Triangulation supports agricultural spread of the Transeurasian languages.

The origin and early dispersal of speakers of Transeurasian languages-that is, Japanese, Korean, Tungusic, Mongolic and Turkic-is among the most disputed issues of Eurasian population history1-3. A key problem is the relationship between linguistic dispersals, agricultural expansions and population movements4,5. Here we address this question by 'triangulating' genetics, archaeology and linguistics in a unified perspective. We report wide-ranging datasets from these disciplines, including a comprehensive Transeurasian agropastoral and basic vocabulary; an archaeological database of 255 Neolithic-Bronze Age sites from Northeast Asia; and a collection of ancient genomes from Korea, the Ryukyu islands and early cereal farmers in Japan, complementing previously published genomes from East Asia. Challenging the traditional 'pastoralist hypothesis'6-8, we show that the common ancestry and primary dispersals of Transeurasian languages can be traced back to the first farmers moving across Northeast Asia from the Early Neolithic onwards, but that this shared heritage has been masked by extensive cultural interaction since the Bronze Age. As well as marking considerable progress in the three individual disciplines, by combining their converging evidence we show that the early spread of Transeurasian speakers was driven by agriculture.

Multivariable Cost Frontiers-Qualitative Financial Analyses Using Operational Metrics From the Implementation of a Surgery Fellowship.

OBJECTIVE: We expand the application of cost frontiers and introduce a novel approach using qualitative multivariable financial analyses. SUMMARY BACKGROUND DATA: With the creation of a 5 + 2-year fellowship program in July 2016, the Division of Vascular Surgery at the University of Vermont Medical Center altered the underlying operational structure of its inpatient services. METHOD: Using WiseOR (Palo Alto, CA), a web-based OR management data system, we extracted the operating room metrics before and after August 1, 2016 service for each 4-week period spanning from September 2015 to July 2017. The cost per minute modeled after Childers et al's inpatient OR cost guidelines was multiplied by the after-hours utilization to determine variable cost. Zones with corresponding cutoffs were used to graphically represent cost efficiency trends. RESULTS: Caseload/FTE for attending surgeons increased from 11.54 cases per month to 13.02 cases per month ( P = 0.0771). Monthly variable costs/FTE increased from $540.2 to $1873 ( P = 0.0138). Monthly revenue/FTE increased from $61,505 to $70,277 ( P = 0.2639). Adjusted monthly reve-nue/FTE increased from $60,965 to $68,403 ( P = 0.3374). Average monthly percent of adjusted revenue/FTE lost to variable costs increased from 0.85% to 2.77% ( P = 0.0078). Adjusted monthly revenue/case/FTE remained the same from $5309 to $5319 ( P = 0.9889). CONCLUSION: In summary, we demonstrate that multivariable cost (or performance) frontiers can track a net increase in profitability associated with fellowship implementation despite diminishing returns at higher caseloads.

Measuring and Comparing Clinical Productivity of Individual Anesthesiologists.

Measuring and comparing clinical productivity of individual anesthesiologists is confounded by anesthesiologist-independent factors, including facility-specific factors (case duration, anesthetizing site utilization, type of surgical procedure, and non-operating room locations), staffing ratio, number of calls, and percentage of clinical time providing anesthesia. Further, because anesthesia care is billed with different units than relative value units, comparing work with other types of clinical care is difficult. Finally, anesthesia staffing needs are not based on productivity measurements but primarily the number and hours of operation of anesthetizing sites. The intent of this review is to help anesthesiologists, anesthesiology leaders, and facility leaders understand the limitations of anesthesia unit productivity as a comparative metric of work, how this metric often devalues actual work, and the impact of organizational differences, staffing models and coverage requirements, and effectiveness of surgical case load management on both individual and group productivity.

Diagnosis and predicted outcomes of patients with cystic fibrosis related liver disease considered for lung transplantation.

INTRODUCTION: There is no gold standard criterion for the diagnosis of cystic fibrosis-related liver disease (CFRLD) and there is uncertainty over its impact on the outcome of lung transplantation. METHOD: Lung recipients (n = 238) were divided into two groups-CFRLD and non-CFRLD based on a modified aspartate aminotransferase-to-platelet ratio index (APRI) score (mAPRI) to diagnose CFRLD and predict severity of liver disease. Groups were compared to assess validity of the diagnosis and survival outcomes. RESULT: The new diagnostic criterion was effective at differentiating CFRLD from non-CFRLD. There was no significant difference in the survival between two groups at short, medium, or long term demonstrated by the Kaplan-Meier plot with survival of 85%, 73%, 47%, 18.6%, and 4.7% at 1, 2, 5, 10, and 15 years respectively. A mAPRI score of greater than .2 had a sensitivity of 43.0% but a specificity of 82.5 % for diagnosis of CFRLD and 46.5% sensitivity but 100% specificity in predicting an ultrasound/biopsy proven hepatic abnormality associated with CFRLD. CONCLUSION: A mAPRI sore is a highly specific non-invasive tool for diagnosis of CFRLD. Recipients with CFRLD but grossly preserved hepatocellular function have a similar outcome to patients without CFRLD.

Identification and Characterization of Oral Injury in Suspected Child Abuse Cases: One Health System's Experience.

OBJECTIVES: Accurately differentiating inflicted from accidental injury in infants and toddlers is critical. Many studies have documented characteristics of inflicted bruises, fractures, and head injuries facilitating the development of clinical tools. There are few studies characterizing inflicted oral injuries, and no clinical tools exist. This study identified characteristics that differentiated inflicted from accidental oral injuries in children younger than 24 months. METHODS: Retrospective review using International Classification of Diseases, Ninth Revision billing codes and an internal clinical database tool identified children younger than 24 months between 2004 and 2014. Two groups were created according to the presence or absence of a child abuse diagnosis resulting in an accidental injury and suspected child abuse (SCA) group. Statistical analyses were performed on patient demographics, history of trauma, oral injury characterization, bruises, and fractures. RESULTS: Billing codes were applied differently between the accidental injury and SCA groups, even when the same injury was described. Patients with SCA were younger and less mobile when compared with those with accidental injuries (P < 0.0001). Tongue injuries (P < 0.0001) and oropharynx bruising (P = 0.0018) were observed more and lacerations were observed less (P < 0.0001) in the SCA group. The SCA group was less likely to have a trauma history than those with accidental injury (P < 0.0001). CONCLUSIONS: Several differences in patient characteristics, trauma history, injury type, and location were identified between the accidental versus SCA groups. A future clinical tool that incorporates age, history of trauma on presentation, tongue injury, and oropharynx bruising may assist medical providers in placing child physical abuse in the differential diagnosis.

Factors Associated With Outcomes of Patients With Primary Sclerosing Cholangitis and Development and Validation of a Risk Scoring System.

We sought to identify factors that are predictive of liver transplantation or death in patients with primary sclerosing cholangitis (PSC), and to develop and validate a contemporaneous risk score for use in a real-world clinical setting. Analyzing data from 1,001 patients recruited to the UK-PSC research cohort, we evaluated clinical variables for their association with 2-year and 10-year outcome through Cox-proportional hazards and C-statistic analyses. We generated risk scores for short-term and long-term outcome prediction, validating their use in two independent cohorts totaling 451 patients. Thirty-six percent of the derivation cohort were transplanted or died over a cumulative follow-up of 7,904 years. Serum alkaline phosphatase of at least 2.4 × upper limit of normal at 1 year after diagnosis was predictive of 10-year outcome (hazard ratio [HR] = 3.05; C = 0.63; median transplant-free survival 63 versus 108 months; P < 0.0001), as was the presence of extrahepatic biliary disease (HR = 1.45; P = 0.01). We developed two risk scoring systems based on age, values of bilirubin, alkaline phosphatase, albumin, platelets, presence of extrahepatic biliary disease, and variceal hemorrhage, which predicted 2-year and 10-year outcomes with good discrimination (C statistic = 0.81 and 0.80, respectively). Both UK-PSC risk scores were well-validated in our external cohort and outperformed the Mayo Clinic and aspartate aminotransferase-to-platelet ratio index (APRI) scores (C statistic = 0.75 and 0.63, respectively). Although heterozygosity for the previously validated human leukocyte antigen (HLA)-DR*03:01 risk allele predicted increased risk of adverse outcome (HR = 1.33; P = 0.001), its addition did not improve the predictive accuracy of the UK-PSC risk scores. Conclusion: Our analyses, based on a detailed clinical evaluation of a large representative cohort of participants with PSC, furthers our understanding of clinical risk markers and reports the development and validation of a real-world scoring system to identify those patients most likely to die or require liver transplantation.

Industry-Wide Survey of Academic Anesthesiology Departments Provides Up-to-Date Benchmarking Data on Surgical Anesthesia Productivity.

BACKGROUND: Benchmarking group surgical anesthesia productivity continues to be an important but challenging goal for anesthesiology groups. Benchmarking is important because it provides objective data to evaluate staffing needs and costs, identify potential operating room management decisions that could reduce costs or improve efficiency, and support ongoing negotiations and discussions with health system leadership. Unfortunately, good and meaningful benchmarking data are not readily available. Therefore, a survey of academic anesthesiology departments was done to provide current benchmarking data. METHODS: A survey of members of the Society of Academic Associations of Anesthesiology and Perioperative Medicine (SAAAPM) was performed. The survey collected data by facility and included type of facility, number and type of staff and anesthetizing sites each weekday, and the billed American Society of Anesthesiologists (ASA) units and number of cases over 12 months. The facility types included academic medical center (AMC), community hospital (Community), children's hospital (Children), and ambulatory surgical center (ASC). All anesthesia care billed using ASA units were included, except for obstetric anesthesia. Any care not billed or billed using relative value units (RVUs) were excluded. Percentage of nonoperating room anesthetizing sites, staffing ratio, and surgical anesthesia productivity measurements "per case" and "per site" were calculated. RESULTS: Of the 135 society members, 63 submitted complete surveys for 140 facilities (69 AMC, 26 Community, 7 Children, and 38 ASC). In the survey, overall median productivity for AMC and Children was similar (12,592 and 12,364 total ASA units per anesthetizing site), while the ASC had the lowest median overall productivity (8911 total ASA units per anesthetizing site). By size of facility, in the survey, the smaller facilities (<10 sites, ASC or non-ASC) had lower median overall productivity as compared to larger facilities. For AMC and Children, >20% of anesthetizing sites were nonoperating room anesthetizing sites. Anesthesiology residents worked primarily in AMC and Children. In ASC and Community, residents worked only in 18% and 35% of facilities, respectively. More than half the AMCs reported at least 1 break certified nurse anesthetist (CRNA) each day. CONCLUSIONS: To make data-driven decisions on clinical productivity, anesthesiology leaders need to be able to make meaningful comparisons at the facility level. For a group that provides care in multiple facilities, one can make internal comparisons among facilities and follow measurements over time. It is valuable for leaders to also be compare their facilities with industry-wide measurements, in other words, benchmark their facilities. These results provide benchmarking data for academic anesthesiology departments.

Standardizing the assessment of emotional development in adults with intellectual and developmental disability.

OBJECTIVE: The Scale of Emotional Development-Short (SED-S) is an instrument to assess the level of emotional development (ED) in people with intellectual and developmental disability. Index cases are developed as a didactic tool to standardize the application of the scale. METHOD: In a stepwise process, a European working group from six countries developed five index cases, one for each level of ED. All cases were first scored by 20 raters using the SED-S and then rephrased to reduce inter-rater variations (SD > 0.5). RESULTS: All five index cases yielded overall ratings that matched the intended level of ED. Across the range of ED, Regulating Affect needed rephrasing most to ensure a distinct description within each level of ED. CONCLUSIONS: The tri-lingual, cross-cultural evolution of five index cases contributes to a standardized application of the SED-S and can serve as training material to improve the inter-rater reliability of the SED-S across different cultures and languages.

Primary sclerosing cholangitis.

Primary sclerosing cholangitis is a rare, chronic cholestatic liver disease characterised by intrahepatic or extrahepatic stricturing, or both, with bile duct fibrosis. Inflammation and fibrosis of bile ducts and the liver are followed by impaired bile formation or flow and progressive liver dysfunction. Patients might be asymptomatic at presentation or might have pruritus, fatigue, right upper quadrant pain, recurrent cholangitis, or sequelae of portal hypertension. The key diagnostic elements are cholestatic liver biochemistry and bile duct stricturing on cholangiography. Genetic and environmental factors are important in the cause of the disease, with the intestinal microbiome increasingly thought to play a pathogenetic role. Approximately 70% of patients have concurrent inflammatory bowel disease and patients require colonoscopic screening and surveillance. Primary sclerosing cholangitis is associated with increased malignancy risk and surveillance strategies for early cholangiocarcinoma detection are limited. No single drug has been proven to improve transplant-free survival. Liver transplantation is effective for advanced disease but at least 25% of patients develop recurrent disease in the graft.

Gathering momentum for the way ahead: fifth report of the Lancet Standing Commission on Liver Disease in the UK.

This report presents further evidence on the escalating alcohol consumption in the UK and the burden of liver disease associated with this major risk factor, as well as the effects on hospital and primary care. We reiterate the need for fiscal regulation by the UK Government if overall alcohol consumption is to be reduced sufficiently to improve health outcomes. We also draw attention to the effects of drastic cuts in public services for alcohol treatment, the repeated failures of voluntary agreements with the drinks industry, and the influence of the industry through its lobbying activities. We continue to press for reintroduction of the alcohol duty escalator, which was highly effective during the 5 years it was in place, and the introduction of minimum unit pricing in England, targeted at the heaviest drinkers. Results from the introduction of minimum unit pricing in Scotland, with results from Wales to follow, are likely to seriously expose the weakness of England's position. The increasing prevalence of obesity-related liver disease, the rising number of people diagnosed with type 2 diabetes and its complications, and increasing number of cases of end-stage liver disease and primary liver cancers from non-alcoholic fatty liver disease make apparent the need for an obesity strategy for adults. We also discuss the important effects of obesity and alcohol on disease progression, and the increased risk of the ten most common cancers (including breast and colon cancers). A new in-depth analysis of the UK National Health Service (NHS) and total societal costs shows the extraordinarily large expenditures that could be saved or redeployed elsewhere in the NHS. Excellent results have been reported for new antiviral drugs for hepatitis C virus infection, making elimination of chronic infection a real possibility ahead of the WHO 2030 target. However, the extent of unidentified cases remains a problem, and will also apply when new curative drugs for hepatitis B virus become available. We also describe efforts to improve standards of hospital care for liver disease with better understanding of current service deficiencies and a new accreditation process for hospitals providing liver services. New commissioning arrangements for primary and community care represent progress, in terms of effective screening of high-risk subjects and the early detection of liver disease.

Disease burden and costs from excess alcohol consumption, obesity, and viral hepatitis: fourth report of the Lancet Standing Commission on Liver Disease in the UK.

This report contains new and follow-up metric data relating to the eight main recommendations of the Lancet Standing Commission on Liver Disease in the UK, which aim to reduce the unacceptable harmful consequences of excess alcohol consumption, obesity, and viral hepatitis. For alcohol, we provide data on alcohol dependence, damage to families, and the documented increase in alcohol consumption since removal of the above-inflation alcohol duty escalator. Alcoholic liver disease will shortly overtake ischaemic heart disease with regard to years of working life lost. The rising prevalence of overweight and obesity, affecting more than 60% of adults in the UK, is leading to an increasing liver disease burden. Favourable responses by industry to the UK Government's soft drinks industry levy have been seen, but the government cannot continue to ignore the number of adults being affected by diabetes, hypertension, and liver disease. New direct-acting antiviral drugs for the treatment of chronic hepatitis C virus infection have reduced mortality and the number of patients requiring liver transplantation, but more screening campaigns are needed for identification of infected people in high-risk migrant communities, prisons, and addiction centres. Provision of care continues to be worst in regions with the greatest socioeconomic deprivation, and deficiencies exist in training programmes in hepatology for specialist registrars. Firm guidance is needed for primary care on the use of liver blood tests in detection of early disease and the need for specialist referral. This report also brings together all the evidence on costs to the National Health Service and wider society, in addition to the loss of tax revenue, with alcohol misuse in England and Wales costing £21 billion a year (possibly up to £52 billion) and obesity costing £27 billion a year (treasury estimates are as high as £46 billion). Voluntary restraints by the food and drinks industry have had little effect on disease burden, and concerted regulatory and fiscal action by the UK Government is essential if the scale of the medical problem, with an estimated 63 000 preventable deaths over the next 5 years, is to be addressed.

Measuring Clinical Productivity of Anesthesiology Groups: Surgical Anesthesia at the Facility Level.

Benchmarking and comparing group productivity is an essential activity of data-driven management. For clinical anesthesiology, accomplishing this task is a daunting effort if meaningful conclusions are to be made. For anesthesiology groups, productivity must be done at the facility level in order to reduce some of the confounding factors. When industry or external comparisons are done, then the use of total ASA units per anesthetizing sites allows for overall productivity comparisons. Additional productivity components (total ASA units/h, h/case, h/operating room/d) allow for leaders to develop productivity dashboards. With the emergence of large groups that provide care in multiple facilities, these large groups can choose to invest more effort in collecting data and comparing facility productivity internally with group-defined measurements including total ASA units per full time equivalent.

Guidelines on the management of abnormal liver blood tests.

These updated guidelines on the management of abnormal liver blood tests have been commissioned by the Clinical Services and Standards Committee (CSSC) of the British Society of Gastroenterology (BSG) under the auspices of the liver section of the BSG. The original guidelines, which this document supersedes, were written in 2000 and have undergone extensive revision by members of the Guidelines Development Group (GDG). The GDG comprises representatives from patient/carer groups (British Liver Trust, Liver4life, PBC Foundation and PSC Support), elected members of the BSG liver section (including representatives from Scotland and Wales), British Association for the Study of the Liver (BASL), Specialist Advisory Committee in Clinical Biochemistry/Royal College of Pathology and Association for Clinical Biochemistry, British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN), Public Health England (implementation and screening), Royal College of General Practice, British Society of Gastrointestinal and Abdominal Radiologists (BSGAR) and Society of Acute Medicine. The quality of evidence and grading of recommendations was appraised using the AGREE II tool. These guidelines deal specifically with the management of abnormal liver blood tests in children and adults in both primary and secondary care under the following subheadings: (1) What constitutes an abnormal liver blood test? (2) What constitutes a standard liver blood test panel? (3) When should liver blood tests be checked? (4) Does the extent and duration of abnormal liver blood tests determine subsequent investigation? (5) Response to abnormal liver blood tests. They are not designed to deal with the management of the underlying liver disease.

Intracellular LINGO-1 negatively regulates Trk neurotrophin receptor signaling.

Neurotrophins, essential regulators of many aspects of neuronal differentiation and function, signal via four receptors, p75, TrkA, TrkB and TrkC. The three Trk paralogs are members of the LIG superfamily of membrane proteins, which share extracellular domains consisting of leucine-rich repeat and C2 Ig domains. Another LIG protein, LINGO-1 has been reported to bind and influence signaling of p75 as well as TrkA, TrkB and TrkC. Here we examine the manner in which LINGO-1 influences the function of TrkA, TrkB and TrkC. We report that Trk activation promotes Trk association with LINGO-1, and that this association promotes Trk degradation by a lysosomal mechanism. This mechanism resembles the mechanism by which another LIG protein, LRIG1, promotes lysosomal degradation of receptor tyrosine kinases such as the EGF receptor. We present evidence indicating that the Trk/LINGO-1 interaction occurs, in part, within recycling endosomes. We show that a mutant form of LINGO-1, with much of the extracellular domain deleted, has the capacity to enhance TrkA signaling in PC12 cells, possibly by acting as an inhibitor of Trk down-regulation by full length LINGO-1. We propose that LINGO-1 functions as a negative feedback regulator of signaling by cognate receptor tyrosine kinases including TrkA, TrkB and TrkC.

LINGO-1 protein interacts with the p75 neurotrophin receptor in intracellular membrane compartments.

Axon outgrowth inhibition in response to trauma is thought to be mediated via the binding of myelin-associated inhibitory factors (e.g. Nogo-66, myelin-associated glycoprotein, oligodendrocyte myelin glycoprotein, and myelin basic protein) to a putative tripartite LINGO-1·p75(NTR)·Nogo-66 receptor (NgR) complex at the cell surface. We found that endogenous LINGO-1 expression in neurons in the cortex and cerebellum is intracellular. Mutation or truncation of the highly conserved LINGO-1 C terminus altered this intracellular localization, causing poor intracellular retention and increased plasma membrane expression. p75(NTR) associated predominantly with natively expressed LINGO-1 containing immature N-glycans, characteristic of protein that has not completed trans-Golgi-mediated processing, whereas mutant forms of LINGO-1 with enhanced plasma membrane expression did not associate with p75(NTR). Co-immunoprecipitation experiments demonstrated that LINGO-1 and NgR competed for binding to p75(NTR) in a manner that is difficult to reconcile with the existence of a LINGO-1·p75(NTR)·NgR ternary complex. These findings contradict models postulating functional LINGO-1·p75(NTR)·NgR complexes in the plasma membrane.

The impact on hospital resource utilisation of treatment of hepatic encephalopathy with rifaximin-α.

BACKGROUND & AIMS: Rifaximin-α reduces the risk of recurrence of overt hepatic encephalopathy. However, there remain concerns regarding the financial cost of the drug. We aimed to study the impact of treatment with rifaximin-α on healthcare resource utilisation using data from seven UK liver treatment centres. METHODS: All seven centres agreed a standardised data set and data characterising clinical, demographic and emergency hospital admissions were collected retrospectively for the time periods 3, 6 and 12 months before and following initiation of rifaximin-α. Admission rates and hospital length of stay before and during therapy were compared. Costs of admissions and drug acquisition were estimated using published sources. Multivariate analyses were carried out to assess the relative impact of various factors on hospital length of stay. RESULTS: Data were available from 326 patients. Following the commencement of rifaximin, the total hospital length of stay reduced by an estimated 31-53%, equating to a reduction in inpatient costs of between £4858 and £6607 per year. Taking into account drug costs of £3379 for 1-year treatment with rifaximin-α, there was an estimated annual mean saving of £1480-£3228 per patient. CONCLUSIONS: Initiation of treatment with rifaximin-α was associated with a marked reduction in the number of hospital admissions and hospital length of stay. These data suggest that treatment of patients with rifaximin-α for hepatic encephalopathy was generally cost saving.

Resilience and the population history of the Kuril Islands, Northwest Pacific: A study in complex human ecodynamics.

Living in remote places can strain the adaptive capacities of human settlers. It can also protect communities from external social, political and economic forces. In this paper, we present an archaeological population history of the Kuril Islands. This string of small volcanic islands on the margins of the Northwest Pacific was occupied by maritime hunting, fishing and gathering communities from the mid-Holocene to recent centuries. We bring together (1) 380 new and previously published archaeological radiocarbon dates, (2) a new paleodemographic model based on a radiocarbon-timestamped temporal frequency distribution of archaeological deposits, (3) recently published paleoclimate trends, and (4) recently published archaeological proxy evidence for changes in the extent of social networks. We demonstrate that, over the last two millennia, inhabitants of the Kuril Islands underwent dramatic demographic fluctuations. Explanations of these fluctuations are considered in the context of environmental hazards, social networks and the emergence of an East Asian "World System", elucidating the tension between local and external adaptive strategies to social and ecological uncertainty. Results suggest that population resilience to local climate and environmental variability was achieved by virtue of social networks that maintained non-local support in times of crisis. Conversely, the expansion of the East Asian political economy into neighboring regions of the southern margin of the Kuril Islands perhaps in conjunction with exposure to epidemic diseases appears to have undermined the adaptive strategies, resulting in an increase in the vulnerability of Kuril populations to environmental fluctuations.

U.K. guidelines on the management of variceal haemorrhage in cirrhotic patients.

These updated guidelines on the management of variceal haemorrhage have been commissioned by the Clinical Services and Standards Committee (CSSC) of the British Society of Gastroenterology (BSG) under the auspices of the liver section of the BSG. The original guidelines which this document supersedes were written in 2000 and have undergone extensive revision by 13 members of the Guidelines Development Group (GDG). The GDG comprises elected members of the BSG liver section, representation from British Association for the Study of the Liver (BASL) and Liver QuEST, a nursing representative and a patient representative. The quality of evidence and grading of recommendations was appraised using the AGREE II tool.The nature of variceal haemorrhage in cirrhotic patients with its complex range of complications makes rigid guidelines inappropriate. These guidelines deal specifically with the management of varices in patients with cirrhosis under the following subheadings: (1) primary prophylaxis; (2) acute variceal haemorrhage; (3) secondary prophylaxis of variceal haemorrhage; and (4) gastric varices. They are not designed to deal with (1) the management of the underlying liver disease; (2) the management of variceal haemorrhage in children; or (3) variceal haemorrhage from other aetiological conditions.