Untreated Cohort Research Articles

Multi-Omics Reveals Mechanisms of Partial Modulation of COVID-19 Dysregulation by Glucocorticoid Treatment.

Treatments for COVID-19 infections have improved dramatically since the beginning of the pandemic, and glucocorticoids have been a key tool in improving mortality rates. The UK’s National Institute for Health and Care Excellence guidance is for treatment to be targeted only at those requiring oxygen supplementation, however, and the interactions between glucocorticoids and COVID-19 are not completely understood. In this work, a multi-omic analysis of 98 inpatient-recruited participants was performed by quantitative metabolomics (using targeted liquid chromatography-mass spectrometry) and data-independent acquisition proteomics. Both ‘omics datasets were analysed for statistically significant features and pathways differentiating participants whose treatment regimens did or did not include glucocorticoids. Metabolomic differences in glucocorticoid-treated patients included the modulation of cortisol and bile acid concentrations in serum, but no alleviation of serum dyslipidemia or increased amino acid concentrations (including tyrosine and arginine) in the glucocorticoid-treated cohort relative to the untreated cohort. Proteomic pathway analysis indicated neutrophil and platelet degranulation as influenced by glucocorticoid treatment. These results are in keeping with the key role of platelet-associated pathways and neutrophils in COVID-19 pathogenesis and provide opportunity for further understanding of glucocorticoid action. The findings also, however, highlight that glucocorticoids are not fully effective across the wide range of ‘omics dysregulation caused by COVID-19 infections.

Effectiveness of Subcutaneous Casirivimab and Imdevimab in Ambulatory Patients with COVID-19.

IntroductionData on real-world effectiveness of subcutaneous (SC) casirivimab and imdevimab (CAS+IMD) for the treatment of coronavirus disease 2019 (COVID-19) are limited. The objective of this study was to assess the effectiveness of SC CAS+IMD versus no antibody treatment among patients with COVID-19.MethodsThis retrospective cohort study linked Komodo Health and CDR Maguire Health and Medical data. Patients diagnosed with COVID-19 in ambulatory settings (August 1–October 30, 2021) treated with SC CAS+IMD were exact- and propensity score-matched to fewer than five untreated treatment-eligible patients and followed for the composite endpoint of 30-day all-cause mortality or COVID-19-related hospitalization. Kaplan–Meier estimators were used to calculate outcome risk overall and across subgroups. Cox proportional-hazards models were used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI).ResultsOf 13,522 patients treated with CAS+IMD, 12,972 were matched to 41,848 untreated patients. The 30-day composite outcome risk was 1.9% (95% CI 1.7–2.2) and 4.4% (95% CI 4.2–4.6) in the treated and untreated cohorts, respectively; treated patients had a 49% lower relative risk of the composite outcome (aHR 0.51; 95% CI 0.46–0.58) and a 67% relative risk of 30-day mortality (aHR 0.33, 95% CI 0.18–0.60). Effectiveness was consistent across vaccination status and various subgroups.DiscussionPatients with COVID-19 benefitted from treatment with SC CAS+IMD versus untreated patients. The results were consistent across subgroups of patients, including older adults, immunocompromised patients, and patients vaccinated against COVID-19. Results were robust across numerous sensitivity analyses.ConclusionSC CAS+IMD is effective in reducing 30-day COVID-19-related hospitalization or mortality in real-world outpatient settings during the Delta-dominant period.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-022-00691-z.

Comparison of gait patterns in cerebral palsy between a treated and untreated cohort

Comparison of gait patterns in cerebral palsy between a treated and untreated cohort

Association of Chinese herbal medicine use with the depression risk among the long-term breast cancer survivors: A longitudinal follow-up study.

Breast cancer patients are at elevated risk of depression during treatment, thus provoking the chance of poor clinical outcomes. This retrospective cohort study aimed to investigate whether integrating Chinese herbal medicines citation(CHM) into conventional cancer therapy could decrease the risk of depression in the long-term breast cancer survivors. A cohort of patients aged 20-70 years and with newly diagnosed breast cancer during 2000-2008 was identified from a nationwide claims database. In this study, we focused solely on survivors of breast cancer at least1 year after diagnosis. After one-to-one matching for age, sex, and baseline comorbidities, breast cancer patients who received (n = 1,450) and did not receive (n = 1,450) CHM treatment were enrolled. The incidence rate and hazard ratio citation(HR) for depression between the two groups was estimated at the end of 2012. A Cox proportional hazard model was constructed to examine the impact of the CHM use on the risk of depression. During the study period, the incidence rate of depression was significantly lower in the treated cohort than in the untreated cohort [8.57 compared with 11.01 per 1,000 person-years citation(PYs)], and the adjusted HR remained significant at 0.74 (95% CI 0.58-0.94) in a Cox proportional hazards regression model. The corresponding risk further decreasing to 43% among those using CHM for more than 1 year. Finding from this investigation indicated that the lower risk of depression observed in breast cancer patients treated with CHM, suggesting that CHM treatment should be considered for disease management toward breast cancer. Yet, the optimal administered dose should be determined in further clinical trials.

Antiviral Therapy for Chronic Hepatitis B Infection Improves Outcomes After Total Hip Arthroplasty: A Multicenter Retrospective Study

BackgroundPrevious studies have shown that chronic hepatitis B virus (HBV) infection may place patients at increased risk of postoperative adverse events. However, there is limited information on the effects of antiviral treatment (AVT) on postoperative outcomes following total hip arthroplasties (THAs). MethodsA multicenter retrospective database query was used to identify patients infected with HBV undergoing THAs between 2012 and 2017. All eligible patients were divided into 2 cohorts on the basis of AVT before surgery: the treated group and the untreated group. The treated cohort was matched at a ratio of 1:3 to the untreated cohort by propensity score matching. Operating times, blood losses, all-type complications, surgical complications, lengths of stay, 90-day readmissions, unplanned reoperations, and implant revisions were compared between the 2 cohorts. After these patients were further stratified by liver fibrosis status, multivariate logistic analyses were performed by controlling for differences in demographics and comorbidities. In total, 918 patients chronically infected with HBV were identified. Over four-fifths of these patients (83.0%) did not receive preoperative AVT. Of interest, more than half of the untreated patients (54.1%) were previously undiagnosed. ResultsThe untreated group had significantly longer mean operating time (82 versus 76 minutes, P = .007) and higher mean blood loss (515 versus 465 mL, P = .03) than the treated group. Moreover, they were more prone to experiencing surgical complications (25.4% versus 16.7%, P = .01), longer lengths of stay (6.2 versus 5.4 days, P = .0005), readmissions (12.4% versus 5.8%, P = .02), reoperations (16.7% versus 9.6%, P = .03), and revisions (11.1% versus 4.5%, P = .02). Multivariate regression analyses found that AVT significantly decreased all-type complications, reoperations, and revisions in patients with significant fibrosis (all P < .05). ConclusionThe AVT of HBV infection prior to THAs could reduce the risk of developing postoperative complications, regardless of the presence of liver fibrosis. This finding emphasizes that surgeons should recommend HBV screening and treatment integrated into preoperative medical optimization.

Spatially resolved proteomic profiling identifies tumor cell CD44 as a biomarker associated with sensitivity to PD-1 axis blockade in advanced non-small-cell lung cancer

BackgroundMost patients with advanced non-small-cell lung cancer (NSCLC) fail to derive significant benefit from programmed cell death protein-1 (PD-1) axis blockade, and new biomarkers of response are needed. In this...

Effects of Surgical Treatment for Obstructive Sleep Apnea on Renal and Survival Outcomes in Patients with Chronic Kidney Disease: A Taiwanese Nationwide Cohort Study.

The association between surgical treatment for obstructive sleep apnea (OSA) in chronic kidney disease (CKD) patients and end-stage renal disease (ESRD) and survival outcomes is not established, and this study aimed to evaluate this association. A retrospective cohort analysis was conducted from 2001 to 2015, including 32,220 eligible CKD patients with incident OSA. By 1:3 propensity score matching, 1078 CKD patients with incident OSA who received surgery (treated cohort) and 3234 untreated cohort who never received surgery were analyzed. The risk of ESRD in the competing mortality was significantly lower in the treated cohort than in the untreated cohort, with an adjusted hazard ratio (aHR) of 0.38 (95% confidence interval (CI0, 0.15–0.97; p = 0.043). In addition, the adjusted HRs of overall, cardiovascular, and non-cardiovascular mortality in the treated and untreated cohorts were 2.54 (95% CI, 1.79–3.59; p < 0.0001), 1.46 (95% CI, 0.29–7.22; p = 0.64), and 2.62 (95% CI, 1.83–3.75; p < 0.0001), respectively. Furthermore, the risks of overall and non-cardiovascular mortality for the treated cohort primarily occurred during a 3-month follow-up. In conclusion, surgical treatment for incident OSA in CKD patients was associated with decreased ESRD risk, but with increased non-cardiovascular mortality risk, especially within 3 months after surgical treatment.

Association between Anti-Hepatitis C Viral Intervention Therapy and Risk of Sjögren's Syndrome: A National Retrospective Analysis.

Hepatitis C virus (HCV) infection is a potential risk factor for Sjögren’s syndrome (SS). However, it is unclear whether anti-HCV intervention therapy could decrease SS risk. A retrospective cohort analysis from 1997–2012 comprising 17,166 eligible HCV-infected adults was conducted. By 1:2 propensity score matching, a total of 2123 treated patients and 4246 untreated patients were subjected to analysis. The incidence rates and risks of SS and death were evaluated through to the end of 2012. In a total follow-up of 36,906 person-years, 177 (2.8%) patients developed SS, and 522 (8.2%) died during the study period. The incidence rates of SS for the treated and untreated cohorts were 5.3 vs. 4.7/1000 person-years, and those of death for the treated and untreated cohorts were 10.0 vs. 14.8/1000 person-years. A lower risk of death (adjusted hazard ratio, 0.68; 95% CI, 0.53–0.87) was present in HCV-infected patients receiving anti-HCV therapy in multivariable Cox regression, and this remained consistent in multivariable stratified analysis. However, there were no relationships between anti-HCV therapy and its therapeutic duration, and SS risk in multivariable Cox regression. In conclusion, anti-HCV intervention therapy was not associated with lower SS risk in HCV-infected patients, but associated with lower death risk.

Healthcare Resource Utilization and Direct Cost of Patients with Atopic Dermatitis in Dubai, United Arab Emirates: A Retrospective Cohort Study.

IntroductionAtopic dermatitis (AD) data are scarce in Dubai [United Arab Emirates (UAE)]. Therefore, this study aimed at understanding real-world healthcare resource utilization (HCRU) and related costs, specialties, treatment landscape, consultation-based prevalence and incidence, and patient characteristics.MethodsThis retrospective, longitudinal, insurance e-claims (Dubai Private Insurance—insured expatriates) database studied AD in Dubai between 1 January 2014 and 31 March 2020. Two cohorts of patients based on treatment status as the eligibility criteria were selected from 442,956 patients with at least two AD diagnosis claims: treated AD [mild to moderate (10,134 patients) and moderate to severe (3515 patients)] and untreated or on drugs not included in the treated AD cohort (10,806 patients).ResultsAcross treated AD (mild to moderate and moderate to severe) and untreated AD cohorts, mean age was ~ 29 years; the majority were from dermatology (65–44%) and pediatrics (29–32%) specialty. Key HCRU cost contributors were hospitalizations and outpatient visits in both the treated AD groups. Mean annual disease-specific HCRU cost per patient was highest for the moderate-to-severe treated (531.5 USD) cohort, followed by the mild-to-moderate treated (378.4 USD) cohort, and lowest for the untreated (144.0 USD) cohort; patients with AD with any infection, asthma, or allergic rhinitis showed a similar trend. However, AD-diagnosed patients with Staphylococcus infection had the highest mean HCRU cost among the mild-to-moderate treated AD cohort, followed by the moderate-to-severe treated AD cohort.ConclusionThis study indicated AD to be a common skin disease with a prevalence rate of 4–5% in Dubai (UAE), with the majority of patients (about 90%) being treated by specialists. However, there is a significant underuse of newer innovative therapies (including biologics). Also, disease severity (moderate-to-severe AD) was associated with high direct medical cost, which could be controlled by early intervention. Furthermore, AD treatment choice could focus on major direct HCRU cost contributors such as hospitalizations, comorbid conditions, and infections.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13555-022-00769-z.

A Remote Digital Monitoring Platform to Assess Cognitive and Motor Symptoms in Huntington Disease: Cross-sectional Validation Study.

BackgroundRemote monitoring of Huntington disease (HD) signs and symptoms using digital technologies may enhance early clinical diagnosis and tracking of disease progression, guide treatment decisions, and monitor response to disease-modifying agents. Several recent studies in neurodegenerative diseases have demonstrated the feasibility of digital symptom monitoring.ObjectiveThe aim of this study was to evaluate a novel smartwatch- and smartphone-based digital monitoring platform to remotely monitor signs and symptoms of HD.MethodsThis analysis aimed to determine the feasibility and reliability of the Roche HD Digital Monitoring Platform over a 4-week period and cross-sectional validity over a 2-week interval. Key criteria assessed were feasibility, evaluated by adherence and quality control failure rates; test-retest reliability; known-groups validity; and convergent validity of sensor-based measures with existing clinical measures. Data from 3 studies were used: the predrug screening phase of an open-label extension study evaluating tominersen (NCT03342053) and 2 untreated cohorts—the HD Natural History Study (NCT03664804) and the Digital-HD study. Across these studies, controls (n=20) and individuals with premanifest (n=20) or manifest (n=179) HD completed 6 motor and 2 cognitive tests at home and in the clinic.ResultsParticipants in the open-label extension study, the HD Natural History Study, and the Digital-HD study completed 89.95% (1164/1294), 72.01% (2025/2812), and 68.98% (1454/2108) of the active tests, respectively. All sensor-based features showed good to excellent test-retest reliability (intraclass correlation coefficient 0.89-0.98) and generally low quality control failure rates. Good overall convergent validity of sensor-derived features to Unified HD Rating Scale outcomes and good overall known-groups validity among controls, premanifest, and manifest participants were observed. Among participants with manifest HD, the digital cognitive tests demonstrated the strongest correlations with analogous in-clinic tests (Pearson correlation coefficient 0.79-0.90).ConclusionsThese results show the potential of the HD Digital Monitoring Platform to provide reliable, valid, continuous remote monitoring of HD symptoms, facilitating the evaluation of novel treatments and enhanced clinical monitoring and care for individuals with HD.

Abstract 2028: Spatially resolved proteomic profiling identifies tumor cell CD44 as a novel indicative biomarker of sensitivity to PD-1 axis blockade in advanced non-small cell lung cancer (NSCLC)

Abstract Introduction: Most patients with advanced NSCLC fail to develop durable responses from PD-1 axis blockade, and more robust predictive biomarkers are needed. In this study, we aimed to discover and validate spatially resolved protein markers associated with sensitivity to PD-1 axis inhibition across multiple NSCLC cohorts. Methods: We first used the GeoMx Digital Spatial Profiling (DSP) system in a discovery cohort of 56 NSCLC patients treated with PD-1 axis inhibitors at Yale (USA). Pre-treatment tumors were represented in a tissue microarray (YTMA471) and analyzed using a 71-plex primary antibody panel. Proteins were measured from three molecularly defined tissue compartments: tumor (CK+), leukocytes (CD45+/CD68-), and macrophages (CD68+). We used quantitative immunofluorescence (QIF) to orthogonally validate candidate biomarkers. For external validation of identified predictors, we assessed pre-treatment whole tissue sections from a cohort of 128 NSCLC patients treated with single-agent PD-1 axis inhibitors at the Hospital 12 de Octubre (Madrid, Spain) using DSP (39-plex protein panel, measured from CK+ and CD45+ compartments). In addition, we analyzed two immunotherapy untreated cohorts to address prognostic significance: YTMA423 (Yale, USA; n = 252) and CIMA-CUN (UNAV, Spain; n = 124), using QIF and DSP respectively. Results: Using continuous log-scaled data, we found 5 markers independently associated with progression-free survival (PFS) in the tumor compartment (including PD-L1, p = 0.002). Among the novel candidate predictors, tumor cell CD44, a marker of pluripotency and stemness, was associated with longer PFS (multivariate HR = 0.63, p= 0.002). Using QIF, we orthogonally validated that CD44 expression in the tumor compartment was associated with longer PFS (p &amp;lt;0.001) and overall survival (OS) (p = 0.03). In the external validation cohort, CD44 expressed in the tumor compartment, but not in the immune compartment, was predictive of clinical benefit (OR 1.22, p = 0.018), and was significantly associated with longer PFS (first tertile cutpoint: HR 0.62, p = 0.03). In contrast, high CD44 expression was not associated with survival in the two untreated cohorts. Using DSP data from two cohorts, regions of interest with elevated expression of CD44 in tumor cells consistently showed prominent (Fold Change&amp;gt;1.5, p&amp;lt;0.05) upregulation of TIM-3, and PD-L1 and multiple co-stimulatory molecules (including CD40, ICOS, CD27). Conclusion: This work highlights CD44 as a novel indicative biomarker of sensitivity to PD-1 axis blockade in NSCLC. NSCLCs with high CD44 expression in epithelial cells may be associated with an immune contexture primed for higher response to immune checkpoint blockade. Further studies are needed to understand the interplay between CD44+ cancer stem cell phenotype and mechanisms of immune evasion. Citation Format: Myrto Moutafi, Magdalena Molero, Sandra Martinez-Morilla, Javier Baena, Ioannis Vathiotis, Niki Gavrielatou, Laura Castro, Gorka Ruiz de Garibay, Vera Adradas, Daniel Orive, Karmele Valencia, Alfonso Galvo, Luis M. Montuenga, Santiago Ponce, Kurt Schalper, Luis Paz-Ares, David L. Rimm, Jon Zugazagoitia. Spatially resolved proteomic profiling identifies tumor cell CD44 as a novel indicative biomarker of sensitivity to PD-1 axis blockade in advanced non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2028.

Abstract 3881: Immune profiling of advanced prostate cancer harboring homologous recombination deficiency

Abstract Background: Most patients with metastatic prostate cancer (mPCa) do not derive benefit from immune checkpoint inhibitors (ICI). Homologous recombination deficiency (HRD) affects up to 6-8% of patients with localized PCa and up to 30% of patients with metastatic castrate-resistant prostate cancer (mCRPC) and is predictive of response to PARP inhibitors. The potential activity of ICI in this subset of patients is unknown and the tumor microenvironment (TME) associated with HRD is poorly understood. We used PCa tumors of patients with known HRD alterations as a model to study clinically relevant, therapeutically targetable drivers of tumor immunology. Methods: Archival tumor tissue of patients with known germline or somatic HRD alterations enrolled in our institutional GU Biobank (n=13) was used for immunohistochemistry to evaluate the expression of the following immune markers in both tumor cells (TC) and stromal lymphocytes (SL): CD8, adenosine receptor 2a (A2aR), GAL9, IL-2, LAG3, PD-L2, and TIM-3. The same markers were analyzed in untreated (n=104), neoadjuvant hormone therapy treated (NHT) (n=16), neuroendocrine (NEPC) (n=41) and CRPC (n=22) tissue. Two-tailed t-test and Pearson R correlations were performed for analysis. Results: Among screened HRD alterations,BRCA1/2 were the most frequently identified (BRCA1/2n=6, FANCCn=1, FANCD2=2, PALB2=1, CDK12n=1, ATRn=2). CD8+ cells were primarily localized in the stroma of HRD cohort specimens and were more abundant compared to NEPC (p≤ 0.05) and untreated tumors (p≤0.01). The HRD cohort had higher levels of A2aR, in TC and SL (p≤0 .0001 for both) and higher levels of PD-L2 in TC (p≤0.0001) compared to all other cohorts and in the SL (p≤0.05) compared to untreated, CRPC and NEPC cohorts. Lower levels of LAG3 were found in the HRD cohort TC compared to NHT cohort, and in HRD cohort SL compared to all cohorts (p≤0.0001 for both). There was no difference in TIM-3 or GAL9 expression. Conclusions: Evaluation of stromal and tumor cell immune profiling indicates that compared to other subtypes, PCa with HRD alteration have a unique immune profile abundant in CD8+ cell, and PD-L2 and A2aR expression. Not only does this indicate an immune active TME but also identifies therapeutically actionable immunotherapeutic pathways which may render clinical benefit in this patient population. Citation Format: Maryam Soleimani, Sonia Kung, Neetu Saxena, Ladan Fazli, Lucia Nappi. Immune profiling of advanced prostate cancer harboring homologous recombination deficiency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3881.

Pembrolizumab (pembro) plus mFOLFOX7 or FOLFIRI for metastatic colorectal cancer (CRC) in KEYNOTE-651: Long-term follow-up of cohorts B and D.

3521 Background: Response to antiPD-1 monotherapy is poor in patients (pts) with advanced microsatellite stable (MSS)/mismatch-repair proficient (pMMR) CRC. Combination of chemotherapy with antiPD-1 pembro may potentiate the antitumor immune response and provide greater antitumor activity than either agent alone. Combination of pembro and mFOLFOX7 or FOLFIRI in the ongoing phase 1b multicohort KEYNOTE-651 (NCT03374254) study in metastatic MSS/pMMR CRC showed antitumor activity. We present results with approximately 20 mo of additional follow-up. Methods: Pts had metastatic MSS/pMMR CRC and were previously untreated (cohort B) or received 1 prior line including a fluoropyrimidine + oxaliplatin (cohort D). Pts received pembro 200 mg Q3W + mFOLFOX7 Q2W (cohort B) or pembro 200 mg Q3W + FOLFIRI Q2W (cohort D). Primary end points were safety (DLT) and RP2D. Secondary end point was ORR per RECIST v1.1 by investigator review. DOR, DCR, and PFS per RECIST v1.1, and OS were exploratory end points. Results: Median study follow-up (range) at data cutoff (Oct 15, 2021) was 30.2 mo (25.0-43.6) for cohort B (n = 31) and 33.5 mo (25.2-43.2) for cohort D (n = 32). Treatment was discontinued in 29 pts (94%) in cohort B and 28 pts (88%) in cohort D, mostly because of PD (61% and 66%, respectively). At prior analysis (Feb 10, 2020), RP2D was confirmed as the starting dose in both cohorts; no new DLT had occurred. In cohort B, gr 3/4 TRAEs occurred in 18 pts (58%), most commonly neutropenia and decreased neutrophil count (both n = 5; 16%); 19 pts (61%) discontinued drug because of a TRAE. In cohort D, gr 3/4 TRAEs occurred in 17 pts (53%), most commonly, neutropenia (n = 7; 22%), diarrhea and fatigue (both n = 4; 13%); 3 pts (9%) discontinued drug because of a TRAE. There were no gr 5 TRAEs in either cohort. Efficacy by cohort and KRAS mutation status are below (Table). PD-L1 data and DNA/RNA-based biomarker data including GEP, consensus signatures, TMB, and LoF mutations will be included in the presentation. Conclusions: After 2.5 y of follow-up, the combination of pembro with either mFOLFOX7 or FOLFIRI continued to demonstrate a manageable safety profile with no new safety signals. Efficacy data from these single-arm cohorts appear comparable to historical data for current SOC. Clinical trial information: NCT03374254. [Table: see text]

Oral Coenzyme Q10 supplementation leads to better preservation of kidney function in steroid-resistant nephrotic syndrome due to primary Coenzyme Q10 deficiency

Primary Coenzyme Q10 (CoQ10) deficiency is an ultra-rare disorder caused by defects in genes involved in CoQ10 biosynthesis leading to multidrug-resistant nephrotic syndrome as the hallmark kidney manifestation. Promising early results have been reported anecdotally with oral CoQ10 supplementation. However, the long-term efficacy and optimal prescription remain to be established. In a global effort, we collected and analyzed information from 116 patients who received CoQ10 supplements for primary CoQ10 deficiency due to biallelic pathogenic variants in either the COQ2, COQ6 or COQ8B genes. Median duration of follow up on treatment was two years. The effect of treatment on proteinuria was assessed, and kidney survival was analyzed in 41 patients younger than 18 years with chronic kidney disease stage 1-4 at the start of treatment compared with that of an untreated cohort matched by genotype, age, kidney function, and proteinuria. CoQ10 supplementation was associated with a substantial and significant sustained reduction of proteinuria by 88% at 12 months. Complete remission of proteinuria was more frequently observed in COQ6 disease. CoQ10 supplementation led to significantly better preservation of kidney function (5-year kidney failure-free survival 62% vs. 19%) with an improvement in general condition and neurological manifestations. Side effects of treatment were uncommon and mild. Thus, our findings indicate that all patients diagnosed with primary CoQ10 deficiency should receive early and life-long CoQ10 supplementation to decelerate the progression of kidney disease and prevent further damage to other organs.

Neuroprotective association of preoperative renin-angiotensin system blocking agents use in patients undergoing carotid interventions.

The optimal medical management strategy in the periprocedural period for patients undergoing carotid artery interventions is not well described. Renin-angiotensin-system blocking (RASB) agents are considered to be among the first line anti-hypertensive agents; however, their role in the perioperative period is unclear. The objective of this study was to examine the relationship between the use of RASB agents on periprocedural outcomes in patients undergoing carotid interventions-carotid endarterectomy (CEA), transfemoral carotid artery stenting (CAS), and transcervical carotid artery revascularization (TCAR). The Society for Vascular Surgery Quality Initiative database was queried for all patients undergoing CAS, CEA, and TCAR between 2003 and 2020. Patients were stratified into two groups based upon their use of RASB agents in the periprocedural period. The primary endpoint was periprocedural neurologic events (including both strokes and transient ischemic attacks (TIAs)). The secondary endpoints were peri-procedural mortality and significant cardiac events, including myocardial infarction, dysrhythmia, and congestive heart failure. Over 150,000 patients were included in the analysis: 13,666 patients underwent TCAR, 13,811 underwent CAS, and 125,429 underwent CEA for carotid artery stenosis. Overall, 52.2% of patients were maintained on RASB agents. Among patients undergoing CEA, patients on RASB agents had a significantly lower rate of periprocedural neurologic events (1.7% versus 2.0%, p =0.001). The peri-procedural neurological event rate in the TCAR cohort was similarly reduced in those treated with RASB agents, but did not reach statistical significance (2.0% vs 2.4%, p = 0.162). Among patients undergoing CAS, there was no difference in perioperative neurologic events between the RASB treated and untreated cohorts (3.4% vs 3.2%, p = 0.234); however, the use of RASB agents was significantly associated with lower mortality (1.2% vs 1.7%, p =0.001) with CAS. The use of preoperative RAS-blocking agents did not appear to affect the overall rates of adverse cardiac events with any of the three carotid intervention types, or periprocedural mortality following CEA or TCAR. On multivariable analysis, the use of RAS-blocking agents was independently associated with lower rates of post-procedural neurologic events in patients undergoing CEA (OR 0.819, CI 0.747-0.898; p = 0.01) and TCAR (OR 0.869, CI 0.768-0.984; p = 0.026), but not in those undergoing CAS (OR 0.967, CI 0.884-1.057; p = 0.461). The use of peri-procedural RASB agents was associated with a significantly decreased rate of neurologic events in patients undergoing both CEA and TCAR. This effect was not observed in patients undergoing CAS. As carotid interventions warrant absolute minimization of perioperative complications in order to provide maximum efficacy with regard to stroke protection, the potential neuro-protective effect associated with RASB agents use following CEA and TCAR warrants further examination.

Effects of Noni Oil on Hair Quality

Purpose: This study aims to investigate the effects of noni oil on damaged hair.Methods: Three doses of noni oil, namely, 2, 4, and 6 g, were added to hair quality enhancers and applied to the hairs in a sample bleached at level eight. The sample was then compared with damaged hair. A color meter was used to measure the L* value to identify changes in hair brightness. In addition, tensile strength, absorbance using methylene blue, and glossiness were measured to verify improvement in damaged hair.Results: The mean L* value of the sample increased with increased oil content, which indicated a statistical difference between damaged hair and sample 8L(6). The mean tensile strengths of all the hairs in the sample bleached at level eight and with oil treatment increased when compared with those of the hairs in the untreated damaged hair cohort. Statistical analysis demonstrated significant differences in hairs 8L(2), 8L(4), and 8L(6) from the sample. The mean absorbance of all hairs in the sample increased when compared with that of the damaged hair, with significant differences noted for hairs 8L(2), 8L(4), and 8L(6) from the sample from damaged hair. Last, the mean glossiness of hairs 8L(2), 8L(4), and 8L(6) from the sample increased with significant differences.Conclusion: Statistical analyses of the mean values between damaged hair and the hairs in the sample treated with oil revealed significant differences in brightness for the hair to which 6 g of noni oil were applied [8L(6)], tensile strength, absorbance, and glossiness. This finding indicates the effects of noni oil on damaged hair in terms of quality. Further studies using a variety of oils and natural extracts in this regard are in order.

A multicenter cohort analysis of fractures in histamine-2-receptor antagonist treated pediatric patients

Background Histamine 2 receptor antagonists (H2RA) are amongst the most entrenched antacid therapies available including over-the-counter. They have an excellent safety profile including no known teratogenic risk. Fracture risk is generally recognized with chronic proton pump inhibitor (PPI) therapy in adults and children although the related mechanism is poorly understood. The analogous risk in H2RAs, including in children, is unclear. We studied the fracture risk and characteristics among hospitalized pediatric patients exposed to H2RA compared to an untreated cohort. Methods The Pediatric Health Information System (PHIS) multicenter database was queried for hospital encounters of children aged 6 months − 15.5 years and between 7/2016 and 8/2017. Patients with comorbidities and medications including PPI that predispose for fractures were excluded from the cohort and a propensity-matched control was identified. The subjects and controls were followed for 2 years for hospitalization with fracture diagnoses. Results Our cohort included 3526 patients with exposure to H2RA and matched controls. Fractures were reported in 1% of patients (67) with no statistical difference between the groups. Upper, then lower extremity fractures were the most common in both groups. Axial skeleton fractures were the least frequently encountered fractures among both groups. Conclusion H2RA exposure is not associated with an increased risk of fracture in hospitalized children exposed to H2RA when compared with a matched untreated cohort, further studies are needed to determine if long-term exposure to H2RA may be associated with fracture risk in both those with and without comorbidities or on fracture predisposing medication.

Immune profiling of advanced prostate cancer harboring homologous recombination deficiency.

163 Background: Most patients with metastatic prostate cancer (mPCa) do not derive benefit from immune checkpoint inhibitors (ICI). Homologous recombination deficiency (HRD) affects up to 30% of patients with metastatic castrate-resistant prostate cancer (mCRPC) and is predictive of response to PARP inhibitors. The potential activity of ICI in this subset of patients is unknown and the tumour microenvironment (TME) associated with HRD is poorly understood. We used mPCa tumours of patients with known HRD alterations as a model to study clinically relevant, therapeutically targetable drivers of tumour immunology. Methods: Archival tumor tissue of patients with known germline or somatic HRD alterations enrolled in our institutional GU Biobank (n = 13) was used for immunohistochemistry to evaluate the expression of the following immune markers in both tumour cells (TC) and stromal lymphocytes (SL): CD8, adenosine receptor 2a (A2aR), GAL9, IL-2, LAG3, PD-L2, and TIM-3. The same markers were analyzed in untreated (n = 104), and neoadjuvant hormone therapy treated (NHT) (n = 16) tissue. Two-tailed t-test and Pearson R correlations were performed for analysis. Results: Among screened HRD alterations, BRCA1/2 were the most frequently identified ( BRCA1/2 n = 6, FANCC n = 1, FANCD2 n = 2, PALB2 n = 1, CDK12 n = 1, ATR n = 2). CD8+ cells were primarily localized in the stroma of HRD cohort specimens rather than in the glandular epithelia. The HRD cohort had higher levels of A2aR, in TC and SL (p≤0.0001 for both). When compared to the untreated cohort, PD-L2 levels were higher in SL of the HRD cohort (p≤0.05) while lower in the TC (p≤0.01). Lower levels of LAG3 were found in the HRD cohort TC compared to NHT cohort (p≤0.01). There were significantly lower levels of GAL9 in the TC of the HRD cohort compared to untreated (p &lt; 0.0001) tumours. There were no differences in TIM-3 levels between the cohorts. Conclusions: Evaluation of stromal and tumour cell immune profiling indicates that compared to other subtypes, mPCa with HRD alteration have a unique immune profile abundant in CD8+ cell, and high in PD-L2 and A2aR expression. Not only does this indicate an immune active TME but also identifies therapeutically actionable pathways which may render clinical benefit in this patient population.

Contemporary clinical and economic outcomes among oral anticoagulant treated and untreated elderly patients with atrial fibrillation: Insights from the United States Medicare database

BackgroundOral anticoagulants (OACs) mitigate the risk of stroke in atrial fibrillation (AF) patients.ObjectiveElderly AF patients who were treated with OACs (apixaban, dabigatran, edoxaban, rivaroxaban, or warfarin) were compared against AF patients who were not treated with OACs with respect to their clinical and economic outcomes.MethodsNewly diagnosed AF patients were identified between January 2013 and December 2017 in the Medicare database. Evidence of an OAC treatment claim on or after the first AF diagnosis was used to classify patients into treatment-defined cohorts, and these cohorts were further stratified based on the initial OAC prescribed. The risks of stroke/systemic embolism (SE), major bleeding (MB), and death were analyzed using inverse probability treatment weighted time-dependent Cox regression models, and costs were compared with marginal structural models.ResultsThe two treatment groups were composed of 1,421,187 AF patients: OAC treated (N = 583,350, 41.0% [36.4% apixaban, 4.9% dabigatran, 0.1% edoxaban, 26.7% rivaroxaban, and 31.9% warfarin patients]) and untreated (N = 837,837, 59.0%). OAC-treated patients had a lower adjusted risk of stroke/SE compared to untreated patients (hazard ratio [HR]: 0.70; 95% confidence interval [CI]: 0.68–0.72). Additionally patients receiving OACs had a lower adjusted risk of death (HR: 0.56; 95% CI: 0.55–0.56) and a higher risk of MB (HR: 1.57; 95% CI: 1.54–1.59) and this trend was consistent across each OAC sub-group. The OAC-treated cohort had lower adjusted total healthcare costs per patient per month ($4,381 vs $7,172; p < .0001).ConclusionFor the OAC-treated cohort in this elderly US population, stroke/SE and all-cause death were lower, while risk of MB was higher. Among OAC treated patients, total healthcare costs were lower than those of the untreated cohort.

A phase 1b/2, open-label study of tivozanib in combination with durvalumab in subjects with advanced hepatocellular carcinoma (Deductive).

TPS499 Background: Tivozanib (T, a potent and selective VEGFR 1, 2 &amp; 3 TKI) and durvalumab (D, a PD-L1 antibody) have both demonstrated single agent activity in HCC and have been combined safely with other therapies. T blocks all three VEGF receptors, and when combined with a PD-L1 inhibitor may improve patient outcomes. The combination of atezolizumab and bevacizumab (which blocks VEGF-A ligand binding to VEGFR2) has improved the standard of care in advanced hepatocellular cancer with a median PFS of 6.8 months and 1-year overall survival of 67.2%. All the currently used agents in the second-line setting, have been evaluated in pts with HCC only after exposure to sorafenib. Treatment option for the patients with HCC that progress on atezolizumab and bevacizumab, are therefore limited. Methods: Deductive (NCT03970616) is a phase 2, multicenter, open-label study to assess the safety and efficacy of tivozanib in combination with durvalumab in patients with advanced HCC. Cohort A (n=20) includes patients with untreated advanced HCC. Cohort B (n=20) includes patients with advanced HCC who have progressed on/after treatment with prior bevacizumab and atezolizumab. Eligibility criteria include age &gt;18 years, histologically or cytologically confirmed HCC, measurable or evaluable disease, Child-Pugh Class A, and ECOG PS of 0 or 1. Subjects will receive tivozanib 0.89 mg orally once daily for 21 consecutive days followed by 7 days off, and durvalumab 1500 mg intravenously every 4 weeks, and will be treated until progression or unacceptable toxicity. Study assessments include CT scan or MRI of the chest, abdomen, and pelvis every 8 weeks following Cycle 1 Day 1 until the end of treatment, and every 12 weeks during the first year and every 6 months thereafter until disease progression or start of another anti-cancer therapy. The primary objective is to establish the safety and tolerability of tivozanib in combination with durvalumab in subjects who are untreated (cohort A) or have been pre-treated with both bevacizumab and atezolizumab (cohort B). Secondary endpoints include estimation of objective response rate (ORR), median PFS and OS. Exploratory endpoints are to assess the durvalumab pharmacokinetics in the presence of tivozanib. Deductive is currently enrolling at 12 sites in the United States. Clinical trial information: NCT03970616.