Charting the future of patient care: A strategic leadership guide to harnessing the potential of artificial intelligence.

Artificial Intelligence (AI) applications have the potential to revolutionize conventional healthcare practices, creating a more efficient and patient-centred approach with improved outcomes. This guide discuses eighteen AI-based applications in clinical decision-making, precision medicine, operational efficiency, and predictive analytics, including a real-world example of AI's role in public health during the early stages of the COVID-19 pandemic. Additionally, we address ethical questions, transparency, data privacy, bias, consent, accountability, and liability, and the strategic measures that must be taken to align AI with ethical principles, legal frameworks, legacy information technology systems, and employee skills and knowledge. We emphasize the importance of informed and strategic approaches to harness AI's potential and manage its challenges. Moreover, this guide underscores the importance of evaluating and integrating new skills and competencies to navigate and use AI-based technologies in healthcare management, such as technological literacy, long-term strategic vision, change management skills, ethical decision-making, and alignment with patient needs.

Whole-brain traumatic controlled cortical impact to the left frontal lobe: Magnetic resonance image-based texture analysis.

This research assesses the capability of texture analysis (TA) derived from high-resolution (HR) T2-weighted magnetic resonance imaging to identify primary sequelae following 1-5 hours of controlled cortical impact mild or severe traumatic brain injury (TBI) to the left frontal cortex (focal impact) and secondary (diffuse) sequelae in the right frontal cortex, bilateral corpus callosum, and hippocampus in rats. The TA technique comprised first-order (histogram-based) and second-order statistics (including gray-level co-occurrence matrix, gray-level run length matrix, and neighborhood gray-level difference matrix). Edema in the left frontal impact region developed within 1 hour and continued throughout the 5-hour assessments. The TA features from HR images confirmed the focal injury. There was no significant difference among radiomics features between the left and right corpus callosum or hippocampus from 1 to 5 hours following a mild or severe impact. The adjacent corpus callosum region and the distal hippocampus region (s), showed no diffuse injury 1-5 hours after mild or severe TBI. These results suggest that combining HR images with TA may enhance detection of early primary and secondary sequelae following TBI.

Protocol for a systematic review of the validity of animal models of polydipsia with a basis in schizophrenia aetiology.

Objective: Primary polydipsia most commonly affects those with schizophrenia. The pathophysiology of this occurrence is not established. The aim of this systematic review is to critically assess the internal and external validity of the preclinical animal models available. Search strategy: PubMed and Embase will be searched systematically to identify all relevant animal studies that describe polydipsia induction with a basis in schizophrenia aetiology. The SYRCLE (SYstematic Review Center for Laboratory animal Experimentation) search filters to identify all animal studies in both databases will be used. All studies published up to the date of the search will be considered. Screening and annotation: Two independent reviewers will screen the retrieved studies for eligibility based on (1) title and abstract and (2) full text. Disagreements between researchers will be resolved by discussion and referral back to the predefined eligibility criteria with involvement of a third researcher if required.

Paradoxical Cerebral Air Embolism after Cardiac Ablation in Williams-Beuren Syndrome: A Clinico-Pathological Correlation.

Non-traumatic neurological deterioration is a medical emergency that may arise from diverse causes, to include cerebral infarction or intracranial hemorrhage, meningoencephalitis, seizure, hypoxic-ischemic or toxic/metabolic encephalopathy, poisoning, or drug intoxication. We describe the abrupt onset of neurological deterioration in a 53-year-old man with Williams-Beuren syndrome, a sporadically occurring genetic disorder caused by chromosomal microdeletion at 7q11.23. The clinical phenotype of Williams-Beuren syndrome is suggested by distinctive elfin facies, limited intellect, unique personality features, growth abnormalities, and endocrinopathies. The causative microdeletion of chromosomal material will frequently involve loss of the elastin gene, ELN, with resulting arteriopathy, supravalvular aortic stenosis, non-ischemic cardiopathy, and atrial fibrillation. Our patient sustained acute neurological decline within one month after undergoing a cardiac ablative procedure to convert atrial fibrillation to sinus rhythm. We present our findings in the setting of a clinico-pathological correlation, in which we reveal the cause of the abrupt neurological deterioration and discuss how our patient was affected by an uncommon stroke disorder.

Community aquatic therapy for Parkinson's disease: an international qualitative study.

PURPOSE: To explore the opinions of people living with Parkinson's disease about access to and participation in community aquatic therapy. METHODS: Focus groups and individual interviews were conducted with people living with Parkinson's disease in Ireland (n = 24) and Australia (n = 10). All discussions were audio-recorded, transcribed verbatim, and thematically analysed. RESULTS: Four main themes were identified. Primarily, participants were optimistic about their reasons for choosing aquatic therapy and found it beneficial to their health and well-being. Optimal components of aquatic therapy identified were access to individually tailored aquatic programs, completed as a minimum once a week, at a moderate to high-intensity level, and guided by a credentialed instructor. Fear was a significant barrier for a small proportion of participants and was linked to water competence, past experiences, and fall risk associated with the aquatic environment. Participants identified a strong need for education and increased awareness about aquatic therapy benefits to promote greater engagement. CONCLUSION: Aquatic therapy is a popular exercise choice for people with Parkinson's disease, especially in the early to middle disease stages. Considering the views of people living with Parkinson's disease can aid the design and implementation of interventions and future aquatic research internationally.Implications for RehabilitationAquatic therapy is emerging as an effective physiotherapy approach for managing motor and non-motor symptoms in Parkinson's disease.Little is known regarding community-based aquatic therapy programs from the perspectives of people living with Parkinson's disease internationally.People with Parkinson's disease may benefit from timely information about the unique benefits, prerequisites, and local aquatic therapy facilities to promote greater uptake of aquatic programs.Tailored aquatic therapy interventions delivered within a group setting by a credentialed healthcare professional may increase long-term adherence.

Evidence-Based Aquatic Therapy Guidelines for Parkinson's Disease: An International Consensus Study.

BACKGROUND: Aquatic therapy is one therapy option for people living with Parkinson's disease (PD). However, the optimal prescription, dosage, and delivery remain unclear. OBJECTIVE: i) To generate consensus statements, ii) to establish evidence-based clinical practice aquatic therapy guidelines for PD. METHODS: Seventy-three international experts were invited to participate in a 3-step modified Delphi study. Gaps in the aquatic therapy evidence, patient preferences, and stakeholder engagement were considered when developing the initial list of 43-statements identified by the research development group. Practice experts rated each statement on an 11-point Likert scale. Consensus for inclusion was set at a priori of ≥70% of respondents scoring an item ≥7. Two rounds of Delphi questionnaires were completed online, and the expert comments were analyzed using content analysis. An online consensus meeting with an expert subgroup (n = 10) then advised on the guideline's acceptability and debated items until consensus for inclusion was reached. RESULTS: Fifty experts participated in the Delphi round one (83% response rate) and 45 in round two (90% response rate), representing 15 countries. In round one, 35 statements met the criteria for consensus. Content analysis informed the revised statements in round two, where 12 of the remaining 16 statements met consensus. The final agreed aquatic therapy guidelines include key information about dosage, content, safety, contraindications, and the optimal aquatic therapy delivery throughout the disease course. CONCLUSION: Stakeholders, including international practice experts, informed a rigorous evidence-based approach to integrate the best available evidence, patient preferences, and practice expertise to inform these guidelines.

Challenges in Medicine: The Odyssey of a Patient with Isolated IgG4-Related Eosinophilic Angiocentric Fibrosis Presenting as a Locally Destructive Sinonasal Mass.

Eosinophilic angiocentric fibrosis (EAF) is an exceeding rare clinical entity and is considered a part of the spectrum of IgG4-related disease (IgG4RD). We hereby present such an unusual case of a 60-year-old female who presented to us with recurrent sinonasal mass, after a decade long haul of multiple clinical evaluations, biopsies, and debulking surgery without a definitive diagnosis. Over this period, the mass eroded through the ethmoid cells along with nasal septal destruction leading to saddle nose deformity, extended superiorly through the cribriform plates to right frontal lobe, and compressed the optic nerve leading to visual loss. Although initial biopsy was negative, repeat biopsy was performed owing to high clinical suspicion due to all the classic histopathological findings compatible with the diagnosis of eosinophilic angiocentric fibrosis IgG4-related disease (EAF-IgG4RD). Steroids are the recommended first-line therapy; however, our case was resistant to steroids needing rituximab to halt the disease progression. Our case interestingly also had T-cell clonality and isolated isocitrate dehydrogenase 2 enzyme mutation on next-generation sequencing, suggesting a possible role of novel molecular-targeted therapies in this rare disease. This case highlights the clinical challenges physicians face towards diagnosing and treating EAF-IgG4RD, emphasizing the need for high clinical suspicion and the possible role of targeted therapies for this rare disease.

Non-invasive peripheral focused ultrasound neuromodulation of the celiac plexus ameliorates symptoms in a rat model of inflammatory bowel disease.

NEW FINDINGS: What is the central question of this study? Does peripheral non-invasive focused ultrasound targeted to the celiac plexus improve inflammatory bowel disease? What is the main finding and its importance? Peripheral non-invasive focused ultrasound targeted to the celiac plexus in a rat model of ulcerative colitis improved stool consistency and reduced stool bloodiness, which coincided with a longer and healthier colon than in animals without focused ultrasound treatment. The findings suggest that this novel neuromodulatory technology could serve as a plausible therapeutic approach for improving symptoms of inflammatory bowel disease. ABSTRACT: Individuals suffering from inflammatory bowel disease (IBD) experience significantly diminished quality of life. Here, we aim to stimulate the celiac plexus with non-invasive peripheral focused ultrasound (FUS) to modulate the enteric cholinergic anti-inflammatory pathway. This approach may have clinical utility as an efficacious IBD treatment given the non-invasive and targeted nature of this therapy. We employed the dextran sodium sulfate (DSS) model of colitis, administering lower (5%) and higher (7%) doses to rats in drinking water. FUS on the celiac plexus administered twice a day for 12 consecutive days to rats with severe IBD improved stool consistency scores from 2.2 ± 1 to 1.0 ± 0.0 with peak efficacy on day 5 and maximum reduction in gross bleeding scores from 1.8 ± 0.8 to 0.8 ± 0.8 on day 6. Similar improvements were seen in animals in the low dose DSS group, who received FUS only once daily for 12 days. Moreover, animals in the high dose DSS group receiving FUS twice daily maintained colon length (17.7 ± 2.5 cm), while rats drinking DSS without FUS exhibited marked damage and shortening of the colon (13.8 ± 0.6 cm) as expected. Inflammatory cytokines such as interleukin (IL)-1ß, IL-6, IL-17, tumour necrosis factor-α and interferon-γ were reduced with DSS but coincided with control levels after FUS, which is plausibly due to a loss of colon crypts in the former and healthier crypts in the latter. Lastly, overall, these results suggest non-invasive FUS of peripheral ganglion can deliver precision therapy to improve IBD symptomology.

Adipose-Derived Inflammatory and Coagulant Mediators in Patients With Sepsis.

ABSTRACT: Results from preclinical sepsis studies using rodents are often criticized as not being reproducible in humans. Using a murine model, we previously reported that visceral adipose tissues (VAT) are highly active during the acute inflammatory response, serving as a major source of inflammatory and coagulant mediators. The purpose of this study was to determine whether these findings are recapitulated in patients with sepsis and to evaluate their clinical significance. VAT and plasma were obtained from patients undergoing intra-abdominal operations with noninflammatory conditions (control), local inflammation, or sepsis. In mesenteric and epiploic VAT, gene expression of pro-inflammatory (TNFα, IL-6, IL-1α, IL-1ß) and pro-coagulant (PAI-1, PAI-2, TSP-1, TF) mediators was increased in sepsis compared with control and local inflammation groups. In the omentum, increased expression was limited to IL-1ß, PAI-1, and PAI-2, showing a depot-specific regulation. Histological analyses showed little correlation between cellular infiltration and gene expression, indicating a resident source of these mediators. Notably, a strong correlation between PAI-1 expression in VAT and circulating protein levels was observed, both being positively associated with markers of acute kidney injury (AKI). In another cohort of septic patients stratified by incidence of AKI, circulating PAI-1 levels were higher in those with versus without AKI, thus extending these findings beyond intra-abdominal cases. This study is the first to translate upregulation of VAT mediators in sepsis from mouse to human. Collectively, the data suggest that development of AKI in septic patients is associated with high plasma levels of PAI-1, likely derived from resident cells within VAT.

Spontaneous Rupture of Mesenteric Vasculature Associated with Fibromuscular Dysplasia in a 28-Year-Old Male.

Spontaneous rupture of mesenteric vasculature associated with fibromuscular dysplasia is an unreported phenomenon. We describe a case in a 28-year-old male with a history of chronic abdominal pain who presented to our facility in hemorrhagic shock secondary to a ruptured transverse mesocolon middle colic aneurysm status postemergent transverse colectomy. He was found to have chronic vertebral, renovisceral, and iliac aneurysms as well as acute superior and inferior mesenteric artery dissection and chronic bilateral vertebral artery dissections. He subsequently developed disseminated intravascular coagulopathy, resulting in saddle pulmonary embolus as well as right renal artery and splenic artery thrombosis. Ultimately, the patient expired.

Preliminary evaluation of a novel, fully automated, Telenostic device for rapid field-diagnosis of cattle parasites.

New ideas for diagnostics in clinical parasitology are needed to overcome some of the difficulties experienced in the widespread adoption of detection methods for gastrointestinal parasites in livestock. Here we provide an initial evaluation of the performance of a newly developed automated device (Telenostic) to identify and quantify parasitic elements in fecal samples. This study compared the Telenostic device with the McMaster and Mini-FLOTAC for counting of strongyle eggs in a fecal sample. Three bovine fecal samples were examined, in triplicate, on each of the three fecal egg-counting devices. In addition, both manual (laboratory technician) and automated analysis (image analysis algorithm) were performed on the Telenostic device to calculate fecal egg counts (FEC). Overall, there were consistent egg counts reported across the three devices and calculation methods. The Telenostic device compared very favourably to the Mini-FLOTAC and McMaster. Only in sample C, a significant difference (P < 0.05) was observed between the egg counts obtained by Mini-FLOTAC and by the other methods. From this limited dataset it can be concluded that the Telenostic-automated test is comparable to currently used benchmark FEC methods, while improving the workflow, test turn-around time and not requiring trained laboratory personnel to operate or interpret the results.

IFN-γ and IL-17A regulate intestinal crypt production of CXCL10 in the healthy and inflamed colon.

During intestinal inflammation, immature cells within the intestinal crypt are called upon to replenish lost epithelial cell populations, promote tissue regeneration, and restore barrier integrity. Inflammatory mediators including TH1/TH17-associated cytokines influence tissue health and regenerative processes, yet how these cytokines directly influence the colon crypt epithelium and whether the crypt remains responsive to these cytokines during active damage and repair, remain unclear. Here, using laser-capture microdissection and primary colon organoid culture, we show that the cytokine milieu regulates the ability of the colonic crypt epithelium to participate in proinflammatory signaling. IFN-γ induces the TH1-recruiting, proinflammatory chemokine CXCL10/IP10 in primary murine intestinal crypt epithelium. CXCL10 was also induced in colonic organoids derived from mice with active, experimentally induced colitis, suggesting that the crypt can actively secrete CXCL10 in select cytokine environments during colitis. Colon expression of cxcl10 further increased during infectious and noninfectious colitis in Il17a-/- mice, demonstrating that IL-17A exerts a negative effect on CXCL10 in vivo. Furthermore, IL-17A directly antagonized CXCL10 production in ex vivo organoid cultures derived from healthy murine colons. Interestingly, direct antagonism of CXCL10 was not observed in organoids derived from colitic mouse colons bearing active lesions. These data, highlighting the complex interplay between the cytokine milieu and crypt epithelia, demonstrate proinflammatory chemokines can be induced within the colonic crypt and suggest the crypt remains responsive to cytokine modulation during inflammation.NEW & NOTEWORTHY Upon damage, the intestinal epithelium regenerates to restore barrier function. Here we observe that the local colonic cytokine milieu controls the production of procolitic chemokines within the crypt base and colon crypts remain responsive to cytokines during inflammation. IFN-γ promotes, while IL-17 antagonizes, CXCL10 production in healthy colonic crypts, while responses to cytokines differ in inflamed colon epithelium. These data reveal novel insight into colon crypt responses and inflammation-relevant alterations in signaling.

Is Aquatic Therapy Optimally Prescribed for Parkinson's Disease? A Systematic Review and Meta-Analysis.

BACKGROUND: Aquatic therapy offers an alternative physiotherapy approach to managing the motor and non-motor symptoms associated with Parkinson's disease (PD). OBJECTIVE: This review examined exercise prescription for aquatic therapy in PD and evaluated if aquatic therapy is as effective as land-based physiotherapy for improving movement, disability and wellbeing in people living with PD. METHODS: A systematic search of eight databases was conducted to identify suitable randomized controlled trials from inception until August 2019. Aquatic therapy prescription data and outcomes of interest included gait, balance, motor disability, mobility, falls, mood, cognitive function and health related quality of life data was extracted and synthesised. A meta-analysis was performed where appropriate. RESULTS: Fourteen studies involving 472 participants (Hoehn & Yahr scale I-IV) met the inclusion criteria. Eight were of modest quality, scoring 70-80% on the PEDro scale. Seven studies were included in the meta-analysis. Exercise prescription was highly variable and often insufficiently dosed. Similar gains were shown for aquatic therapy and land exercises for balance, motor disability or quality of life. A statistically significant difference was found for mobility as measured using the TUG (-1.5 s, 95 % CI -2.68 to -0.32; p = 0.01, I2 = 13%), in favor of aquatic therapy. CONCLUSION: Aquatic therapy had positive outcomes for gait, balance and mobility that were comparable to land-based physiotherapy in the early stages of PD. The optimal dosage, content and duration of aquatic interventions for PD could not be confirmed in this meta-analysis. Many trials appeared to be under-dosed and therapy duration was low, ranging from 3-11 weeks.

Atlantic salmon Salmo salar passing a natural barrier before and after construction of a hydroelectric station.

A hydro power plant constructed around a waterfall on a coastal spate river, used the fall as a natural fish pass and applied a previous telemetry study on local Atlantic salmon Salmo salar to determine the abstraction conditions for the site. The current study used the same telemetry approach to monitor the efficacy of S. salar passage and to compare migratory behaviour at the waterfall pre and post the hydro development. The probability of S. salar successfully crossing the waterfall was higher post-hydro when 80% of tagged fish successfully crossed in comparison to the pristine pre-hydro period when 44% of tagged fish ascended. The flow range used by tagged S. salar to cross the waterfall ranged from 2.49-7.87 m3 s-1 in the pre-hydro period but broadened to 1.32-12.91 m3 s-1 during the post-hydro period. This was principally due to the hydro diverting water away from the waterfall during spate conditions, damping the flow across the barrier and facilitating upstream migration within a more suitable discharge range. During 2017-2018 implementation of the hydro-operation protocol elongated the duration of the migratory window for successful upstream migration by 36-128%. A strong diurnal pattern was observed for movements across the Salmon Leap waterfall during both the pre-hydro and post-hydro monitoring periods with most tagged S. salar crossing the complex obstacle in daylight.

Successful Combined Heart and Kidney Transplantation in Patient With Fabry's Disease: A Case Report.

Fabry's disease is a X-linked hereditary disease that causes the accumulation of glycosphingolipids in tissues and organs, including the kidneys and heart. This can result in both chronic kidney disease and cardiac dysfunction, including arrhythmias and heart failure. We describe a case of a 62-year-old male with Fabry's disease undergoing successful combined heart and kidney transplantation for chronic renal failure and low-output systolic heart failure. The patient has normal cardiac function and normal renal function 7 years after transplantation, while being maintained on enzyme replacement therapy with recombinant human alpha-galactosidase A. Fabry's disease is not a contraindication for organ transplantation, even in patients presenting with both renal failure and heart failure.

Assessing the criteria for definition of perimembranous ventricular septal defects in light of the search for consensus.

BACKGROUND: Discussions continue as to whether ventricular septal defects are best categorized according to their right ventricular geography or their borders. This is especially true when considering the perimembranous defect. Our aim, therefore, was to establish the phenotypic feature of the perimembranous defect, and to establish the ease of distinguishing its geographical variants. METHODS AND RESULTS: We assessed unrepaired isolated perimembranous ventricular defects from six historic archives, subcategorizing them using the ICD-11 coding system. We identified 365 defects, of which 94 (26%) were deemed to open centrally, 168 (46%) to open to the outlet, and 84 (23%) to the inlet of the right ventricle, with 19 (5%) being confluent. In all hearts, the unifying phenotypic feature was fibrous continuity between the leaflets of the mitral and tricuspid valves. This was often directly between the valves, but in all instances incorporated continuity through the atrioventricular portion of the membranous septum. In contrast, we observed fibrous continuity between the leaflets of the tricuspid and aortic valves in only 298 (82%) of the specimens. When found, discontinuity most commonly was seen in the outlet and central defects. There were no discrepancies between evaluators in distinguishing the borders, but there was occasional disagreement in determining the right ventricular geography of the defect. CONCLUSIONS: The unifying feature of perimembranous defects, rather than being aortic-to-tricuspid valvar fibrous continuity, is fibrous continuity between the leaflets of the atrioventricular valves. While right ventricular geography is important in classification, it is the borders which are more objectively defined.

DNA damage response genes mark the early transition from colitis to neoplasia in colitis-associated colon cancer.

Chronic intestinal inflammation predisposes patients with Inflammatory Bowel Disease (IBD) to Colitis-Associated Cancer (CAC). In the setting of chronic inflammation, microsatellite instability (MSI) results from early loss of DNA damage response (DDR) genes, ultimately leading to tumor formation. Despite continued efforts to improve early detection of high risk, pre-dysplastic regions in IBD patients, current macroscopic and genetic surveillance modalities remain limited. Therefore, understanding the regulation of key DDR genes in the progression from colitis to cancer may improve molecular surveillance of CAC. To evaluate DDR gene regulation in the transition from colitis to tumorigenesis, we utilized the well-established Azoxymethane/Dextran Sodium Sulfate (AOM/DSS) pre-clinical murine model of CAC in C57BL/6 mice. In order to assess colonic tumor burden in the setting of mutagen and intestinal irritation, tumors were visualized and graded in real time through high-resolution murine colonoscopy. Upon sacrifice, colons were opened and assessed for macroscopic tumor via high magnification surgical lenses (HMSL). Tissues were then sectioned and separated into groups based on the presence or absence of macroscopically visible tumor. Critical DDR genes were evaluated by semi-quantitative RT-PCR. Interestingly, colon tissue with macroscopically visible tumor (MVT) and colon tissue prior to observable tumor (the non-macroscopically visible tumor-developing group, NMVT) were identical in reduced mRNA expression of mlh1, anapc1, and ercc4 relative to colitic mice without mutagen, or those receiving mutagen alone. Colitis alone was sufficient to reduce colonic ercc4 expression when compared to NMVT mice. Therefore, reduced ercc4 expression may mark the early transition to CAC in a pre-clinical model, with expression reduced prior to the onset of observable tumor. Moreover, the expression of select DDR genes inversely correlated with chronicity of inflammatory disease. These data suggest ercc4 expression may define early stages in the progression to CAC.

Association of altered collagen content and lysyl oxidase expression in degenerative mitral valve disease.

BACKGROUND: Collagen cross-linking is mediated by lysyl oxidase (LOX) enzyme in the extracellular matrix (ECM) of mitral valve leaflets. Alterations in collagen content and LOX protein expression in the ECM of degenerative mitral valve may enhance leaflet expansion and disease severity. METHODS: Twenty posterior degenerative mitral valve leaflets from patients with severe mitral regurgitation were obtained at surgery. Five normal posterior mitral valve leaflets procured during autopsy served as controls. Valvular interstitial cells (VICs) density was quantified by immunohistochemistry, collagen Types I and III by picro-sirius red staining and immunohistochemistry, and proteoglycans by alcian blue staining. Protein expression of LOX and its mediator TGFß1 were quantified by immunofluorescence and gene expression by PCR. RESULTS: VIC density was increased, structural Type I collagen density was reduced, while reparative Type III collagen and proteoglycan densities were increased (P<.0001) with an increase in spongiosa layer thickness in myxomatous valves. These changes were associated with a reduction in LOX (P<.0001) and increase in TGFß1 protein expression (P<.0001). However, no significant change was seen in gene expression. Linear regression analysis identified a correlation between Type I collagen density and LOX grade (R2=0.855; P<.0001). CONCLUSIONS: Reduced Type I collagen density with a simultaneous increase in Type III collagen and proteoglycan densities possibly contributes to spongiosa layer expansion resulting in incompetent mitral valve leaflets. Observed changes in Type I and III collagen densities in Degenerative Mitral Valve Disease may be secondary to alterations in LOX protein expression, contributing to disorganization of ECM and disease severity.