMI when compared to matched HeFH controls not having been diagnosed with SARS-CoV-2 infection. Effective cholesterol lowering is essential for the prevention, or at least alleviation, of the detrimental effects of SARS-CoV-2 infection among HeFH patients. Due to the pre-existing subclinical or even clinical atherosclerotic cardiovascular disease in subjects with HeFH, cholesterol-lowering treatment needs to be continued or, better still, intensified during, and for an extended period post, SARS-CoV-2 infection.

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Quantitative analysis of postmortem urine, instead of blood, for buprenorphine and metabolites may provide additional evidence for the diagnosis of fatal buprenorphine poisoning. In this study, 247 autopsy urine samples, previously testing positive for buprenorphine or norbuprenorphine, were quantitatively reanalysed with a recently developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for unconjugated buprenorphine (BUP), norbuprenorphine (NBUP), naloxone (NAL), and their respective conjugated metabolites, buprenorphine glucuronide (BUPG), norbuprenorphine glucuronide (NBUPG), and naloxone glucuronide (NALG). The cases were divided, according to medical examiners' decision, to buprenorphine poisonings and other causes of death. The groups were compared for urinary concentrations and metabolite concentration ratios of the six analytes. All median concentrations were higher in the buprenorphine poisoning group. The median concentration of BUPG was significantly higher and the median metabolite ratios NBUP/BUP, NBUPG/BUPG, and NBUPtotal/BUPtotal were significantly lower in poisonings than in other causes of death. Naloxone-related concentrations and ratios were not significantly different between the groups.

Introduction: The current manuscript presents a protocol for a systematic review and meta-analysis of the evidence regarding the determinants of responsiveness to multidisciplinary management of chronic pain, with pain intensity, pain-related interference, physical functioning and health-related quality of life as the main outcomes, with consideration to multiple secondary outcomes. Methods and analysis: To identify relevant studies, the Ovid MEDLINE, PubMed, Ovid PsycINFO, EBSCO CINAHL and Scopus databases will be searched for all studies exploring factors associated with responsiveness to multidisciplinary pain management from study inception to the present. Cohorts, case-control studies and randomised controlled trials will be included. Independent screening for eligible studies will be completed by a total of four researchers using defined criteria. Data extraction will be executed by two researchers. Study heterogeneity will be estimated using the I2 index. A meta-analysis will be performed using random effects models. Publication bias will be evaluated by means of funnel plots and Egger's test. Ethics and dissemination: The proposed study does not involve collection of primary data. Therefore, no ethical approval is required. The results of the systematic review and meta-analysis will be presented in a peer-reviewed journal and at conferences. Prospero registration number: CRD42021236424.

Inpatients have a particular risk of sustaining medical adverse events (MAEs). This analysis aimed to identify patterns of change in deaths due to MAEs among US inpatients. The analysis was based on nationwide cause-of-death data from 1999 to 2019. To adjust for secular trends in overall mortality, MAE deaths were examined proportional to total deaths. Statistical analysis was performed by means of joinpoint regression modeling. Over the analysis period, a total of 18,126,135 certified deaths occurred among inpatients. MAEs were used as the underlying cause of death in 43,899 cases (0.24%). MAE deaths showed a significant increase from mid-2010s onwards; the estimated increase in MAE deaths was up to 15.6% per year (95% confidence interval 11.3–20.1) from 2014 to 2019. Procedure-related events mainly drove the trend. As the present data are insufficient to substantiate and disentangle underlying factors, future analyses are warranted.

Gestation increases the biomechanical loading of lower extremities. Gestational loading may influence anthropometrics of articular surfaces in similar means as bone diaphyseal properties. This study aimed to investigate whether gravidity (i.e. number of pregnancies) and parity (i.e. number of deliveries) is associated with knee breadth among middle-aged women. The study sample comprised 815 women from the Northern Finland Birth Cohort 1966. The median parity count of our sample was 2 and the median gravidity count 3. At the age of 46, questionnaires were used to enquire gravidity and parity, and posteroanterior knee radiographs were used to obtain two knee breadth parameters (tibial plateau mediolateral breadth (TPML) and femoral condylar mediolateral breadth (FCML)) as representatives of articular size. The associations of gravidity and parity with knee breadth were analyzed using general linear models with adjustments for height, weight, leisure-time physical activity, smoking, and education years. Individuals with osteoarthritic changes were excluded from our sample. The mean TPML in our sample was 70.3 mm and the mean FCML 71.6 mm respectively. In the fully adjusted models, gravidity and parity showed positive associations with knee breadth. Each pregnancy was associated with 0.11–0.14% larger knee breath (p

The effectiveness of the so-called skele- tal markers of activity as functional indicators is widely debated. Among them, certain morphological features of the anterior aspect of the femoral head-neck junction (Poirier's facet, cervical fossa of Allen, etc.) have been considered in relation to some behaviors and specific activities (e.g., squatting, horseback riding, etc.). How- ever, disagreement on terminology and descriptions, the absence of standardized scoring methods and poor knowledge of the variability and distribution of these features make it difficult to interpret their meaning. The aim of this study is to analyze the variability of the anterior aspect of the femoral neck through a new scor- ing method taking into account three main traits: Poi- rier's facet, plaque, and cribra (including the Allen's fossa). This method has been applied to a sample of 225 adult individuals of both sexes coming from an identified modern skeletal collection, achieving low intraobserver and interobserver error values. The results highlight some significant trends: plaque, almost always bilateral, appears to be a normal condition of the femur, being present in approximately 90% of the individuals. Cribra is more frequent in females and decreases with age. Poi- rier's facet shows a very low frequency. This method allows the representation of both the anatomical diver- sity of the region already described in literature and part of the variability never considered before. Our results suggest caution in considering these features as markers related to specific activities.

Resolving the absolute timescale of phylogenetic trees stipulates reliable estimates for the rate of DNA sequence evolution. For this end, various calibration methods have been developed and studied intensively. Intraspecific rate variation among distinct genetic lineages, however, has gained less attention. Here, we have assessed lineage-specific molecular rates of human mitochondrial DNA (mtDNA) by performing tip-calibrated Bayesian phylogenetic analyses. Tip-calibration, as opposed to traditional nodal time stamps from dated fossil evidence or geological events, is based on sample ages and becoming ever more feasible as ancient DNA data from radiocarbon-dated samples accumulate. We focus on subhaplogroups U2, U4, U5a, and U5b, the data including ancient mtDNA genomes from 14C-dated samples (n = 234), contemporary genomes (n = 301), and two outgroup sequences from haplogroup R. The obtained molecular rates depended on the data sets (with or without contemporary sequences), suggesting time-dependency. More notable was the rate variation between haplogroups: U4 and U5a stand out having a substantially higher rate than U5b. This is also reflected in the divergence times obtained (U5a: 17,700 years and U5b: 29,700 years), a disparity not reported previously. After ruling out various alternative causes (e.g., selection, sampling, and sequence quality), we propose that the substitution rates have been influenced by demographic histories, widely different among populations where U4/U5a or U5b are frequent. As with the Y-chromosomal subhaplogroup R1b, the mitochondrial U4 and U5a have been associated with remarkable range extensions of the Yamnaya culture in the Bronze Age. Introduction Results - MtDNA Haplogroup U Genomes - Substitution Models Chosen - Molecular Rate Estimates - Dependability of the Rate Estimates - Comparison of Divergence Time Estimates with Previously Published Estimates Discussion - Time-Dependency Shown With Different Data Sets - Lineage-Specificity in Mutation Rates - Other Potential Causes for Rate Variation among Lineages - Different Demographic Trajectories of Hg-U Sublineages - Range Expansion a Plausible Explanation for Higher U5a Rate Conclusion Materials and Methods - Data Analysis Methods

Background Articular surface size is traditionally considered to be a relatively stable trait throughout adulthood. Increased joint size reduces bone and cartilage tissue strains. Although physical activity (PA) has a clear association with diaphyseal morphology, the association between PA and articular surface size is yet to be confirmed. This cross-sectional study aimed to clarify the role of moderate-to-vigorous PA (MVPA) in knee morphology in terms of tibiofemoral joint size. Methods A sample of 1508 individuals from the population-based Northern Finland Birth Cohort 1966 was used. At the age of 46, wrist-worn accelerometers were used to monitor MVPA (≥3.5 METs) during a period of two weeks, and knee radiographs were used to obtain three knee breadth measurements (femoral biepicondylar breadth, mediolateral breadth of femoral condyles, mediolateral breadth of the tibial plateau). The association between MVPA and knee breadth was analyzed using general linear models with adjustments for body mass index, smoking, education years, and accelerometer weartime. Results Of the sample, 54.8% were women. Most individuals were non-smokers (54.6%) and had 9—12 years of education (69.6%). Mean body mass index was 26.2 (standard deviation 4.3) kg/m2. MVPA was uniformly associated with all three knee breadth measurements among both women and men. For each 60 minutes/day of MVPA, the knee breadth dimensions were 1.8—2.0% (or 1.26—1.42 mm) larger among women (p p Conclusions Higher MVPA is associated with larger tibiofemoral joint size. Our findings indicate that MVPA could potentially increase knee dimensions through similar biomechanical mechanisms it affects diaphyseal morphology, thus offering a potential target in reducing tissue strains and preventing knee problems. Further studies are needed to confirm and investigate the association between articulation area and musculoskeletal health.

Laboratories and their criminal justice systems are confronted with challenges for implementing new technologies, practices, and policies even when there appears to be demonstrative benefits to operational performance. Impacting decisions are the often higher costs associated with, for example, new technologies, limited current budgets, and making hard decisions on what to sacrifice to take on the seemingly better approach. A prospective cost–benefit analysis (CBA) could help an agency better formulate its strategies and plans and more importantly delineate how a relatively small increase to take on, for example, a new technology can have large impact on the system (e.g., the agency, other agencies, victims and families, and taxpayers). To demonstrate the process and potential value a CBA was performed on the use of an alternate and more expensive swab with reported better DNA yield and being certified human DNA free (i.e., nylon 4N6FLOQSwabs®), versus the traditional less costly swab (i.e., cotton swab). Assumptions are described, potential underestimates and overestimates noted, different values applied (for low and modest to high), and potential benefits (monetary and qualitative) presented. The overall outcome is that the cost of using the more expensive technology pales compared with the potential tangible and intangible benefits. This approach could be a guide for laboratories (and associated criminal justice systems) worldwide to support increased funding, although the costs and benefits may vary locally and for different technologies, practices, and policies. With well-developed CBAs, goals of providing the best services to support the criminal justice system and society can be attained.

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This dissertation focusses on the genetic diversity of the Chachapoyas in the context of northeast Peruvian and South American populations. The genetic survey of indigenous human populations from the Americas is still far from being comprehensive, which is in stark contrast with other areas of the globe, such as Europe, where an in-depth understanding of the genetic variation and its use in forensic and medical genetics has been attained. This highlights the need for increasing genetic research in Peru as to continue laying the foundation for human genetics and its applications in other fields such as forensics. The montane forests of northeast Peru are one of the most biologically diverse ecosystems in the world and it is there where the ancient Chachapoyas throve and where their descendants nowadays live. Archaeological, historical and linguistic records inform of a complex region where local populations interacted with others throughout prehistory up until the time of European contact in the 16th century. Although traces of past cultural diversity persist in the Chachapoyas region, the series of demographic, environmental and cultural impacts have blurred this cultural differentiation and debilitated the local identities of present-day peoples. Among other factors, cultural diversity in the region has also been shaped by a series of population-level phenomena, which are the focus of this research. To address various questions that emanate from archaeology and ethnohistory, samples from the modern Chachapoyas and three of their neighbors were genotyped for various types of markers (mtDNA, Y-chromosome and autosomal data). These and reference data were analyzed to uncover patterns of population structure and gain insights into the demographic history of the studied populations, with particular emphasis in the Chachapoyas. The new data show exceptionally high levels of genetic diversity in the Chachapoyas region and contrasting patterns of genetic affinities for lineage markers. In clear contrast with the archaeological and ethnohistorical evidence, there was negligible population substructure within Chachapoyas. Asymmetrical European gene flow for autosomes was detected throughout the region but the pattern does not mirror Inca settlement densities at subregional level. Signatures of demographic collapse likely associated with the Spanish conquest were observed in both mtDNA and Y-chromosome, although for males the reduction appeared more drastic. In addition to these insights, the new autosomal STR and SNP datasets generated unveiled another level of variation by providing, in addition to traditional length-based genotypes, sequence-based information for several Peruvian populations which may be of utility for individual identification in the context of South America. Koillis-Perussa, Andien vuoriston ja Amazonasin välisellä alueella eli n. 800 – 1500 jaa alkuperäisväestöjä, joita Inkat kutsuivat yhteisesti nimellä Chachapoyas. Näiden ”Pilvien sotureiden” alueet valloittivat ensin Inkat v. 1491 ja sitten eurooppalaiset konkistadorit v. 1531. Valloituksia seuranneet väestönsiirrot, sodat ja tautiepidemiat johtivat Chachapoya-kulttuurin häviämiseen. Jälkipolvia tämä kadonnut kansa on kuitenkin kiehtonut: todellisten arkeologien ohella Chachapoya-esineistä on ollut kiinnostunut myös fiktiivinen arkeologi Indiana Jones. Tässä väitöskirjassa Chachapoya-väestön rakennetta ja historiaa on tutkittu genetiikan keinoin. Väestöhistoria, esim. väestön koko ja yhteydet toisiin väestöihin, muovaa perimää ja on pääteltävissä DNA-muuntelusta. Tutkimusta varten kerättiin näytteitä Chachapoya-alueen nykyasukkailta, läheisestä Huancas-isolaatista sekä Amazonasin alueelta (Jivarot) ja Andeilta (Cajamarca), joista DNA-merkkidata määritettiin. Lisäksi kirjallisuudesta kerättiin laaja DNA-vertailuaineisto Etelä-Amerikan (alkuperäis)väestöille. DNA-aineistosta etsittiin populaatiogenetiikan menetelmin vastauksia arkeologisissa ja lingvistisissä tutkimuksissa heränneisiin kysymyksiin Chachapoya-väestöstä. Tulokset osoittavat, että Chachapoya-alueella perimässä on enemmän muuntelua kuin useimmilla Etelä-Amerikan alkuperäisväestöillä. Etnohistoriallisissa lähteissä kuvattua erilaistumista Chachapoya-alueen sisällä ei DNA-datassa kuitenkaan havaittu. DNA-muuntelussa havaittiin merkkejä väestökadosta, jonka ajoittumista eurooppalaisten tuloon ei voida poissulkea. Y-kromosomimuuntelun perusteella miesten kuolleisuus on ollut naisia suurempaa, aivan kuten aikalaislähteet kertovat. Etelä-Amerikan väestöjen perinnöllisen muuntelun kartoittaminen on toistaiseksi ollut esim. Eurooppaan verrattuna suppeaa. Tämä väitöskirjatutkimus paikkaa osaltaan tätä aukkoa. Väitöskirjan päätavoite oli kartoittaa Koillis-Perun väestöjen geneettistä muuntelua ja ymmärtää paremmin alueen geenipoolia muokanneita väestöhistorian prosesseja. Perustutkimuksen lisäksi tutkimuksessa tuotettu STR- ja SNP-merkkidatat hyödyttävät myös yhteiskunnallisesti tärkeää oikeusgenetiikkaa Perussa. Tulokset muistuttavat meitä myös siitä, että Perun alkuperäisväestöt eivät eurooppalaisten tultua kadonneet vaan muuttuivat, ja myös Chachapoya-perintö elää edelleen alueen nykyväestön perimässä.

The aim of this study is to determine the features and changes in the medicolegal childhood deaths that occurred in Sivas, Turkey; and to contribute in the establishment of a database on childhood deaths. The authors evaluated the deaths of children aged to 0 to 18 years, whose autopsies were performed in Sivas Cumhuriyet University between 2006 and 2009. The childhood deaths were reviewed with respect to sex, age, event region, event date, event type, crème scene, cause of death. The evaluation of 90 cases was made by use of Chi-square test in SPSS (Ver: 10.0). During four years, of 547 forensic death cases that underwent autopsy, 90 were aged between 0 to 18 years. 57 (63.3%) of the cases were male. The main cause of death was traffic accident in 24 (26.7%) cases. In order to avoid children deaths, the preventive and curative health services should be strengthened, and the training programs must be provided for parents. To avoid child abuse, it should be a concern of the government bodies and civil society. As a result, the child protection programme is needed in our regions and new regulations should be enacted to protect children against accidents, injuries, hazards and abuse. ©2010 Academic Journals., Butun, C.; Department of Forensic Medicine, Medical School, University of Cumhuriyet, Sivas, Turkey; email: celalbutun@yahoo.com

International audience; Alzheimer’s disease (AD) is characterized by alterations in monoamines, oxidative stress, and metabolic dysfunctions. We aim toassess the therapeutic impacts of roots or leaf extract from Urtica dioica (UD; stinging nettle) against scopolamine (SCOP)-induced memory dysfunction, amnesia, and oxidative stress in rats. Spatial memory was assessed by Y maze test. Tissue analysesof norepinephrine (NE), dopamine (DA), serotonin (5-HT), malondialdehyde (MDA), nitric oxide (NO), glutathione (GSH,GSSG), AMP, ADP, and ATP were assessed by HPLC. mRNA levels of Tau and Hsp70 were estimated by PCR. UD extractsparticularly nettle root (NR) significantly normalized the SCOP-induced memory deficits even more potent than sermion (SR)and donepezil (DON). Similarly, NR had potent therapeutic impacts on the levels of cortical and hippocampal monoamines e.g.DA, NE, and 5-HT. SCOP induced a dramatic oxidative stress as measured by MDA, NO, and GSSG levels; however, UDextracts showed significant anti-oxidative stress impacts. Additionally, UD extracts restored ATP levels and reduced the levels ofAMP and ADP compared to SCOP-treated rats. Furthermore, cortical Tau and hippocampal Hsp70 were modulated by UDextracts particularly NR compared to the SCOP group. In conclusion, UD extracts particularly roots have potential therapeuticimpacts against SCOP-induced neuroinflammatory and/or Alzheimer-like phenotype in rats.

Objectives: To examine the allele frequencies of HumFABP2 locus in 155 individuals from different regions of Turkey. Methods: The study was carried out in Cumhuriyet University Hospital, Sivas, Turkey, between March and June 2006. The allele and genotype frequencies for HumFABP2 were determined by polymerase chain reaction (PCR) using the manufacturer's recommended protocol, and using the commercially available Macherey-Nagel DNA isolation kit. The PCR amplification was carried out in a Perkin-Elmer GeneAmp PCR System 9600 thermal cycler following the manufacturer's recommendations. The allele frequencies in the Turkish population was computed, and the heterozygote rate was calculated. Results: In this population study of 155 samples, we found 75 (48.39%) heterozygote and 80 (51.61%) homozygote. The results showed heterozygotic cases as 150/250 bp, and homozygotic cases as 150 bp. Conclusions: Allele frequency data of HumFABP2 as a PCR-based genetic marker could be used in identity testing to estimate the frequency of a multiple PCR based profile in the Turkish population.

A recent meta-analysis of over 20,000 individuals showed that hospitalized COVID-19 patients with acute myocardial injury had more than fourfold higher mortality than those without such injury. Since the COVID-19 pandemic exacerbates already existing health inequalities, there is an urgent need to create measures to protect the most vulnerable patient groups, including those with a pre-existing increased risk of atherosclerotic cardiovascular disease (ASCVD). A typical example is familial hypercholesterolemia (FH), a common genetic disease affecting over 30 million individuals worldwide. If left untreated or undertreated, FH patients suffer from complications of premature ASCVD, such as acute coronary syndromes, resulting in acute myocardial injury/infarction. A recent population-based analysis provided strong evidence suggesting that COVID-19 poses an even higher risk for myocardial injury in FH patients. From the long-term preventive point of view, it is important to note that, in addition to the acutely elevated risk of myocardial injury, an elevated risk of ASCVD and its complications will persist after COVID-19. The decline in outpatient preventive care during the pandemic is likely to influence ASCVD risk and outcomes, particularly in high-risk patients, such as those with FH. This commentary aims to raise global awareness of the challenges that clinicians treating FH patients continue to face during the COVID-19 pandemic, with two low- to middle-income countries, South Africa and Brazil, serving as examples. Non

Objectives Gunshot wounds are frequently studied using computed tomography (CT) to examine tissue damage. In this study, we aimed to test the potential of post-mortem CT (PMCT) in shooting distance estimation at distances 0–100 cm. We hypothesized that in addition to the wound channel, we could also potentially detect tissue damage caused by muzzle pressure on PMCT. Results A total of 59 gunshot wounds (23 contact shots, 21 close-range shots, 15 distant shots) were inflicted on eight piglet carcasses with a .22 Long Rifle handgun. PMCT scans were obtained using clinical equipment, and they were evaluated for wound characteristics by visual inspection and numeric measurements. In our data, contact shots could be clearly distinguished from close-range and distant shots by a hyperdense ring-shaped area surrounding the outermost part of the wound channel. Close-range and distant shot wounds did not have this feature and were difficult to distinguish from each other. The mean wound channel diameter ranged from 3.4 to 5.4 mm, being smallest in contact shots and largest in distant shots. These preliminary findings suggest that PMCT may aid the estimation of shooting distance. As this study only addressed low velocity gunshot wounds in carcasses, further studies are warranted.

Formalin fixation, albeit an outstanding method for morphological and molecular preservation, induces DNA damage and cross-linking, which can hinder nucleic acid screening. This is of particular concern in the detection of low-abundance targets, such as persistent DNA viruses. In the present study, we evaluated the analytical sensitivity of viral detection in lung, liver, and kidney specimens from four deceased individuals. The samples were either frozen or incubated in formalin (±paraffin embedding) for up to 10 days. We tested two DNA extraction protocols for the control of efficient yields and viral detections. We used short-amplicon qPCRs (63–159 nucleotides) to detect 11 DNA viruses, as well as hybridization capture of these plus 27 additional ones, followed by deep sequencing. We observed marginally higher ratios of amplifiable DNA and scantly higher viral genoprevalences in the samples extracted with the FFPE dedicated protocol. Based on the findings in the frozen samples, most viruses were detected regardless of the extended fixation times. False-negative calls, particularly by qPCR, correlated with low levels of viral DNA (150 base pairs). Our data suggest that low-copy viral DNAs can be satisfactorily investigated from FFPE specimens, and encourages further examination of historical materials.

In vitro to in vivo extrapolation represents a critical challenge in toxicology. In this paper we explore extrapolation strategies for acetaminophen (APAP) based on mechanistic models, comparing classical (CL) homogeneous compartment pharmacodynamic (PD) models and a spatial-temporal (ST), multiscale digital twin model resolving liver microarchitecture at cellular resolution. The models integrate consensus detoxification reactions in each individual hepatocyte. We study the consequences of the two model types on the extrapolation and show in which cases these models perform better than the classical extrapolation strategy that is based either on the maximal drug concentration (Cmax) or the area under the pharmacokinetic curve (AUC) of the drug blood concentration. We find that an CL-model based on a well-mixed blood compartment is sufficient to correctly predict the in vivo toxicity from in vitro data. However, the ST-model that integrates more experimental information requires a change of at least one parameter to obtain the same prediction, indicating that spatial compartmentalization may indeed be an important factor.

Aims To determine trends in 3,4 methylenedioxymethamphetamine (MDMA)-related death rates across Australia, Finland, Portugal and Turkey and to analyse causes of death across countries; and 3. analyse the toxicology of deaths across countries. Design Analysis of MDMA-related deaths extracted from a national coronial database in Australia (2001-2019) and national forensic toxicology databases in Finland (2001-2017), Portugal (2008-2019) and Turkey (2007-2017). Presentation of MDMA use and seizure data (market indicators). Setting Australia, Finland, Portugal and Turkey. Cases All deaths in which MDMA was considered by the forensic pathologist to be contributory to death. Measurements Information collected on cause and circumstances of death, demographics, and toxicology. Findings 1,400 MDMA-related deaths were identified in Turkey, 507 in Australia, 100 in Finland, and 45 in Portugal. The median age ranged from 24 to 27.5 years and males represented between 81 and 95% of the deaths across countries. Standardised mortality rates significantly increased across all four countries from 2011-2017, during a period of increased purity and availability of MDMA. The underlying cause of death was predominantly due to drug toxicity in Australia (n=309, 61%), Finland (n=70, 70%) and Turkey (n=840, 60%), and other causes in Portugal (n=25, 56%). Minorities of all deaths across the countries were due to MDMA toxicity alone (13-25%). These deaths had a significantly higher blood MDMA concentration than multiple drug toxicity deaths in Australia, Finland and Turkey. Drugs other than MDMA commonly detected were stimulants (including cocaine, amphetamine and methamphetamine) (Australia 52% and Finland 61%) and alcohol (Australia 46% and Portugal 49%). In addition to MDMA toxicity, benzodiazepines (81%) and opioids (64%) were commonly identified in these deaths in Finland. In comparison, synthetic cannabinoids (15%) and cannabis (14%) were present in a minority of deaths in Turkey. Conclusions Deaths related to 3,4 methylenedioxymethamphetamine (MDMA) increased in Australia, Finland, Portugal and Turkey between 2011 and 2017. MDMA toxicity alone can be fatal but multiple drug toxicity remains more prevalent.

BackgroundDeaths due to medical care appear common. Individuals with low socioeconomic position seem to be at a higher risk for sustaining a medical adverse event and premature death. This time series analysis aimed to assess educational gradients behind adverse event deaths in the US over the period 2010–2019.MethodsPublicly available mortality and census data were retrieved from official sources. The data included age, sex, educational attainment, and underlying cause of death. Adverse event deaths were identified by ICD-10 codes Y40—Y84 and Y88. Four education categories were created in accordance with the International Standard Classification of Education 2011 coding scheme [No high school or General Educational Development (GED); High school or GED; Some college; Bachelor's degeree or higher]. To capture also highly educated individuals, the analysis was delimited to ≥30-year-olds. Age-adjusted mortality rates (AMRs) were compared between education categories by means of mortality plots and linear mixed models.ResultsA total of 25,897,334 certified deaths occurred among ≥30-year-olds during the study period. The underlying cause of death was an adverse event in a rarity of cases (0.12%, n = 31,997). Individuals with Bachelor's degeree or higher had the lowest adverse event AMRs (6.1–12.4 per million per year), followed by the Some college category (9.6–18.6), the High school or GED category (17.1–35.4), and finally the No high school or GED category (20.0–36.0). AMRs showed a gradual increase as education level decreased (p ≤ 0.001 against those with Bachelor's degeree or higher). Moreover, the temporal increase in adverse event AMRs was more pronounced among individuals with low than high education; the contrasts between categories were greatest toward the end of the study period.ConclusionThe findings of this study suggest that the widening socioeconomic gradients in mortality extend also to fatal adverse events. Future studies should aim to analyze whether access to care, severity of the condition at presentation, quality of care, and social determinants of health may drive the gradients.

Background: The reduction of child and adolescent deaths (defined as decedents aged 0–19 years) remains a crucial public health priority also in high-income countries such as Finland. There is evidence of a relationship between socioeconomic gradients and child mortality, but the association is considered complex and relatively poorly understood. Exploiting a Finnish dataset with nationwide coverage, the present study aimed to shed light on the sociodemographic predictors of child and adolescent mortality at the municipality level. Methods: A public database of Statistics Finland was queried for municipality-level data on sociodemographic traits and child and adolescent deaths in Finland during the years 2011—2018. The sociodemographic indicators included total population size, child and adolescent population size, sex distribution, mean age, education, unemployment, median income, population density, rurality, percentage of individuals living in their birth municipality, household size, overcrowded households, foreign language speakers, divorce rate, car ownership rate, and crime rate. The sociodemographic indicators were modelled against child and adolescent mortality by means of generalized estimating equations. Results: A total of 2371 child and adolescent deaths occurred during the eight-year study period, yielding an average annual mortality rate of 26.7 per 100 000 individuals. Despite a fluctuating trend, the average annual decline in child and adolescent deaths was estimated to be 3% (95% confidence interval 1—5%). Of the sociodemographic indicators, population density was associated with higher child and adolescent mortality (rate ratio 1.03, 95% confidence interval 1.01—1.06), whereas the percentage of foreign language speakers was associated with lower child and adolescent mortality (0.96, 0.93—0.99). Conclusion: Densely populated areas should be the primary focus of efforts to reduce child and adolescent mortality. Of note is also the apparently protective effect of foreign language speakers for premature mortality. Future studies are welcomed to scrutinize the mediating pathways and individual-level factors behind the associations detected in this study.

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