Care Cohort Research Articles

The Design of a Data Management System for a Multicenter Palliative Care Cohort Study.

Prospective cohort studies of individuals with serious illness and their family members, such as children receiving palliative care and their parents, pose challenges regarding data management. To describe the design and lessons learned regarding the data management system for the Pediatric Palliative Care Research Network's Shared Data and Research (SHARE) project, a multicenter prospective cohort study of children receiving pediatric palliative care (PPC) and their parents, and to describe important attributes of this system, with specific considerations for the design of future studies. The SHARE study consists of 643 PPC patients and up to two of their parents who enrolled from April 2017 to December 2020 at seven children's hospitals across the United States. Data regarding demographics, patient symptoms, goals of care, and other characteristics were collected directly from parents or patients at 6 timepoints over a 24-month follow-up period and stored electronically in a centralized location. Using medical record numbers, primary collected data was linked to administrative hospitalization data containing diagnostic and procedure codes and other data elements. Important attributes of the data infrastructure include linkage of primary and administrative data; centralized availability of multilingual questionnaires; electronic data collection and storage system; time-stamping of instrument completion; and a separate but connected study administrative database used to track enrollment. Investigators planning future multicenter prospective cohort studies can consider attributes of the data infrastructure we describe when designing their data management system.

Hand osteoarthritis is associated with limitations in paid and unpaid work participation and related societal costs: the HOSTAS cohort

ObjectivesData on work participation impairment and related societal costs for patients with hand osteoarthritis (OA) are scarce. Therefore, we aimed to investigate the association of hand OA with work limitations...

Patient Acceptable Symptom State (PASS) in patients with primary Sjögren's syndrome in daily clinical practice.

To explore Patient Acceptable Symptom State (PASS) in a standard of care cohort of patients with primary Sjögren's syndrome (pSS) and to compare patient characteristics including EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) between PASS and non-PASS groups. All pSS patients fulfilling ACR/EULAR classification criteria from the Registry of Sjögren's Syndrome LongiTudinal (RESULT) cohort, who had available PASS data at baseline were included. Patient-reported outcomes included the PASS question: "Considering all the different ways your disease is affecting you, if you were to stay in this state for the next few months, do you consider your current state satisfactory?"; yes: PASS / no: non-PASS. Of the 278 included pSS patients, 199 (72%) had an acceptable symptom state according to the PASS question, and median ESSPRI was 6 (IQR 4-7). In the PASS group, 118 (59%) patients had an unacceptable symptom state according to ESSPRI (score ≥5). In multivariable regression analyses, ESSPRI and disease duration were independently associated with presence of PASS. The accuracy of ESSPRI to predict PASS was fair (AUC of 0.78). The cut-off point of ESSPRI for presence of PASS with the highest Youden's index was 7.2 (sensitivity 85%, specificity 56%), followed by 5.2 (sensitivity 48%, specificity 90%). The majority of pSS patients reported being in an acceptable symptom state according to the PASS question, despite high ESSPRI scores. In our standard of care cohort, the optimal cut-off point of ESSPRI to predict PASS is different when focusing on sensitivity (±7) or specificity (±5).

Guideline-concordant utilization of magnetic resonance imaging in adults receiving chiropractic manipulative therapy vs other care for radicular low back pain: a retrospective cohort study.

BackgroundLumbar magnetic resonance imaging (LMRI) is often performed early in the course of care, which can be discordant with guidelines for non-serious low back pain. Our primary hypothesis was that adults receiving chiropractic spinal manipulative therapy (CSMT) for incident radicular low back pain (rLBP) would have reduced odds of early LMRI over 6-weeks’ follow-up compared to those receiving other care (a range of medical care, excluding CSMT). As a secondary hypothesis, CSMT recipients were also expected to have reduced odds of LMRI over 6-months’ and 1-years’ follow-up.MethodsA national 84-million-patient health records database including large academic healthcare organizations (TriNetX) was queried for adults age 20–70 with rLBP newly-diagnosed between January 31, 2012 and January 31, 2022. Receipt or non-receipt of CSMT determined cohort allocation. Patients with prior lumbar imaging and serious pathology within 90 days of diagnosis were excluded. Propensity score matching controlled for variables associated with LMRI utilization (e.g., demographics). Odds ratios (ORs) of LMRI over 6-weeks’, 6-months’, and 1-years’ follow-up after rLBP diagnosis were calculated.ResultsAfter matching, there were 12,353 patients per cohort (mean age 50 years, 56% female), with a small but statistically significant reduction in odds of early LMRI in the CSMT compared to other care cohort over 6-weeks’ follow-up (9%, 10%, OR [95% CI] 0.88 [0.81–0.96] P = 0.0046). There was a small but statistically significant increase in odds of LMRI among patients in the CSMT relative to the other care cohort over 6-months’ (12%, 11%, OR [95% CI] 1.10 [1.02–1.19], P < 0.0174) and 1-years’ follow-up (14%, 12%, OR [95% CI] 1.21 [1.13–1.31], P < 0.0001).ConclusionsThese results suggest that patients receiving CSMT for newly-diagnosed rLBP are less likely to receive early LMRI than patients receiving other care. However, CSMT recipients have a small increase in odds of LMRI over the long-term. Both cohorts in this study had a relatively low rate of early LMRI, possibly because the data were derived from academic healthcare organizations. The relationship of these findings to other patient care outcomes and cost should be explored in a future randomized controlled trial.RegistrationOpen Science Framework (https://osf.io/t9myp). Supplementary InformationThe online version contains supplementary material available at 10.1186/s12891-022-05462-y.

Clinical, biochemical, and miRNA profile of subjects with positive screening of primary aldosteronism and nonclassic apparent mineralocorticoid excess.

To identify and characterize clinical and biochemical parameters of subjects with both PA and NCAME conditions (NCAME&PA) and study the miRNA cargo in their urinary extracellular vesicles as potential biomarkers for this novel condition. We performed a cross-sectional study of 206 Chilean adult subjects from a primary care cohort. We measured blood pressure (BP), cortisol (F), cortisone (E), aldosterone, plasma renin activity (PRA), microalbuminuria (MAC), plasma NGAL, MMP9, fractional-potassium-excretion (FEK). Subjects were classified as NCAME&PA, PA, NCAME, essential hypertensives (EH), or healthy controls (CTL). EV-miRNAs were quantified by Taqman-qPCR. We found that 30.6% subjects had an abnormal endocrine phenotype: NCAME&PA (6.8%), PA (11.2%) or NCAME (12.6%), and the prevalence of AHT was 92.9%, 82.6%, and 65%, respectively. NCAME&PA subjects had both lower cortisone (p < 0.05) and lower PRA (p < 0.0001), higher FEK (p = 0.02) and higher MAC (p = 0.01) than EH or CTL. NCAME&PA subjects had also higher NGAL levels than CTL and PA (p < 0.05). Exosome miR-192, miR-133a and miR-21 expression decreased with phenotype severity and correlated with BP and PRA (p < 0.05). We identified adult subjects with a combined condition of NCAME and PA associated with higher BP, increased renal and endothelial damage markers than control and EH. Additionally, we observed a differential expression of a specific miRNAs, suggesting a potential role of these miRNAs associated to this novel combined phenotype.

Long COVID-19 in children: an Italian cohort study

BackgroundLong COVID-19 syndrome is a complex of symptoms that occurs after the acute SARS-CoV-2 infection, in the absence of other possible diagnoses. Studies on Long COVID-19 in pediatric population are scanty and heterogeneous in design, inclusion criteria, outcomes, and follow-up time. The objective of the present study is to assess the prevalence of Long COVID-19 syndrome in a cohort of Italian pediatric primary care patients, observed for a period of time of 8 to 36 weeks from healing. Prevalence was also assessed in a cohort of pediatric patients hospitalized during acute infection.MethodsData concerning 629 primary care patients with previous acute SARS-CoV-2 infection were collected by a questionnaire filled in by Primary Care Pediatrician (PCP). The questionnaire was administrated to patients by 18 PCPs based in 8 different Italian regions from June to August 2021. Data concerning 60 hospitalized patients were also collected by consultation of clinical documents.ResultsCumulative incidence of Long COVID-19 resulted to be 24.3% in primary care patients and 58% in hospitalized patients. The most frequently reported symptoms were abnormal fatigue (7%), neurological (6.8%), and respiratory disorders (6%) for the primary care cohort. Hospitalized patients displayed more frequently psychological symptoms (36.7%), cardiac involvement (23.3%), and respiratory disorders (18.3%). No difference was observed in cumulative incidence in males and females in both cohorts. Previous diseases did not influence the probability to develop Long COVID-19. The prevalence of Long COVID-19 was 46.5% in children who were symptomatic during acute infection and 11.5% in asymptomatic ones. Children aged 0 to 5 years had a greater risk to develop respiratory symptoms, while adolescents (aged 11–16 years) had a greater risk to develop neurological and psychological Long COVID-19 symptoms.ConclusionsOur study demonstrates that Long COVID-19 is a reality in pediatric age and could involve even patients with mild or no acute symptoms. The results stress the importance of monitoring primary care pediatric patients after acute COVID-19 infection and the relevance of vaccination programs in pediatric population, also in order to avoid the consequences of Long COVID-19 syndrome.

Increasing advance directive completion within the 4R oncology model in breast cancer patients prior to surgery in a racially diverse patient population.

e13511 Background: Advance directives (ADs) are an important part of life care planning in patients with cancer. There is a lack of effective interventions that increase AD rates in breast cancer patients prior to surgery. In this quality improvement project, we implemented a 4R Oncology intervention in a community-based cancer center within an integrated health care system. 4R (Right Info / Care / Patient / Time) is a novel care planning and delivery model, which enables patients and care teams to manage complex time-sensitive care with a multi-modality 4R Care Sequence plan, coupled with follow-up workflows. Methods: Patients with newly diagnosed non-metastatic breast cancer who attended a multidisciplinary clinic and underwent definitive surgery at one facility were included in the study. Patients received usual care from 10/1/19 to 9/30/20 (usual care cohort). From 10/1/20 to 9/30/21 (intervention cohort), patients were provided a 4R Care Sequence, which included AD completion prior to surgery, and those without AD were referred for follow-up with a health educator to discuss AD completion. Demographics, NCCN thermometer distress scores, and AD completion rates were compared between the usual care and intervention cohorts using descriptive statistics. Results: Characteristics of age, gender, race/ethnicity, language interpreter usage, Elixhauser Comorbidity Index, NCCN distress scores &gt; 4, surgery type, tumor grade, ER/PR/HER-2 status were similar between the usual care (N=140) and intervention cohorts (N=141). The intervention improved AD completion rates in a time-sensitive fashion prior to surgery between usual care and intervention cohorts, both in total (15% vs 74%, p&lt;.01), and in 3 of the 5 race/ethnicity groups (Table). AD completion rates increased in patients of all races/ethnicities, but increases were not statistically significant for Hispanic patients, likely due to low numbers of these patients in both cohorts. Patients with higher distress scores completed ADs at similar rates to those with lower distress scores. Conclusions: Delivery of 4R Care Sequences, coupled with a health educator follow-up can significantly increase rates of time-sensitive AD completion, regardless of patients’ distress score. Patients across race/ethnicity groups benefited from the intervention, but further efforts are needed to understand the impact of this intervention in patients who are Hispanic. Through an effective care delivery model, patients can be provided with standardized equitable care. [Table: see text]

A multicentre evaluation exploring the impact of an integrated health and social care intervention for the caregivers of ICU survivors

BackgroundCaregivers and family members of Intensive Care Unit (ICU) survivors can face emotional problems following patient discharge from hospital. We aimed to evaluate the impact of a multi-centre integrated health and social care intervention, on caregiver and family member outcomes.MethodsThis study evaluated the impact of the Intensive Care Syndrome: Promoting Independence and Return to Employment (InS:PIRE) programme across 9 sites in Scotland. InS:PIRE is an integrated health and social care intervention. We compared caregivers who attended this programme with a contemporary control group of ICU caregivers (usual care cohort), who did not attend.ResultsThe primary outcome was anxiety measured via the Hospital Anxiety and Depression Scale at 12 months post-hospital discharge. Secondary outcome measures included depression, carer strain and clinical insomnia. A total of 170 caregivers had data available at 12 months for inclusion in this study; 81 caregivers attended the InS:PIRE intervention and completed outcome measures at 12 months post-hospital discharge. In the usual care cohort of caregivers, 89 completed measures. The two cohorts had similar baseline demographics. After adjustment, those caregivers who attended InS:PIRE demonstrated a significant improvement in symptoms of anxiety (OR: 0.42, 95% CI: 0.20–0.89, p = 0.02), carer strain (OR: 0.39; 95% CI: 0.16–0.98 p = 0.04) and clinical insomnia (OR: 0.40; 95% CI: 0.17–0.77 p < 0.001). There was no significant difference in symptoms of depression at 12 months.ConclusionsThis multicentre evaluation has shown that caregivers who attended an integrated health and social care intervention reported improved emotional health and less symptoms of insomnia, 12 months after the delivery of the intervention.

A quarter-century report on neuromyelitis optica spectrum disorder in Thailand: A single-center tertiary care cohort

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune demyelinating astrocytopathy with a high relapse-related disability. This is the largest long-term study of Thai NMOSD patients.Objectives: To compare characteristics and outcomes of aquaporin 4 (AQP4)-IgG-positive and AQP4-IgG-negative patients.Methods: A retrospective review of NMOSD patients at a university hospital was performed from January 1994 to July 2021.Results: From 165 NMSOD patients, the overall female-to-male ratio was 14:1. The mean onset age was 37.5 ± 14.3 years, and the median disease duration was 10.2 years. Transverse myelitis (46.1%) and optic neuritis (39.4%) were the most common presentations. Around 60% remained fully ambulatory at the last follow-up. Severe visual loss and ambulation aids were comparable in both groups, but the AQP4-IgG-positive had severe bowel and/or bladder dysfunction more often than the AQP4-IgG-negative (p = 0.026). The mortality rate was 6.7%, mainly from infection. Multivariate analysis showed that longer time-to-diagnosis and higher disability scores were associated with death. Diagnosis within one year yielded better visual and motor outcomes and lower annualized relapse rate.Conclusions: Thai AQP4-IgG-positive and AQP4-IgG-negative NMOSD patients had similar baseline characteristics. Relapse and mortality rates were comparable to global NMOSD patients. Diagnosis within one year promises better outcomes.

Use of funded multicenter prospective longitudinal databases to inform clinical trials in rare diseases-Examination of cholestatic liver disease in Alagille syndrome.

The conduct of long‐term conventional randomized clinical trials in rare diseases is very difficult, making evidenced‐based drug development problematic. As a result, real‐world data/evidence are being used more frequently to assess new therapeutic approaches in orphan diseases. In this investigation, inclusion and exclusion criteria from a published trial of maralixibat in Alagille syndrome (ALGS, ITCH NCT02057692) were applied to a prospective longitudinal cohort of children with cholestasis (LOGIC NCT00571272) to derive contextual comparator data for evolving clinical trials of intestinal bile acid transport inhibitors in ALGS. A natural history/clinical care cohort of 59 participants who met adapted inclusion and exclusion criteria of ITCH was identified from 252 LOGIC participants with ALGS with their native liver. Frequency weighting was used to match the age distribution of ITCH and yielded a cohort (Alagille Syndrome Natural History [ALGS NH]) that was very similar to the baseline status of ITCH participants. During a 2‐year prospective follow‐up there was a significant reduction in pruritus in the weighted ALGS NH cohort as assessed by the clinician scratch score (−1.43 [0.28] −1.99, −0.87; mean [SEM] 95% confidence interval). During the same time period, the total bilirubin, albumin, and alanine aminotransferase levels were unchanged, whereas platelet count dropped significantly (−65.2 [16.2] −98.3, −32.1). Weighted survival with native liver was 91% at 2 years in the ALGS NH. These investigations provide valuable real‐world data that can serve as contextual comparators to current clinical trials, especially those without control populations, and highlight the value and importance of funded multicenter, prospective, natural history studies.

MO518: Chronic Kidney Disease in Primary Care and the Risk of Cardiovascular Comorbidity and Mortality

Abstract BACKGROUND AND AIMS The prevalence of chronic kidney disease (CKD) is increasing globally. Often, the condition develops silently over time, with no or only a few symptoms in earlier stages. Therefore, early recognition in primary care may have an important role in ensuring diagnosis and proper intervention. We aimed to determine the prevalence and outcome of CKD in a large primary care cohort in Denmark. METHOD We performed an observational cohort study using data from individuals above age 40 followed in primary care in the greater Copenhagen area between 2000 and 2015 and linked them to Danish health registries. A run-in period of 3 months was included to ensure stable conditions and rule out acute changes in eGFR at baseline. The date of the second measurement of eGFR during the study period was considered the subject's index date (baseline). Outcomes were relevant diagnoses such as stroke, myocardial infarction (MI), hospitalisations for heart failure (HHF) and peripheral artery disease (PAD) (last update 2018), all-cause mortality and cardiovascular mortality. Kidney function (eGFR) was estimated by the CKD-EPI formula based on serum creatinine and expressed in mL/min/1.73 m2. Conventional CKD groups are used with CKD 1 and 2 (normal—eGFR &amp;gt; 60 mL/min/1.73 m2) as reference groups for the hazard ratio estimates. Outcomes were presented as the number of events/100 person-years (PY). We conducted survival (all-cause mortality outcome) and competing risk (rest of the outcomes) analyses using the Cox proportional hazards model to calculate the (cause-specific) hazard ratios for the outcomes according to CKD group. We further explored the continuous associations between kidney function and the outcomes examined by using eGFR as a continuous variable with penalised splines. All models were adjusted for known risk factors (age, gender, diabetes, hypertension, existing CVD, heart failure, LDL cholesterol, use of antihypertensive treatment). RESULTS We included a population of 171 133 individuals. As expected, the majority (n = 157002) was in CKD 1 or 2 at the index date, and only a small proportion (0.05%) was in CKD stage 5. In general, event rates were low in CKD stages 1 and 2 and rose with higher stages of CKD. In the adjusted analyses, we observed a stepwise increase in hazard rates for every outcome with every increment in CKD stage (Fig. 1). This was confirmed by the continuous analysis. Compared with CKD stage 1 + 2, individuals in CKD stage 4 had approximately double the hazard rate of PAD, MI, cardiovascular and all-cause mortality. CONCLUSION Our data from a large primary care cohort demonstrate an early increase in risk for adverse outcomes already at CKD stage 3. This provides the basis and underlines the importance of studying early intervention in primary care.

Genesis of Antibiotic Resistance (AR) LXXX: Turbulence Modeling(TM) of Hemodynamics in Simplified Severe Sepsis Protocol‐2 (SSSP‐2)‐NCT01663701: Temporal Correlation of Fluid Bolus, CPPopt(PRx), “Zone of Obstruction”, Comatose (GCS 3), and In‐Hospital Mortality (ihm)

Based on Flow‐3DÒ Hydro FD simulation Model 04 (Courtesy: Flow‐3DÒ) and fluid flow patterns, here we present a plausible scheme of hemodyn. sequel in ERP induced fluid volume expansion, that lead to 100% ihm usual care cohort of SSSP‐2 (PMID: 28973227). Rationale: From the pressure‐volume curve of D ICP vs DCBV (ΔV cm3) of the intracerebral space Figure1. https://cppopt.org/prx/ (PMID: 632857) it is proposed that subsequent to fluid bolus, the patients in usual care and sepsis protocol cohort of SSSP‐2 may have had a good compensatory reserve (part I) within&lt; 24hrs. The exponential part of the curve (part II) would likely represent the patients who have had a poor compensatory reserve with a slow ΔV of the intracerebral space (CBV) that caused a significant change in the ICP in less than ~48 hrs. The cause of 100% ihm in usual care cohort, could be derived as the patients with high CBV and consequently high ICP levels (part III)that lead to cerebral vessels collapse and impairing pressure‐volume relationship implied in impaired positive brain vessel function index possibly by capillary pruning‐string events within ~ 48hrs to ~72 hrs. An increase in CVP, lead to an anaerobic milieu to spur the growth of anaerobic AR‐ClPr (G+/G‐) bacilli merging with “Zone of Obstruction” (ZoO), hitherto DDx, CC/MCC/CCI/DRG, Comorbidity–polypharmacy score (CPS) and ultimately Comatose (GCS 3‐8) (PMID: 31474933). Hemodynamically, when there is an ÝABP/ CPP/CBV the arterioles dilate and hence the CBF, CBV and consequently the ÝICP. Geometry: (Table 2.1 p63, ISBN: 9780128024089). Hemodyn/neurol monitoring parameters:CPPopt, CVP ≥ 8 cm H20, ScVO2 ≤ 70%, GCS 3‐8, and time to event 120 hrs ± 48 hrs. Governing. Equation(s): Dimensional form of Momentum equation (9.10) at the wall u= v=0, considering the pressure gradient dp/dx&lt;0, then [d2u/dy2]y=0=1/μ *dp/dx Eq 9.42; Fig 9.5 Flow separation and formation of wake behind ZoO (LPE Aggregates ‐Toxins of AR‐ClPr origin) form blunt bodies/streamline bodies referred as “ZoO” of unknown dimension; Fig 9.6 velocity distribution within a boundary layer; considered panel a: favorable pressure gradient = dp/dx&lt;0; panel b: APG = dp/dx&gt;0 (p468 – 471; ISBN:13:978‐0071329194). Derivation &amp; Prospect: Subsequent to fluid bolus, within 120 hrs., BLS occurs expediting the ZoO, in metarteriole, capillary bed, and arteriovenous anastomosis doffing off vaso vasorum in turn vasomotion of the limbic region in particular cingulate nuclei, Amygdala, amygdaloid body, thalamic nuclei, parahippocampal gyrus, hypothalamus. Such an increase in CPPopt, and CBV engendered APG, eddies, ZoO, in cerebral pre‐capillary bed followed by a vasoconstriction of capillary sphincters, the collapse of arteriovenous anastomosis, possible occlusion of thoroughfare channel in true capillaries form a cyclical aerobic‐anaerobic milieu in vivo (en vivo) for the growth G+/G‐ AR‐ClPr, in turn spur toxic shock syndrome, CCP to GCS 3 consequential 100% ihm, within 120 hrs. in SSSP‐2.

Genesis of Antibiotic Resistance (AR) LXXXV: Turbulence Modeling(TM) of Hemodynamics in Simplified Severe Sepsis Protocol‐2 (SSSP‐2)‐NCT01663701: Clinical Connotation of Monitoring ISP [BP(PP), MAP, CBF, ICP, CPPopt, Comatose GCS 3, and CCP] for Attenuation of IHM

Based on the theoretical inferences derived from industrial CFD modules: Flow‐3DÒ Hydro FD simulation Model 04; 05_sediment_transport FLOW‐3D HydroÒ, (Courtesy: Flow‐3D HydroÒ), The Beauty of Vortex Streets, May 5, 2021; Curve Fitting of Solution Data in COMSOL Multiphysics®, July 27, 2021 © 2021 BY COMSOL INC., https://earthobservatory.nasa.gov/images/90734/two‐views‐of‐von‐karman‐vortices (NASA). and hemodynamic data (SSSP‐2), here we present a plausible physiological basis for the benefit of monitoring ISP for attenuation 100% ihm in the usual care cohort of SSSP‐2 (PMID: 28973227). Hypothesis &amp; Rationale:Monitoring the ISP‐induced transient APG, eases the point of care clinical intervention for the recovery from GCS3 to homeostasis. Geometry: RBC, WBC, platelets, p47; Whole blood viscosity ~ 3 centipoise (cP) or ~0.003 Pascal second (Pa. s) p53; Blood velocity in the Human Blood Vessels: table 2.1 p63, Blood Vol. Distribution: Table 2.2, p64; Stress–Strain Curve, Fig 2.15 p 78; ISBN:9780128024089. Gov Eq: Segmental Cerebral Perfusion Pressure Equation for The Intracranial Compartment: SPP = Pd − ICP = FFR · CPP − Ge · (1 − FFR) · (ICP − Pe) (PMCID: PMC8032738; PMID: 33833266). Derivation &amp; Prospects:ISP has been shown to induce cerebral hypoperfusion in turn vasogenic edema altering contralateral/ipsilateral CBF due to increased blood flow through the anterior communicating artery (Acom). Case Report (PMCID: PMC7332508; PMID: 32637214): A 72‐year‐old male presented with the right‐sided hemiparesis and underwent MRI. MR imaging show an acute infarction of the left frontal lobe [Figure 1] and bilateral internal carotid artery (ICA) stenosis (NASCET: Rt: 90%, peak systolic velocity 425 cm/s and Lt: NASCET 70%, peak systolic velocity 212 cm/s). After 2 months, SPECT showed an decrease in CBF in the right cerebral hemisphere [Figure 2a]. INVOS‐4100 cerebral oximeter based determination of the effect of carotid clamping and shunting on oxygen saturation (rSO2) showed rSO2 readings were lower than ipsilateral rSO2 readings. SPECT showed a decrease in CBF around the infarction [Figure 2b]. SPECT indicated a contralateral increase in CBF [Figure 2b]. Tx, with free‐radical scavenger(Rx), showed an improvement in CBF, and laterality disappeared 2 weeks after CEA [Figure 2c and d]. The CBF of both sides equaled 2 weeks later [Figure 3]. Subsequent MR imaging with fluid‐attenuated inversion recovery (FLAIR) images showed a local high‐intensity lesion around a previous infarction in comparison with before CEA [Figure 4a and b]. FLAIR MR imaging 2 weeks after initial surgery confirmed the complete disappearance of the high‐intensity lesion [Figure 4c]. Taken together, the focal vasogenic edema induced neurologic impairment is shown to be alleviated by treating edema and cerebral ischemia while monitoring hemodynamic parameters. This model could be applied for the attenuation of fluid bolus augmented VKVS, collapsing of cerebral vessels leading to 100% ihm, in the usual care group in SSSP‐2 (PMID: 28973227).

Beliefs about back pain and associations with clinical outcomes: a primary care cohort study

ObjectiveTo investigate associations between beliefs about low back pain (LBP) at baseline and pain intensity and disability at 2-week, 13-week and 52-week follow-up.DesignObservational cohort study.SettingPrimary care private chiropractic clinics in...

Genesis of Antibiotic Resistance (AR) LXXXIV: Turbulence Modeling(TM) of Hemodynamics in Simplified Severe Sepsis Protocol‐2 (SSSP‐2)‐NCT01663701: ISP Afloat Transient APG Thrust VKVS to Hypoxia Rouse Erythropoiesis penultimate to GCS 3, and IHM

Based on the theoretical inferences from the CFD pertaining to VKVS/vortices/shedding frequency/vortex‐induced vibration/ hysteresis effect, Shed Vortex, and Karman/symmetric vortex shedding, Courtesy: Flow‐3D HydroÒ, COMSOL Multiphysics®, © 2021, NASA‐U.S: https://earthobservatory.nasa.gov/images/85989/canary‐islands‐kick‐up‐von‐karman‐vortices, Harvard Natural Sciences Lecture Demonstrations http://sciencedemonstrations.fas.harv… https://www.youtube.com/watch?v=_Hbbkd2d3H8, Vortex shedding; https://www.youtube.com/watch?v=ahohd8ceGR4, and hemodynamic data from NCT01663701, here we present a plausible physiological basis for the effect of fluid bolus augmented VKVS, eliciting ISP, thrust skewed viscosity/velocity profile in congruence hitherto ISP, which may have been the cause that leads to precipitous ihm in the usual care cohort of SSSP‐2 (PMID: 28973227). Hypothesis:ISP dependent APG elicit spasmodic hypoxia to hyperbolic erythropoiesis penultimate to Comatose (GCS 3) to CCP and ihm in 24 hrs. Geometry: Part I: RBC, Platelets, WBC: detailed geometry of RBC, Platelets, WBC, p47‐56; Part II: Approximate geometry, blood velocity, and function of human blood vessels, Table 2.1; 2,2; 2.3; p63; ISBN 9780128024089; Governing Equation: Segmental Cerebral Perfusion Pressure Equation for The Intracranial Compartment: SPP = Pd − ICP = FFR · CPP − Ge · (1 − FFR) · (ICP − Pe), where, SPP is segmental perfusion pressure for the intracranial compartment, Pd—intracranial inflow pressure, ICP—intracranial pressure, Pa—systemic arterial pressure, FFR—Pd/Pa is the fractional flow reserve of the common inflow, CPP=Pa–ICP is cerebral perfusion pressure, Ge is the ratio of extracranial vascular conductance to total (intra‐extracranial) vascular conductance, and Pe is extracranial outflow pressure. (PMCID: PMC8032738; PMID: 33833266). Derivation and Prospects (Physiological Connotation): Earlier we have illustrated the resuscitation (of fluid bolus) induced fluid volume expansion evoked APG exert low shear force on cerebral arterial, endothelium engendering a pro‐thrombotic milieu (vasoconstrictive) (PMID: 17699225), enhancing the ZoO. Such conditions may impart a mechanical trauma to the RBC/WBC/platelets as a function of time in a flow ‐dependent shear forces (PMID: 19033138) evoking turbulence (Recrit= 2000) and increased stress on RBC (PMID: 27048168). Steal mechanism (hypoperfusion) (PMID: 23396797) can induce oscillating acute or chronic ischemia eliciting HIF‐1 in turn erythropoietin production and erythropoiesis (PMPMID: 26927670). As a function of time, such altering blood viscosity dependent velocity pattern in the upstream of the ZoO – blunt‐body/streamline bodies, possibly rupture and cause cerebral hemorrhage (CVA!). Taken together, it is suggested that aforesaid in vivo milieu would likely to be the cause for ihm in less than 24 hrs. in the usual care cohort of NCT01663701. Efforts are in progress to understand the rupturing mechanism(s).

Genesis of Antibiotic Resistance (AR) LXXXIII: Turbulence Modeling(TM) of Hemodynamics in Simplified Severe Sepsis Protocol‐2 (SSSP‐2)‐NCT01663701: Mechanism(S) of Von Kármán Vortex Street Induced Aberrant Velocity Pattern (Dean Number) Spur In Hospital Mortality (ihm)

Based on Flow‐3DÒ Hydro FD simulation Model 04; 05_sediment_transport FLOW‐3D HydroÒ, (Courtesy: Flow‐3D HydroÒ), and clinical hemodynamic data (&amp; derived) from SSSP‐2 trial, here we present a plausible physiological basis for the effect of fluid bolus augmented Von Kármán Vortex Street, thrust velocity profile which may have been the cause that leads to 100% ihm usual care cohort of SSSP‐2 (PMID: 28973227). Hypothesis:Fluid bolus‐induced fluid volume expansion causes the cerebral vessel collapse by a secondary flow of fluid moving away from the vessel wall (boundary layer separation). Rationale:The Dean number (De) is the ratio of the viscous force on the fluid flowing in a curved pipe to the centrifugal force. When the fluid flow fails to develop at the inlet, a possible vortex in the core of the fluid could incur velocity skewing towards the inner wall of the curve. However, if the fluid flow is fully developed the velocity skewing could be toward the outer wall. A secondary flow may develop as a counter‐rotating vortices in the center of the tube tending the flow to move towards the outer side which could be separated by high De along the inner wall. Pulsatile flow is also known to induce secondary flow through the curvature of blood vessels by three possible types of velocities formed by the fluid flow namely a. axial velocity(nz), b. radial velocity(nr), c. angular velocity(nq). Geometry: Approximate geometry, blood velocity and function of human blood vessels, Table 2.1 p63; BP range in systemic and pulmonary circulation vessels for a normal adult, Table 2.3, p64. ISBN 978012802408‐9. Governing Equation: Part A: Dean Number (De) is the ratio of viscous force on a fluid flowing in a curved pipe to the centrifugal force. The De for a channel or curved pipe is defined as: De=Re ·√Dh/2R, where Re = Reynolds number, Dh = hydraulic diameter (m), R=radius of the curvature of the pipe (m) (p18, Equation: 1.21). Derivation:Based on the hemodynamic parameters (BP, MAP, PP, RR, JVP, SAPS‐3 score, of SSSP‐2 (PMID: 28973227), baseline characteristics of patients (Table 1, p1237) and elements of fluid resuscitation (Table 2, p1238), it is suggested that blood vessel outlet with low De, likely to have fluid flow pattern shown in Fig 2.12 panel 2, within 6hrs after the ERP‐Fluid bolus in usual care and SSSP‐2 protocol cohort. However, after 6 hrs. fluid flow patterns in the vessel outlet of usual care, with high De as presented in Fig 2.12, panel 3. Prospects:Taken together, an increase in von Kármán vortex street in turn, caused an increase in ZoO, stalling of the fluid flow, the consequent increase in pressure at the upstream of ZoO, compared to that of downstream causing a burst in cerebral arteries and in turn ihm. A clinical correlation defines, aforesaid state as “distal ischemic steal syndrome (ISS), caused by a substantial decrease or even reversal of blood flow (“steal”) through the cerebral arteries. Such clinical manifestation may have been the cause for the increase in CPPopt resulting in a 100% ihmin usual care.

Genesis of Antibiotic Resistance (AR) LXXXVI: Turbulence Modeling(TM) of Hemodynamics in Simplified Severe Sepsis Protocol‐2 (SSSP‐2)‐NCT01663701: Mechanism(s) of ISP Afloat Transient APG Thrust VKVS free shear flow augmented cerebral vessel collapse, GCS3, &amp; IHM

Based on the theoretical inferences from the CFD pertaining to VKVS/vortices/shedding frequency/vortex‐induced vibration/ hysteresis effect, Shed Vortex, and Karman/symmetric vortex shedding, Courtesy: Flow‐3D HydroÒ, COMSOL Multiphysics®, © 2021, NASA‐U.S: https://earthobservatory.nasa.gov/images/85989/canary‐islands‐kick‐up‐von‐karman‐vortices, Harvard Natural Sciences Lecture Demonstrations http://sciencedemonstrations.fas.harv… https://www.youtube.com/watch?v=_Hbbkd2d3H8, Vortex shedding; https://www.youtube.com/watch?v=ahohd8ceGR4, and hemodynamic data from NCT01663701, here we present a plausible physiological basis for the effect of fluid bolus augmented VKVS, eliciting ISP, thrust skewed viscosity/velocity profile rupturing and cause the cerebral hemorrhage, that leads to precipitous ihm in the usual care cohort of SSSP‐2 (PMID: 28973227). Hypothesis:Fluid bolus augmented VKVS augment incompressible free shear flows in cerebral arteries ensue decomposition of glycocalyx/endothelium as a function of time, viscosity and velocity profiles. Geometry:RBC, WBC, platelets, p47; p53; Table 2.1 p63, Table 2.2, p64; Fig 2.15 p 78; ISBN:9780128024089. Governing Equation, Derivation and Prospects (Physiological Connotation): Subsequent to fluid bolus induced fluid volume expansion is a function altered viscosity (hematocrit) dependent velocity profile as a function of time augment five different free shear flow: a. far wake, downstream of ZoO, b. mixing layer, downstream of ZoO occurring between two parallel streams with different velocity profile, c. plane jet, d. round jet, occur downstream of ZoO, and e. constrained radial jet, occur when two jets of similar velocity profile, (possibly different viscosity) in a turbulent flow; Assumptions based on the hemodynamic data from NCT016637001: I. Aforesaid free shear flow has self‐similarity, self‐preserving; Velocity component: Equation, 3.22; II. two velocity profiles located downstream at locations x1 and x2 are not same: equation, U (x, y)/uo(x) [or (U‐U (x, y)/U0(x) for the wake); III. Boundary layer approximations are not valid for aforesaid free shear flows, IV. molecular transport momentum differs at different location; V: pressure not the same thought vessels, VI: no continuity (equation of motion refer equation 3.23; 3.24; VII: closure coefficient differs for different points in the cerebral/ coronary circulation, applicable governing equations for the eddy‐viscosity model, Eq:3.25, p60‐61; ISBN‐13: 978‐1928729082. Taken together, fluid bolus induced fluid volume expansion augment cyclical anaerobic/aerobic milieu conferring altered generation time(G): G=t/n, where time (t) per generation (n = number of generations) for ClPr exacerbating toxic shock expedite irreversible loss of vasculature penultimate ihm in usual care group of NCT01663701.

Genesis of Antibiotic Resistance (AR) LXXXII: Turbulence Modeling(TM) of Hemodynamics in Simplified Severe Sepsis Protocol‐2 (SSSP‐2)‐NCT01663701: The “Von Kármán Vortex Street” (Vasospasm probability index(VPI)) Fillip Zone of Obstruction Consequent Comatose to ihm

Based on Flow‐3DÒ Hydro FD simulation Model 04 (Courtesy: Flow‐3DÒ), clinical data for spontaneous subarachnoid hemorrhage (SAH) and flow gauge, here we present a plausible physiological basis for fluid bolus induced alteration of velocity profile with a fluid volume expansion, that leads to 100% ihm usual care cohort of SSSP‐2 (PMID: 28973227). Subsequent to SAH, an increase in blood flow velocity in cerebral arteries has been observed. The blood flow velocity after SAH was observed to be between 73 and 215 cm/sec (the frequency range of the pure tones: 140 to 820 Hz). The murmurs occurred after SAH has been suggested to be a transitional state between silent flow(laminar) and the phenomenon of bruit (DDx: Carotid Artery Stenosis, carotid cavernous fistula, fibromuscular dysplasia, Takayasu’s arteries, arteriovenous fistula). The cause of the murmur has been suggested to be periodic shedding of vortices in the cerebral arteries, referred to as “a von Kármán vortex street”.Murmurs are an indication of a pathological increase in blood velocities to reflect the degree of spasm(vascular) (PMID: 6689725). VPI, is a combination of transcranial Doppler(TCD) velocities, cerebral blood flow, and clinical risk factors to predict cerebral vasospasm after aneurysmal SAH (PMID: 18077946). Geometry: Lindegaard ratios and spasm indexes (TCD velocities/hemispheric CBF) to evaluate the probability of cerebral vasospasm after aneurysmal SAH. An increase in blood flow velocity (BFV) is the principal criterion for vasospasm. The Middle Cerebral Artery (MCA) /internal carotid artery (ICA) index (Lindegaard Index) is used to distinguish between vasospasm and cerebral hyperperfusion. The intracranial arteriovenous index (AVI) is used to assess vasospasm after SAH. (PMID 29243981). CPP=MAP‐ICP. The blood flow rate in carotid arteries, Table 4.14 p172, ISBN 9780128024089. Governing Equation:Part A: Strouhal number (St): This formula will generally hold true for the range 250 &lt; Red &lt; 200000: St=0.198 (1‐19.7/Red); where St=fd/U, f = vortex shedding frequency, d = diameter of the cylinder, U = flow velocity.Part B: To calculate pressure drop in cylindrical pipe Poiseuille Equation (Hagen‐Poiseuille Eq): Vmax= DPR2 / 4μL, (Eq 1.47, p32) where DP= pressure difference between the two ends, μ = dynamic viscosity, L= length of the pipe, Q= volumetric flow rate, π = 22/7 @3.14, R= pipe radius. For volumetric flow rate (Q) equals cross‐section area multiplied by velocity (Q=ṼA), so DP=8μL/πR4. To represent pressure drop and flow rate in cerebral arteries Poiseuille’s equation is written as Q=DP π R4/ 8ηL where η = viscosity. Derivation and Prospect:Taken together, direct correlation of S&amp;SX of SSSP‐2 (NCT01663701), that subsequent to the fluid bolus, the usual care cohort of SSSP‐2, may have had SAH within 24 to 48 hrs. During that period the LPE aggregates‐toxins of AR‐ClPrs origin forming the ZoO with a concurrent increase ICP, CBF, CBV, PRx, CPPopt, may have caused the cerebral vessel collapse eliciting CCP followed by 100% ihm.

Genesis of Antibiotic Resistance (AR) LXXXVII: Turbulence Modeling(TM) of Hemodynamics in Simplified Severe Sepsis Protocol‐2 (SSSP‐2)‐NCT01663701: Fluid bolus evoked fluid volume expansion Augmented APG, VSF, reprobate to inviscid fluid (Fluid Stalling, Re=∞; viscosity=0) augment IHM

Based on the theoretical inferences derived from industrial CFD modules, and hemodynamic data (SSSP‐2), here we present a plausible physiological basis for the benefit of monitoring ISP for attenuation 100% ihm in the usual care cohort of SSSP‐2 (PMID: 28973227). Hypothesis: ISP‐ and APG‐dependent vortex shedding frequency(VSF) lead to stalling of blood flow augment rapid onset of mortality by rupturing of cerebral vessels. Rationale: Impact of form drag on streamline bodies. Geometry: Part I: RBC, Platelets, WBC: detailed geometry of RBC, Platelets, WBC, p47‐56; Part II: Apr. Geo:, blood velocity, and function of human blood vessels, Table 2.1; 2,2; 2.3; p63; ISBN 9780128024089; Gov. Eq(s): Part A:Strouhal Number= St = fwD/V, where D is the characteristic length of Leucocyte, platelets, red blood cells (Bluff bodies @LPE –ZoO), fs=Vortex Shedding frequency, V=flow velocity; Part B: Drag Coefficient: Cd= 2Fd / ρu2A, where Fd is drag force‐velocity in the direction of flow, ρ = density of the fluid (blood @ hematocrit), u = flow speed, A=surface area of the vortices; Part C: Euler Equation with an assumption of inviscid, unsteady &amp; irrotational flow: dP/ρ + ½ d (∇f2)+gdz=‐d(∂f/∂t), this eq for unsteady flow along streamline; where V=velocity elements; ∇, Del = gradient operator. Derivation from Eq 4.5 through 4.12, eq.4.9 is modified to yield eq. 4.12. (p187, ISBN: 9780071329194). CFD Simulations acknowledged with utmost gratitude and appreciation: Part I: Von Karman vortex street, by DolfynNet; https://www.youtube.com/watch?v=IDeGDFZSYo8&amp;feature=youtu.be; https://youtu.be/f3LmjJ1N7YE; Part II: streamlines for 2 square obstructions by slffea CFD simulation of 2 square obstructions with streamlines (Source Ack: SLFCFD. https://www.youtube.com/watch?v=‐njBmpInmcU; Part III: Path lines for 2 square obstructions, Re = 1000. SLFCFD. https://www.youtube.com/watch?v=eAmJ4KOBVMQ; Part IV: Point Vortex Dynamics, https://www.youtube.com/watch?v=QiieaJFjQwM; Part V: Vortex Breakdown, FERGUL ‐ Fluids Engineering Research Group at the University of Liverpool. https://www.youtube.com/watch?v=b0TylIqcEsQ; Phys. Fluids 26, 053602 (2014); Part VI: CFD tutorial for Vortex Shedding, https://www.youtube.com/watch?v=cfjEMa2teVM; Derivation &amp; Prospects:Taken together, the shear stress generated by VKVS@VSF, where velocity vector of the outside is upward and the opposite side is downward in a circular motion. ZoO vortices on the outside will be lifted up (upwash) and another side will be pushed down (downwash) of vortices past bluff bodies/ streamline bodies (ZoO vortices@LPE Aggregates‐Toxins of ClPr origin) with minimum effort ultimately degrade/rupture the glycocalyx‐endothelial surface downstream of the point of obstruction forming cerebral ischemia subsequently vasogenic edema stalling the flow. (PMID: 28973227). Such scenario may have been causing the rupture of cerebral arteries in turn hemorrhage, and irreversible loss of function, to CEP 100% ihm, in the usual care group in SSSP‐2 (PMID: 28973227).

PD01-09 PROTEOGENOMIC AND CLINICAL IMPLICATIONS OF RECURRENT SPLICE VARIANTS IN CLEAR CELL RENAL CELL CARCINOMA

You have accessJournal of UrologyCME1 May 2022PD01-09 PROTEOGENOMIC AND CLINICAL IMPLICATIONS OF RECURRENT SPLICE VARIANTS IN CLEAR CELL RENAL CELL CARCINOMA Andrew Chang, Paul Stewart, Nicholas Chakiryan, Alex Soupir, Yijun Tian, Dongliang Du, Jamie Teer, Youngchul Kim, Philippe Spiess, Jad Chahoud, Yonghong Zhang, John Koomen, Anders Berglund, Timothy Robinson, Liang Wang, and Brandon Manley Andrew ChangAndrew Chang More articles by this author , Paul StewartPaul Stewart More articles by this author , Nicholas ChakiryanNicholas Chakiryan More articles by this author , Alex SoupirAlex Soupir More articles by this author , Yijun TianYijun Tian More articles by this author , Dongliang DuDongliang Du More articles by this author , Jamie TeerJamie Teer More articles by this author , Youngchul KimYoungchul Kim More articles by this author , Philippe SpiessPhilippe Spiess More articles by this author , Jad ChahoudJad Chahoud More articles by this author , Yonghong ZhangYonghong Zhang More articles by this author , John KoomenJohn Koomen More articles by this author , Anders BerglundAnders Berglund More articles by this author , Timothy RobinsonTimothy Robinson More articles by this author , Liang WangLiang Wang More articles by this author , and Brandon ManleyBrandon Manley More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002516.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Alternative mRNA splicing is recognized as a key driver of proteomic diversity. In cancer, this splicing process can be altered resulting in generation of aberrant splice variants (SvPs) that can contribute to tumor pathogenesis. However, our understanding of the significance of aberrant SvPs in clear cell renal cell carcinoma (ccRCC) is currently limited. Given the lack of actionable genomic mutations in ccRCC, aberrant SpVs may be the avenue to new pathogenic mechanisms and biomarkers. METHODS: We implemented a novel pipeline to screen for and select SpVs frequent in and relatively specific to ccRCC. We started with RNA-seq data from the Cancer Cell Line Encyclopedia to identify SpVs specific to ccRCC cell lines. These were screened across normal tissue in the Genotype-Tissue Expression Project and excluded if expressed. We analyzed bulk RNA-seq data of ccRCC primary tumors obtained from our institutional Total Cancer Care cohort (TCC; n=111), The Cancer Genome Atlas (TCGA; n=484) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC; n = 110) to analyze SpV expression in these samples. Using raw proteomics files from the CPTAC portal, proteins were identified and quantified using MaxQuant. Associations of SvP with protein expression were filtered by a Spearman correlation cutoff of +/-0.3. The Enrichr R library was used for pathway enrichment. Finally, we correlated SpV expression with overall (OS) and cancer-specific survival (CSS). Using LASSO Cox regression analysis, we derived a SpV-based risk score trained on OS from the TCGA cohort and validated on the TCC and CPTAC cohorts. RESULTS: Our pipeline selected 16 previously uncharacterized SpVs, including variants of suspected oncogenes and tumor suppressors. Proteogenomic analysis identified interesting biological associations. Among patients with high levels of EGFR SpV, we found significantly higher expression of the protein regulatory T cell marker CD70 (padj=0.03). MVK SvP was highly correlated with 25 proteins enriched for the mTOR pathway (padj=0.002). We derived a survival risk score based on expression of 5 SpVs (PDZD2, COBLL1, PTPN14, RNASET2, FGD1) in the TCGA cohort. This risk score remained significant on multivariate analysis (HR 1.4, p=0.002) adjusting for covariates including AJCC stage. This was validated on multivariate analysis in the TCC (HR 3.56, p<0.001) and CPTAC (HR 3.18, p=0.019) cohorts. CONCLUSIONS: Our novel pipeline selected 16 unique SpVs frequent in and relatively specific for ccRCC. Some are associated with proteins expressed in oncogenic pathways, suggesting a potential role in disease pathogenesis. Additionally, our SpV-based risk score is strongly associated with OS and CSS across multiple cohorts. This study provides a template for identifying and characterizing disease-specific aberrant SpVs to aid discovery of new mechanisms and biomarkers. Source of Funding: Kidney Cancer Association Young Investigator Award © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e33 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Andrew Chang More articles by this author Paul Stewart More articles by this author Nicholas Chakiryan More articles by this author Alex Soupir More articles by this author Yijun Tian More articles by this author Dongliang Du More articles by this author Jamie Teer More articles by this author Youngchul Kim More articles by this author Philippe Spiess More articles by this author Jad Chahoud More articles by this author Yonghong Zhang More articles by this author John Koomen More articles by this author Anders Berglund More articles by this author Timothy Robinson More articles by this author Liang Wang More articles by this author Brandon Manley More articles by this author Expand All Advertisement PDF DownloadLoading ...