Rapid Whole Genome Sequencing of Serotype K1 Hypervirulent Klebsiella pneumoniae from an Undocumented Chinese Migrant.

BACKGROUND: Hypervirulent Klebsiella pneumoniae causes severe disseminated infections, typically with hepatic and central nervous system involvement including endophthalmitis. Case Presentation. We report a fatal case of an undocumented Chinese migrant in her 60s who presented to the emergency department with abdominal pain, lethargy, and headache over the preceding two weeks. She had a new diagnosis of diabetes mellitus on admission. Computed tomography scan of the thorax, abdomen, and pelvis showed bilateral pneumonia with liver abscesses. The patient was treated with empirical broad-spectrum antibiotics before K. pneumoniae was isolated from cerebrospinal fluid and blood cultures. The isolate was further characterised as a ST23 (ST: sequence type), serotype K1 hypervirulent strain using Nanopore sequencing. Despite admission to the intensive care unit, the patient died within 48 hrs of admission. CONCLUSIONS: This case demonstrates the need for increased awareness of hypervirulent K. pneumoniae, even in countries where it occurs infrequently. Novel, rapid, sequencing technologies can support diagnosis in unusual presentations.

Enhancing the communication of functional neurological disorder diagnosis: a multidisciplinary education session.

BACKGROUND AND PURPOSE: Functional neurological disorder (FND) is a common diagnosis within neurology. Effective communication of the diagnosis is known to be an important part of treatment and can result in reduction or cessation of symptoms, as well as decreased healthcare utilisation. A single group education session, facilitated by professionals commonly involved in the care of patients with FND, was developed to further enhance patients' and relatives' understanding and acceptance of diagnosis. METHODS: Patients and relatives attending a single education session were asked to complete self-report ratings of understanding of diagnosis, acceptance of diagnosis, belief in treatability and hopefulness regarding recovery, at the beginning and end of the session. Satisfaction data were also collected. RESULTS: Data were obtained from 193 patients and 153 relatives. Patients had experienced a median duration of symptoms of 4 years, and more than 80% of patients reported more than one functional neurological symptom. There were significant increases in terms of understanding, acceptance, belief in treatability and hopefulness for patients and relatives. Effect sizes ranged from large for improved understanding of FND to small-to-medium for increased agreement with FND diagnosis. High levels of satisfaction were also reported. CONCLUSIONS: A multidisciplinary, single group education session is an effective and acceptable method of increasing understanding and acceptance of an FND diagnosis, even for patients with a long duration of symptoms and high symptom burden. It could help improve readiness for further treatment.

Needs assessment can guide creation of a "resident-optimized clinic" in surgery.

BACKGROUND: There is limited data on deliberate teaching of residents in the clinic setting; we sought to investigate the clinic experience at our institution and improve education through creation of a novel "Resident-Optimized Clinic" (ROC). METHODS: An online survey was sent separately to residents and faculty. Based on the results of this survey a modified ROC was developed to try to improve the obstacles to learning in clinic. RESULTS: Qualitative analysis revealed the barriers in clinic were inconsistencies in expectations, lack of autonomy, time, and facility limitations. The modified ROC was rated positively with 100% of participants expressing they had sufficient time and autonomy; and 90% felt the environment was optimized for teaching. CONCLUSIONS: Multiple themes have been identified as problematic for the clinic education experience. The ROC was rated positively by trainees suggesting thoughtful intervention to improve clinic results in a better clinic experience and more educational gain from the clinic environment.

A novel genetic variant of Streptococcus pneumoniae serotype 11A discovered in Fiji.

OBJECTIVES: As part of annual cross-sectional Streptococcus pneumoniae carriage surveys in Fiji (2012-2015), we detected pneumococci in over 100 nasopharyngeal swabs that serotyped as '11F-like' by microarray. We examined the genetic basis of this divergence in the 11F-like capsular polysaccharide (cps) locus compared to the reference 11F cps sequence. The impact of this diversity on capsule phenotype, and serotype results using genetic and serologic methods were determined. METHODS: Genomic DNA from representative 11F-like S. pneumoniae isolates obtained from the nasopharynx of Fijian children was extracted and subject to whole genome sequencing. Genetic and phylogenetic analyses were used to identify genetic changes in the cps locus. Capsular phenotypes were evaluated using the Quellung reaction and latex agglutination. RESULTS: Compared to published 11F sequences, the wcwC and wcrL genes of the 11F-like cps locus are phylogenetically divergent, and the gct gene contains a single nucleotide insertion within a homopolymeric region. These changes within the DNA sequence of the 11F-like cps locus have modified the antigenic properties of the capsule, such that 11F-like isolates serotype as 11A by Quellung reaction and latex agglutination. CONCLUSIONS: This study demonstrates the ability of molecular serotyping by microarray to identify genetic variants of S. pneumoniae and highlights the potential for discrepant results between phenotypic and genotypic serotyping methods. We propose that 11F-like isolates are not a new serotype but rather are a novel genetic variant of serotype 11A. These findings have implications for invasive pneumococcal disease surveillance as well as studies investigating vaccine impact.

Outbreaks attributed to pork in the United States, 1998-2015.

Each year in the United States, an estimated 525 000 infections, 2900 hospitalizations, and 82 deaths are attributed to consumption of pork. We analyzed the epidemiology of outbreaks attributed to pork in the United States reported to the Centers for Disease Control and Prevention (CDC) 1998-2015. During that period, 288 outbreaks were attributed to pork, resulting in 6372 illnesses, 443 hospitalizations, and four deaths. The frequency of outbreaks attributed to pork decreased by 37% during this period, consistent with a decline in total foodborne outbreaks. However, outbreaks attributed to pork increased by 73% in 2015 (19 outbreaks) compared with the previous 3 years (average of 11 outbreaks per year), without a similar increase in total foodborne outbreaks. Most (>99%) of these outbreaks occurred among people exposed in the same state. The most frequent etiology shifted from Staphylococcus aureus toxin during 1998-2001 (19%) to Salmonella during 2012-2015 (46%). Outbreaks associated with ham decreased from eight outbreaks per year during 1998-2001, to one per year during 2012-2015 (P < 0·01). Additional efforts are necessary to reduce outbreaks and sporadic illnesses associated with pork products.

Acid deprotonation driven by cation migration at biased graphene nanoflake electrodes.

In situ IR spectroscopy is used to monitor electrolyte composition and acid protonation state at the interface of graphene nanoflake electrodes. Deprotonation of both electrode-immobilised and solution acids is driven by a local increase in cation activity at the electrode surface on application of a negative electrode potential.

Randomised feasibility study of physiotherapy for patients with functional motor symptoms.

OBJECTIVE: To determine the feasibility of conducting a randomised controlled trial of a specialist physiotherapy intervention for functional motor symptoms (FMS). METHODS: A randomised feasibility study was conducted recruiting patients with a clinically established diagnosis of FMS from a tertiary neurology clinic in London, UK. Participants were randomised to the intervention or a treatment as usual control. Measures of feasibility and clinical outcome were collected and assessed at 6 months. RESULTS: 60 individuals were recruited over a 9-month period. Three withdrew, leaving 29 intervention and 28 controls participants in the final analysis. 32% of patients with FMS met the inclusion criteria, of which 90% enrolled. Acceptability of the intervention was high and there were no adverse events. At 6 months, 72% of the intervention group rated their symptoms as improved, compared to 18% in the control group. There was a moderate to large treatment effect across a range of outcomes, including three of eight Short Form 36 (SF36) domains (d=0.46-0.79). The SF36 Physical function was found to be a suitable primary outcome measure for a future trial; adjusted mean difference 19.8 (95% CI 10.2 to 29.5). The additional quality adjusted life years (QALY) with intervention was 0.08 (95% CI 0.03 to 0.13), the mean incremental cost per QALY gained was £12 087. CONCLUSIONS: This feasibility study demonstrated high rates of recruitment, retention and acceptability. Clinical effect size was moderate to large with high probability of being cost-effective. A randomised controlled trial is needed. TRIAL REGISTRATION NUMBER: NCT02275000; Results.

Hand-held dynamometry strength measures for internal and external rotation demonstrate superior reliability, lower minimal detectable change and higher correlation to isokinetic dynamometry than externally-fixed dynamometry of the shoulder.

OBJECTIVES: To investigate inter and intra-rater reliability of hand held (HHD) and externally fixed (EFD) dynamometry for shoulder internal (IR) and external rotation (ER) strength and their correlation to isokinetic testing. DESIGN: Within participant, inter and intra-rater reliability study. PARTICIPANTS: Twenty active, healthy male and female participants underwent testing by two examiners. OUTCOME MEASURES: Intra-class coefficients (ICC), percentage standard error of measurement (%SEM), and percentage minimal detectable change (%MDC) were calculated for inter-rater, intra-day and intra-rater, inter-week reliability. Maximum and average of three repetitions were compared to the isokinetic results at three speeds (60°/sec, 180°/sec, 240°/sec) for both concentric and eccentric contractions. RESULTS: Inter and intra-tester values demonstrated good to high agreement (HHD, ICC range = 0.89-0.97, %SEM = 4.80-8.60%, %MDC = 13.29-23.70%; EFD, ICC = 0.88-0.96, %SEM = 6.60-11.00%, %MDC = 18.40-30.04%). HHD and EFD showed moderate to very strong correlations to the isokinetic testing (HHD, r = 0.45-0.86; EFD, r = 0.49-0.83). CONCLUSIONS: The results of this study indicate that both EFD and HHD are suitable for clinical practice and research. Hand-held dynamometry is preferred due to its higher intra- and inter-rater reliability and smaller MDC and lower SEM.

Rehabilitation of women with gynaecological cancer: the association between adult attachment, post-traumatic stress disorder and depression.

OBJECTIVE: We hypothesised that being diagnosed with gynaecological cancer influences adult attachment and occurrence of depression and post-traumatic stress disorder (PTSD). The main aim of the study was to assess changes in the attachment dimensions, PTSD and depression from baseline to 5-month post-treatment. Further, we evaluated the association between attachment avoidance/anxiety dimensions and PTSD/depression among women newly diagnosed with ovarian, endometrial, or cervical cancer. METHODS: Consecutive Danish-speaking women aged 20 to 75 years and treated surgically for primary gynaecological cancer were eligible. All patients were offered a rehabilitation programme consisting of two face-to-face sessions and two phone calls carried out by a nurse. Patients were asked to complete the Revised Adult Attachment Scale, the Harvard Trauma Questionnaire and the Major Depression Inventory at baseline and at 5-month follow-up. In all, 151 women consent to participate in the sessions where 51 fulfilled Revised Adult Attachment Scale questionnaire and contribute with socio-demographic data. RESULTS: We found significant positive changes within the attachment anxiety dimension among women with ovarian cancer, a significant reduction of PTSD among endometrial cancer patients and insignificant changes in depression among all cancer types. The attachment anxiety dimension significantly increased the odds for PTSD and depression. CONCLUSIONS: Depression and PTSD were prevalent among ovarian and cervical cancer patients. The adjustment of rehabilitation according to patients' attachment anxiety dimension contains possibilities for indirect impact on PTSD and depression symptoms. Copyright © 2015 John Wiley & Sons, Ltd.

Bio-inspired CO2 conversion by iron sulfide catalysts under sustainable conditions.

The mineral greigite presents similar surface structures to the active sites found in many modern-day enzymes. We show that particles of greigite can reduce CO2 under ambient conditions into chemicals such as methanol, formic, acetic and pyruvic acid. Our results also lend support to the Origin of Life theory on alkaline hydrothermal vents.

Outbreaks of Salmonella infections attributed to beef --United States, 1973-2011.

Non-typhoidal Salmonella is estimated to be the most common bacterial cause of foodborne illness in the United States, causing an estimated one million domestically acquired foodborne illnesses annually. Recent, large outbreaks have highlighted the importance of ground beef as an important source of multidrug-resistant Salmonella. We analysed the epidemiology of salmonellosis outbreaks that were attributed to beef in the United States reported to the Centers for Disease Control and Prevention (CDC) from 1973 to 2011. During 1973-2011, of the 1965 outbreaks of Salmonella where a food vehicle was implicated, 96 were attributed to beef, accounting for 3684 illnesses. We observed a shift in the type of beef implicated in salmonellosis outbreaks, from roast to ground beef. Delicatessen-style roast beef cooked in commercial processing establishments was the predominant type during the 1970s and early 1980s; regulations on cooking and processing essentially eliminated this problem by 1987. Ground beef emerged as an important vehicle in the 2000s; it was implicated in 17 (45%) of the 38 beef-attributed outbreaks reported during 2002-2011. Although this emergence was likely due in part to increased participation in CDC's PulseNet, which was established in 1996, and proactive decisions by the United States Department of Agriculture's Food Safety and Inspection Service, stronger measures are needed to decrease contamination of ground beef with Salmonella.

Principles and methods for automated palynology.

Pollen grains are microscopic so their identification and quantification has, for decades, depended upon human observers using light microscopes: a labour-intensive approach. Modern improvements in computing and imaging hardware and software now bring automation of pollen analyses within reach. In this paper, we provide the first review in over 15 yr of progress towards automation of the part of palynology concerned with counting and classifying pollen, bringing together literature published from a wide spectrum of sources. We consider which attempts offer the most potential for an automated palynology system for universal application across all fields of research concerned with pollen classification and counting. We discuss what is required to make the datasets of these automated systems as acceptable as those produced by human palynologists, and present suggestions for how automation will generate novel approaches to counting and classifying pollen that have hitherto been unthinkable.

Progression of atherosclerosis in the Apo E-/- model: 12-month exposure to cigarette mainstream smoke combined with high-cholesterol/fat diet.

This study was performed to gain information about the influence of two cardiovascular risk factors, cigarette mainstream smoke (MS) and high-cholesterol/fat diet, on the progression of atherosclerosis in apolipoprotein E-deficient (Apo E-/-) mice. Eight to 12-week-old mice were whole-body exposed for up to 12 months (6h/day, 5 days/week) to diluted cigarette mainstream smoke at total particulate matter (TPM) concentrations of 100 or 200mg/m(3), or to filtered fresh air (sham) in combination with a normal chow diet or a high-cholesterol/fat diet. Cholesterol in the aortic arch was elevated in the high-cholesterol/fat diet groups exposed to 200 mg TPM/m(3) compared to sham at all time points. In the brachiocephalic artery (BA), absolute plaque size and fraction area of plaques was elevated over the 12-month time course in mice exposed to 200 mg TPM/m(3) compared to sham (both diets). Exposure to 100 and 200 mg TPM/m(3) altered the number of elastin-rich layers in the BA in mice fed a high-cholesterol/fat diet, indicating changes in plaque morphology at 6 and 9 months. This study shows for the first time the influence of two different risk factors, MS and high-cholesterol/fat diet, both alone and in combination over a period of 12 months, on the progression of atherosclerosis in Apo E-/- mice. Data suggest that long-term exposure to cigarette mainstream smoke accelerates the development of atherosclerosis in Apo E-/- mice, particularly in combination with a high-cholesterol/fat diet.

Developmental trajectory of dynamic resource utilization during walking: toddlers with and without Down syndrome.

After years of walking practice 8-10-year-old children with typical development (TD) and those with Down syndrome (DS) show uniquely different but efficient use of dynamic resources to walk overground and on a treadmill [Ulrich, B.D., Haehl, V., Buzzi, U., Kubo, M., & Holt, K.G. (2004). Modeling dynamic resource utilization in populations with unique constraints: Preadolescents with and without Down syndrome. Human Movement Science, 23, 133-156]. Here we examined the use of global stiffness and angular impulse when walking emerged and across the ensuing months of practice in eight toddlers with TD and eight with DS. Participants visited our lab when first able to walk four to six steps, and at one, three, four, and six months of walking experience. For all visits, toddlers walked overground at their preferred speeds and for the last two visits on a treadmill. Toddlers with TD and DS demonstrated clear and similar developmental trajectories over this period with more similarities than differences between groups. At six months stiffness and impulse values were higher than previously observed for 8-10-year-old children. Stiffness values increased significantly throughout this period, though rate of change slowed for the TD group by three months of experience. Impulse values rose sharply initially and slowed to plateau during the latter months. Treadmill data illustrated toddlers' capacity to adapt dynamic resource use to imposed changes in speed, particularly well after six months of practice. Consistent with our studies of preadolescents and older adults, toddlers with DS produced significantly wider normalized step width than their TD peers. We propose that the challenge of upright bipedal locomotion constrains toddlers with TD and DS to generate similar, necessary and sufficient stiffness and impulse values to walk as they gain control and adapt to playful and self-imposed perturbations of gait over the first six months. The plateau in impulse and slow-down of stiffness increases over the latter months may be the first signs of a downward trend to the lower values produced by older children with several years of walking experience.

Effects of a hip belt on transverse plane trunk coordination and stability during load carriage.

This study examined the transverse plane kinematics of the pelvis, thorax and head while participants walked at a range of speeds on a treadmill under three load conditions: no load, with a loaded backpack with no hip belt and with a loaded backpack with a hip belt. Research has suggested that one mechanism for adapting to heavy loads carried with no hip belt is to reduce the amplitudes and relative phase of transverse plane pelvic and thoracic rotations, in order to minimize rotational torque on the loaded upper body. Transverse plane rotation amplitudes of the pelvis, thorax, backpack and head were calculated from 3D kinematic data for 12 healthy subjects, walking at speeds of 0.5, 0.9, 1.3 and 1.7 ms(-1). Relative phase relation and its variability were also computed for pelvis-thorax rotations and backpack-thorax rotations. Stability of the coordination pattern was estimated as an inverse function of the variability in relative phase. The backpack with the hip belt allowed significantly larger transverse plane rotation amplitudes, along with increased stability of the coordination pattern, than the backpack with no hip belt. Motion patterns of the backpack and thorax suggested that the backpack frame was used to assist with the deceleration and reversal of the loaded thorax, driven by the pelvis through the hip belt connection. Use of the frame in this way may have required less trunk muscle activation and allowed for improved pattern stability.

Smoking accelerates the progression of hypertension-induced myocardial hypertrophy to heart failure in spontaneously hypertensive rats.

OBJECTIVE: Myocardial hypertrophy often develops in response to hypertension, and it is causal to and an independent predictor of heart failure. Several risk factors modify the progression of hypertrophy, the associated progressive impairment of myocardial function, and eventually the transition to overt congestive heart failure. The aim of the present study was to investigate the effects of smoking on the progression of pressure-dependent myocardial hypertrophy. METHODS: Spontaneously hypertensive rats (SHR) were used as a model for pressure-dependent hypertrophy. SHR were exposed to mainstream smoke from the Kentucky reference cigarette 2R4F (450 microg total particulate matter/l) or to fresh air (control), 5 days a week, twice for 1 h per day with a 30-minute fresh air exposure break for 30, 60, or 90 days. Endpoints for hypertrophy-associated changes were heart weight to body weight ratio, ventricular expression of hypertrophy-associated genes, ischemic tolerance, and inotropic responsiveness to isoprenaline in post-ischemic hearts. RESULTS: Smoke-exposed SHR showed a significant elevation in heart weight to body weight ratio, increased mRNA expression of atrial natriuretic factor (ANF), transforming growth factor (TGF)-beta(1), ornithine decarboxylase (ODC), and parathyroid hormone-related protein in both ventricles compared to controls. Hearts from smoke-exposed SHR showed a reduced recovery after 30 min global ischemia during the first 5 min of reperfusion and loss of inotropic stimulation after 30 min reperfusion. Smoke cessation was sufficient to reverse most of these alterations. WKY exposed to smoke did not develop similar changes. CONCLUSION: Our data indicate that several aspects of myocardial hypertrophy are accelerated by smoking.

Biomarkers of exposure and potential harm in adult smokers of 3-7 mg tar yield (Federal Trade Commission) cigarettes and in adult non-smokers.

The paper reports levels of 24-h urine nicotine and five of its major metabolites (expressed as nicotine-equivalents) and blood carboxyhaemoglobin as biomarkers of exposure to particulate- and gas-phase cigarette smoke, respectively, from an exploratory pilot study of adult smokers of 3.0-6.9 mg tar delivery (Federal Trade Commission (FTC) method) cigarettes. On multiple occasions over 6 weeks, blood high-sensitivity C-reactive protein (hs-CRP), fibrinogen, HDL- and LDL-cholesterol, and 24-h urine 8-epi-prostaglandin F2alpha (8-epi-PGF2alpha) and 11-dehydro-thromboxane B2 (11-dehydro-TxB2) were also evaluated as biomarkers of potential harm. All the biomarkers examined, except for LDL-cholesterol, discriminated with high sensitivity and specificity between adult smokers and non-smokers overall. Except for HDL-cholesterol, all biomarker medians were greater in adult smokers than in non-smokers: urine nicotine-equivalents 64.514 versus < 0.034 nmol mg-1 creatinine (p<0.001), carboxyhaemoglobin 4.0 versus 0.4% saturation (p<0.001), hs-CRP 0.27 versus 0.12 mg dl-1 (p=0.05), fibrinogen 292 versus 248 mg dl-1 (p<0.001), HDL-cholesterol 46 versus 53 mg dl-1 (p=0.003), LDL-cholesterol 119 versus 109 mg dl-1 (p=0.18), urine 8-epi-PGF2alpha 1935 versus 1034 pg mg-1 creatinine (p<0.001) and urine 11-dehydro-TxB2 973 versus 710 pg mg-1 creatinine (p<0.001). All the biomarkers of exposure and most of the biomarkers of potential harm showed no time of sampling (by visit week) effect.

A longitudinal study to explain strategies to change weight and muscles among normal weight and overweight children.

Previous research has indicated that both boys and girls strive for a slim body, with boys having an additional focus on a muscular body build. The current study was designed to evaluate the utility of a biopsychosocial model to explain body image and body change strategies among children. The study evaluated changes over time in body image and strategies to lose weight and increase muscles among 132 normal weight and 67 overweight boys (mean age = 9.23 years) and 158 normal weight and 55 overweight girls (mean age = 9.33 years). The predictive role of BMI, positive and negative affect, self-esteem and perceived sociocultural pressures to lose weight or increase muscle on body image and body change strategies over a 16 month period was evaluated. All participants completed the questionnaire on both occasions. The results demonstrated that both overweight boys and girls were more likely to be dissatisfied with their weight, place more importance on their weight, engage in more strategies to lose weight as well as perceive more pressure to lose weight. Overweight boys and girls were also more likely to report lower levels of self-esteem and positive affect, and higher levels of negative affect, and reported a reduction in their self-esteem over time. Regression analyses demonstrated that among overweight boys, low self-esteem and high levels of perceived pressure to lose weight predicted weight dissatisfaction; for overweight girls, weight dissatisfaction was also predicted by low levels of self-esteem. The implication of these findings in terms of factors contributing to the adoption of health risk behaviors among children is discussed.

An immunoepidemiological approach to asthma: identification of in-vitro T-cell response patterns associated with different wheezing phenotypes in children.

BACKGROUND: Increasing evidence suggests that patterns of T-cell immunity to inhalant allergens in genetically diverse human populations are more heterogeneous than previously assumed, and that covert differences in expression patterns might underlie variations in airway disease phenotypes. We tested this proposition in a community sample of children. METHODS: We analysed data from 172 individuals who had been recruited antenatally to a longitudinal birth cohort study. Of the 194 birth cohort participants, data from the 147 probands (age range 8.6-13.5 years) who consented to blood collection were included along with data from 25 consenting siblings (mean age 11 years [range 7.4-17.4]). We ascertained clinical phenotypes related to asthma and allergy. We measured T-cell responses to allergens and mitogens, together with blood eosinophils and IgE/IgG antibodies, and assessed associations between these indices and clinical phenotypes. FINDINGS: Atopy was associated with allergen-specific T-helper (Th)2 responses dominated by interleukin 4, interleukin 5, interleukin 9, interleukin 13, whereas interleukin 10, tumour necrosis factor alpha, and interferon gamma responses were common to both atopics and non-atopics. The wheal size from skin prick with allergen was positively associated with in-vitro interleukin 5 and interferon gamma responses, and negatively associated with interleukin 10. Asthma, especially in atopics, was strongly associated with eosinophilia/interleukin 5, and bronchial hyper-responsiveness (BHR) was associated with eosinophilia plus polyclonal interferon gamma production. BHR in non-atopics was associated with elevated allergen-specific and polyclonal interleukin 10 production. INTERPRETATION: Parallel immunological and clinical profiling of children identified distinctive immune response patterns related to asthma and wheeze compared with BHR, in atopics non-atopics. Immunological hyper-responsiveness, including within the Th1 cytokine compartment, is identified as a hallmark of BHR. RELEVANCE TO PRACTICE: These findings highlight the heterogeneity of immune response patterns in asthmatic children, including those with seemingly homogeneous Th2-driven atopic asthma. Further elucidation of the covert relationships between wheezing phenotypes and underlying immunophenotypes in this age group will potentially lead to more effective treatments for what is an unexpectedly heterogeneous collection of disease subtypes.