Double-blind Study Research Articles

The use of adjuvant chemotherapy in cats with mammary carcinomas undergoing surgical removal.

PICO Question In cats with mammary carcinomas undergoing surgical removal, does the addition of adjuvant chemotherapy compared with surgical removal alone result in increased survival time? Clinical bottom line Category of research Treatment. Number and type of study designs reviewed Five retrospective cohort studies were critically reviewed. Strength of evidence Weak. Outcomes reported In cats with mammary carcinomas undergoing surgical removal, the addition of adjuvant chemotherapy compared with surgical removal alone was significantly associated with an increase in disease-specific survival time in one of the studies. This statistical significance was not found in the other four papers. Conclusion All five studies reviewed presented weak evidence for the clinical question due to their retrospective nature and weak study design. It is, therefore, concluded that there is not enough evidence to suggest that cats with mammary carcinomas that have undergone surgical treatment will have a longer survival time if treated with adjuvant chemotherapy. More prospective, placebo-controlled, double-blinded studies are needed to understand the clinical significance of adjuvant chemotherapy in cats with mammary carcinomas.

Efficacy and Safety of Ruxolitinib Cream for the Treatment of Moderate to Severe Chronic Hand Eczema: Top-Line Results From a 16-Week, Multicenter, Randomized, Double-Blind Study

Hand eczema is a common inflammatory disorder involving skin of the hands. Chronic hand eczema (CHE) is defined as hand eczema that persists for >3 months or recurs ≥2 times within a 12-month period. The efficacy and safety of ruxolitinib (selective Janus kinase [JAK] 1/JAK2 inhibitor) cream was investigated in adults with moderate to severe CHE in a phase 2, randomized, double-blind, vehicle-controlled study (NCT05906628). Patients aged ≥18 years with a diagnosis of CHE for ≥6 months, an Investigator’s Global Assessment (IGA)-CHE score of 3 or 4, and no current or history (≤5 y) of atopic dermatitis were randomized 1:1 to apply twice-daily 1.5% ruxolitinib cream or vehicle cream for 16 weeks of double-blind treatment. Patients (N=186) had a median (range) age of 50.0 (18–80) years, and 59.7% were female. The median (range) Itch numerical rating scale (NRS) score was 6.6 (2.1–10), and 72.6% of patients had an IGA-CHE score of 3. At Week 16, significantly more patients who applied ruxolitinib cream versus vehicle achieved IGA-CHE treatment success (primary endpoint; 53.2% vs 10.9%; P<0.0001), defined as an IGA-CHE score of 0 (clear) or 1 (almost clear) with a ≥2-grade improvement from baseline. Significantly more patients who applied ruxolitinib cream versus vehicle achieved a ≥4-point improvement from baseline in Itch NRS score (Itch NRS4) at Week 4 (46.7% vs 17.6%; P<0.0001; key secondary endpoint) and Week 16 (52.2% vs 23.1%; P<0.0001; key secondary endpoint). Numerical improvements in Itch NRS4 with ruxolitinib cream versus vehicle were observed at Day 2 with statistically significant improvement observed on Day 7 (27.4% vs 9.0%; P=0.0024; key secondary endpoint). Substantially more patients who applied ruxolitinib cream versus vehicle achieved a ≥75% or ≥90% improvement from baseline in Hand Eczema Severity Index (HECSI) score at Week 16 (80.2% vs 26.9% and 64.0% vs 11.5%, respectively). Ruxolitinib cream was generally well tolerated through Week 16 with no new safety signals; no serious infections, major adverse cardiovascular events, malignancies, or thromboses were observed. Application site reactions were infrequent. No treatment-related grade ≥3 treatment-emergent adverse events (TEAEs) were reported, and no patients discontinued owing to a TEAE. In conclusion, ruxolitinib cream demonstrated significant reductions of CHE signs and symptoms versus vehicle through Week 16 and was generally well tolerated, consistent with the known safety profile. (Funding, Incyte Corporation)

Switching from Dupilumab to Upadacitinib in Adults and Adolescents with Moderate-to-Severe Atopic Dermatitis and Inadequate Response to Dupilumab: Efficacy and Safety Results from the Phase 3b/4 LEVEL UP Study

Atopic dermatitis (AD) is a chronic skin disease characterized by intense itch and eczematous skin lesions. Upadacitinib (UPA), a selective oral Janus kinase (JAK) inhibitor, and dupilumab (DUPI), a monoclonal antibody targeting interleukin-4 and interleukin-13 signaling, are both approved treatments for moderate-to-severe AD. LEVEL UP is a phase 3b/4 efficacy assessor blinded monotherapy study comparing UPA to DUPI for treatment of moderate-to-severe AD in adults and adolescents over a 16-week period (Period 1). Patients not achieving ≥75% improvement in the Eczema Area and Severity Index (EASI 75) from baseline at Week 16 entered an additional 16-week extension phase (Period 2). In Period 2, patients either continued/escalated to UPA 30 mg (UPA/UPA 30) or switched from DUPI to UPA 15 mg (DUPI/UPA), with the potential to escalate to 30 mg based on clinical response. Efficacy for skin and itch outcomes in Period 2 were assessed using observed case analysis while on treatment, without statistical comparisons. Here we report efficacy and safety results for the DUPI/UPA switch group. A total of 355 patients who did not achieve EASI 75 at Week 16 entered Period 2 of the study (DUPI/UPA, N=208). At Week 32, response rates in the DUPI/UPA group were: 79.6%, 58.7%, and 19.9% achieving EASI 75, EASI 90, and EASI 100, respectively; 60.2% achieving WP-NRS improvement ≥4 among those with baseline WP-NRS ≥4; 37.0% achieving WP-NRS 0/1 among those with baseline WP-NRS >1; and 26.8% simultaneously achieving EASI 90 and WP-NRS 0/1 by Week 32. Clinically meaningful outcomes were also observed at an earlier visit (Week 20). No new safety signals through Week 32 were identified compared to the established safety profile of UPA. Most patients with an inadequate response to DUPI at Week 16 experienced clinically meaningful improvements in skin clearance and itch at 4 weeks post-switch to UPA, with additional patients achieving these outcomes by 16 weeks post-switch. These findings suggest that switching from DUPI to UPA is an effective treatment strategy for patients who do not meet moderate or optimal treatment targets with DUPI.

Intrathecal Pethidine Plus Dexamethasone Versus Intrathecal Bupivacaine in Lower Extremity Orthopedic Surgeries: A Randomized Clinical Trial

Background: Spinal anesthesia remains the preferred technique for lower abdominal and orthopedic procedures. Objectives: This study compares the effects of an intrathecal injection of pethidine combined with dexamethasone versus intrathecal bupivacaine alone in patients undergoing lower extremity orthopedic surgeries. Methods: In this prospective, randomized, controlled, double-blinded study, 46 participants scheduled for elective lower extremity orthopedic surgeries were randomly allocated into two groups. Group PD (n = 23) received an intrathecal injection of 1 mg/kg preservative-free pethidine combined with 4 mg dexamethasone, diluted with 0.9% sodium chloride saline to a total volume of 3 mL. Group B (n = 23) received an intrathecal injection of 3 mL (15 mg) of 0.5% hyperbaric bupivacaine alone. The primary outcome measured was the time to the first need for rescue analgesia. Secondary outcomes included spinal anesthesia characteristics, intraoperative hemodynamic stability, and incidence of perioperative adverse events. Results: The time to first need for rescue analgesia was significantly longer in Group PD (7.76 ± 0.79 hours) compared to Group B (4.48 ± 0.63 hours). Differences in the onset of sensory and motor blocks between Group PD (6.39 ± 1.12 and 10.09 ± 2.23 minutes, respectively) and Group B (6.43 ± 1.99 and 9.96 ± 2.33 minutes, respectively) were statistically non-significant. However, the regression time for sensory and motor blocks was significantly shorter in Group PD compared to Group B (146.74 ± 15.35 and 119.56 ± 14.13 minutes vs. 188.44 ± 6.84 and 168.04 ± 5.25 minutes, respectively). Incidence of hypotension and shivering was also less frequent in Group PD than in Group B. Conclusions: Intrathecal administration of 1 mg/kg pethidine plus 4 mg dexamethasone provided improved spinal anesthesia, with extended postoperative analgesia, minimal intraoperative hemodynamic disturbances, and reduced incidence of shivering compared to bupivacaine alone in patients undergoing lower extremity orthopedic surgeries. This approach may be particularly beneficial for patients with hypersensitivity to ester or amide local anesthetics, offering a cost-effective alternative to standard local anesthetics.

Effects of clindamycin and amoxycillin as prophylaxis against early implant failure: double-blinded randomized clinical trial.

The objective of this randomized controlled clinical trial (RCT) was to compare the frequency of early implant failure, postoperative infection, and pain/inflammation and the degree of implant stability between healthy non-penicillin-allergic individuals receiving a single prophylactic dose of 600mg clindamycin versus 2g amoxicillin at 1h before implant surgery. A single-center double-blinded RCT study with parallel groups was undertaken. Eighty-two patients fulfilled study inclusion criteria and were randomly assigned to the amoxicillin (n = 41) or clindamycin (n = 41) group. The primary outcome variable was early implant failure. The presence of infection was evaluated immediately after surgery and on days 7, 14, 30, and 90, and postoperative pain/inflammation was assessed daily on days 1 to 7 post-surgery. Resonance frequency analysis was used to measure primary and secondary implant stability. One early implant failure was observed (1/81), in a patient from the amoxicillin group. No statistically significant between-group differences were observed in early implant failure rate, postoperative infection rate up to 90 days, pain/inflammation scores during the first week post-surgery, or primary or secondary stability values. A single dose of 600mg clindamycin before implant surgery does not increase the risk of early implant failure or infection. These findings suggest that a single dose of 600mg clindamycin at 1h before implant surgery is a safe antibiotic prophylactic approach; however, when a more prolonged antibiotic therapy is required, it appears advisable to prescribe an alternative antibiotic to avoid adverse effects.

Efficacy and Safety of a Diet Enriched with EPA and DHA, Turmeric Extract and Hydrolysed Collagen in Management of Naturally Occurring Osteoarthritis in Cats: A Prospective, Randomised, Blinded, Placebo- and Time-Controlled Study

This study evaluated a therapeutic diet high in eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) of marine source (EPA:DHA ratio 0.69:1), turmeric extract, and hydrolysed collagen in cats (N = 30) with naturally occurring osteoarthritis (OA) over a 13-week (W) period, followed by a 4-W washout, using four previously validated pain/functional outcomes. Compared to the placebo diet, the therapeutic diet significantly improved peak vertical force (p = 0.017; W16, 64% responders), correlating to enhanced weight bearing; stair assay compliance (p < 0.001; W16, 87% responders), reflecting reduced fatigue related to OA pain; night-time actimetry (cohort effect; p = 0.05, 67% responders), suggesting greater spontaneous mobility and comfort; and MI-CAT(V) score (cohort effect; p < 0.001, 80% responders), indicating reduced functional impairments. The earliest therapeutic response was observed at W06, marked by an inflection point between actimetric linear regressions of both cohorts, confirmed by significant MI-CAT(V) differences (p < 0.007; W08; W12; W16). The MI-CAT(V) clinical metrology instrument was validated for inter-rater reliability, minimal placebo effect (<15% responders), and OA severity clustering. Despite baseline differences in biomechanical assessments (p < 0.05), both moderate and severe OA clusters responded equally positively to the therapeutic diet. Based on all outcomes, the therapeutic diet showed promise for the long-term management of feline OA, with no observed side effects.

Non-invasive multiple cancer screening using trained detection canines and artificial intelligence: a prospective double-blind study.

The specificity and sensitivity of a simple non-invasive multi-cancer screening method in detecting breast, lung, prostate, and colorectal cancer in breath samples were evaluated in a double-blind study. Breath samples of 1386 participants (59.7% males, median age 56.0 years) who underwent screening for cancer using gold-standard screening methods, or a biopsy for a suspected malignancy were collected. The samples were analyzed using a bio-hybrid platform comprising trained detection canines and artificial intelligence tools. According to cancer screening/biopsy results, 1048 (75.6%) were negative for cancer and 338 (24.4%) were positive. Among the 338 positive samples, 261 (77.2%) were positive for one of the four cancer types that the bio-hybrid platform was trained to detect, with an overall sensitivity and specificity of 93.9% (95% confidence interval [CI] 90.3-96.2%) and 94.3% (95% CI 92.7%-95.5%), respectively. The sensitivity of each cancer type was similar; breast: 95.0% (95% CI87.8-98.0%), lung: 95.0% (95% CI87.8-98.0%), colorectal: 90.0% (95% CI74.4-96.5%), prostate: 93.0% (95% CI84.6-97.0%). The sensitivity of 14 other malignant tumors that the bio-hybrid platform was not trained to detect, but identified, was 81.8% (95% CI 71.8%-88.8%). Early cancer (0-2) detection sensitivity was 94.8% (95% CI 91.0%-97.1%). This bio-hybrid multi-cancer screening platform demonstrated high sensitivity and specificity and enables early-stage cancer detection.

SAFETY AND MATERNAL-FETAL OUTCOMES OF ISOSORBIDE MONONITRATE AND MISOPROSTOL COMBINATION VERSUS MISOPROSTOL ALONE FOR LABOR INDUCTION: A RANDOMIZED DOUBLE-BLIND STUDY

Objective: The induction of labor is essential in managing pregnancies where early delivery benefits outweigh the risks. Misoprostol is a common agent for labor induction but has side effects like uterine hyperstimulation. Isosorbide mononitrate (ISMN), a nitric oxide donor, may enhance cervical ripening and reduce complications when used with misoprostol. This study evaluates the safety and maternal-fetal outcomes of ISMN combined with misoprostol versus misoprostol alone. Methods: A randomized, double-blind study was conducted at Dr. R. P. G. M. C. Kangra. Patients meeting the inclusion criteria were randomly assigned to receive either ISMN with misoprostol or misoprostol with a placebo. Primary outcomes measured were maternal complications (e. g., uterine hyperstimulation, headache, postpartum hemorrhage) and neonatal outcomes (e. g., birth weight, APGAR scores, NICU admission). Secondary outcomes included the need for oxytocin augmentation and the duration of labor stages. Results: The study included 100 patients divided into two groups of 50 each. The ISMN and misoprostol group had significantly fewer headaches and dizziness but showed no significant difference in uterine hyperstimulation or postpartum hemorrhage compared to the misoprostol alone group. The ISMN group required less oxytocin augmentation, and their total labor duration was shorter, though not significantly. Neonatal outcomes were similar across both groups. Conclusion: The combination of ISMN and misoprostol appears to be a safer and potentially more effective alternative to misoprostol alone for labor induction, with fewer maternal complications and similar neonatal outcomes. Further large-scale studies are recommended to confirm these findings and inform clinical practice.

A comparison of analgesic efficacy between oral pregabalin, gabapentin, and melatonin as non-opioid anaesthesia for robotic-assisted laparoscopic surgeries: A prospective randomized double-blinded clinical study

A comparison of analgesic efficacy between oral pregabalin, gabapentin, and melatonin as non-opioid anaesthesia for robotic-assisted laparoscopic surgeries: A prospective randomized double-blinded clinical study

Investigating the efficacy of ergothioneine to delay cognitive decline in mild cognitively impaired subjects: A pilot study.

Dementia, particularly Alzheimer's disease, is a major healthcare challenge in ageing societies. This study aimed to investigate the efficacy and safety of a dietary compound, ergothioneine, in delaying cognitive decline in older individuals. Nineteen subjects aged 60 or above with mild cognitive impairment were recruited for this double-blinded, randomized, and placebo-controlled study (ClinicalTrials.gov identifier: NCT03641404, registration date: 19/08/2018). Subjects received either ergothioneine (25 mg per capsule) or a placebo, taken 3 times a week for one year. The whole blood profile, markers of renal and liver functions, neurocognitive performance, plasma levels of ergothioneine and its metabolites, and plasma biomarkers related to neurodegeneration were measured across the study. Ergothioneine intake did not alter clinical safety markers (blood counts, kidney and liver function) throughout the study, further validating its safety for human consumption. Subjects receiving ergothioneine demonstrated improved performance in assessment of learning ability and stabilized plasma levels of neurofilament light chain, compared with the placebo group, which saw no improvement in cognitive assessments and a significant increase in neurofilament light chain levels. Prolonged intake of ergothioneine showed no toxicity in elderly people. Enhanced Rey Auditory Verbal Learning Test performance and stabilized neurofilament light chain levels suggest improvements in memory and learning abilities and a deceleration of neuronal damage, respectively. Our results add to existing data that ergothioneine is safe for extended consumption and may hold the potential to delay cognitive decline in elderly adults.

Efficacy of electrical stimulation of the zygomaticus muscle in complete facial paralysis: evidence from facial grading and automated image analysis

Surface Functional Electrical Stimulation (FES) is a well-studied intervention for multiple muscular disorders. However, it is still controversially discussed as a complementary therapy for complete facial paralysis. The aim of this intervention is to test a daily home-based ES concept as a pilot study regarding safety, feasibility, and effects on facial functionality and symmetry. In a prospective single-centre pilot study, 10 patients (median 61 years, denervation 130 d) with complete peripheral facial paralysis performed home-based FES of the affected lateral mouth region Stimulation parameters, facial paralysis scores and standardised photographs were assessed in monthly follow-ups. No serious adverse events appeared. Stimulation parameters could be constantly increased indicating effective muscle training while subjectively perceived functionality of the face improved. Thus, smile angle of the paralysed side improved as well. FES is a safe therapy model for application in facial nerve paralysis patients. A feasible stimulation protocol could be applied, which improved the functionality and symmetry of the stimulated facial region. A future controlled, randomised and double-blind follow-up study is needed to investigate these initial results in a further evolved replicable setting.

Effect of dexmedetomidine as an adjuvant to bupivacaine in bilateral posterior quadratus lumborum block for postoperative analgesia after cesarean delivery: A prospective randomized double-blinded study

Effect of dexmedetomidine as an adjuvant to bupivacaine in bilateral posterior quadratus lumborum block for postoperative analgesia after cesarean delivery: A prospective randomized double-blinded study

Nifedipine May Be an Inhibitor of Clozapine Metabolism, as Seen in 5 Patients: 2 from a US Double-Blind Study and 3 from a German TDM Study

Background: Clozapine is the only licensed antipsychotic for treatment-refractory schizophrenia. Therapeutic drug monitoring (TDM) refers to the measurement of clozapine concentration. Clozapine TDM can be used to optimize treatment, particularly by identifying pharmacokinetic interactions between clozapine and comedications. Methods: We identified 5 cases of patients with available clozapine concentrations who were concomitantly receiving nifedipine and clozapine. These cases were drawn from 2 independent datasets: 2 from a double-blind, randomized clinical trial in the United States and 3 from a German TDM naturalistic database. As an index of clozapine clearance, we used the trough-level concentration-to-dose (C/D) ratios to estimate the minimum therapeutic doses. To estimate dose-correction factors for nifedipine treatment, we included only clozapine concentrations at steady state. We divided the clozapine minimum therapeutic doses (MTD) from the on-condition by the off-nifedipine condition. Results: In 4 patients, the ratio of on/off nifedipine for MTD ranged between 0.58 and 0.82. Another patient had no data and had to be compared with published control data (female smoker of African ancestry), providing a correction factor of 0.52 after eliminating 5 concentrations contaminated by the development of obesity. Conclusions: In the absence of access to TDM, when prescribing nifedipine to clozapine-treated patients, we recommend reducing the daily dose of clozapine by one-third because of the weak inhibition of clozapine metabolism. With access to TDM, TDM should guide dosing as unusual patients may need larger dose reductions, as it is possible that in some patients, nifedipine may be a moderate inhibitor requiring halving clozapine dose. Further prospective studies are warranted.

Treatment of prehypertension among adults with HIV: a randomized clinical trial

Objective: Elevated blood pressure (BP), even at prehypertensive levels, increases cardiovascular disease risk among people with HIV (PWH); yet international guidelines in low-income countries recommend treatment initiation at BP at least 140/90 mmHg. We determined the efficacy, feasibility, and acceptability of treating prehypertension in PWH in Haiti. Design: An unblinded randomized clinical trial (enrolled April 2021–March 2022) with 12-month follow-up. Setting: GHESKIO Centres, Port-au-Prince, Haiti. Participants: Two hundred fifty adults with HIV with prehypertension (SBP 120–138 or DBP 80–89) not on medication, aged 18–65 years, virally suppressed, and without pregnancy, diabetes, or kidney disease. Intervention: Participants were randomized to treatment (amlodipine 5 mg) or control (no amlodipine unless two BP ≥140/90 mmHg). Main outcome measure: Primary outcome was mean change in SBP between intervention versus control groups from enrollment to 12 months. Results: Among 250 adults, median age was 49 years, 40.8% were women. Baseline median BP was 129/78 mmHg intervention versus 128/77 mmHg control. After 12 months, the difference in mean change between study groups for SBP was -5.9 mmHg [95% confidence interval (95% CI) -8.8 to -3.0] and for DBP was -5.5 mmHg (95% CI -7.9 to -3.2). At 12 months, 5.6% intervention and 23.0% control participants developed incident hypertension (hazard ratio 0.18; 95% CI 0.07–0.47). There were no differences in viral load suppression at 12 months or drug-related serious adverse events. Intervention acceptability was high among providers and participants in qualitative interviews. Conclusion: In PWH in a resource-poor setting, prehypertension treatment was feasible, acceptable, and effective in reducing mean SBP and incident hypertension. Registration: Clinicaltrials.gov NCT04692467

Non-technical Skills for Urology Trainees: A Double-Blinded Study of ChatGPT4 AI Benchmarking Against Consultant Interaction

Non-technical Skills for Urology Trainees: A Double-Blinded Study of ChatGPT4 AI Benchmarking Against Consultant Interaction

Efficacy of fosaprepitant for the prevention of postoperative nausea and vomiting in patients undergoing gynecologic surgery: a multicenter, randomized, double-blind study

Abstract Purpose This study aims to investigate whether adding fosaprepitant to palonosetron and dexamethasone is effective in preventing postoperative nausea and vomiting (PONV) in high-risk patients undergoing gynecologic surgery. Methods Eligible patients undergoing gynecological surgery were randomized into two groups (1:1). One group received fosaprepitant (150 mg) and the other (control) received a placebo infusion. Both groups received a single dose of palonosetron (0.25 mg) and dexamethasone (5 mg) together with therapeutic medication. The primary endpoint was the absence of vomiting and no use of rescue antiemetics during the first 24 h after surgery; complete response rate (CRR). Results CRR was significantly higher in the fosaprepitant group compared to the control group 0–24 h after surgery (P = 0.037; relative risk [RR], 1.116; 95% confidence interval [CI], 1.007 to 1.235). Moreover, CRR was also significantly higher during the 24–48 h (P = 0.004; RR, 1.148; 95% CI, 1.045 to 1.261) and 48–72 h (P = 0.039; RR, 1.083; 95% CI, 1.005 to 1.168) observation periods respectively. The complete control rate was higher in the fosaprepitant group than in the control group during the 0–24 h observation period (P = 0.012; RR, 1.367; 95% CI, 1.067 to 1.751). Nausea and rescue antiemetic use were comparable between the two groups. The severity of vomiting was significantly higher in the fosaprepitant group than in the control group on the second day (P = 0.016). Dynamic pain visual analog scale score was lower in the fosaprepitant group and quality of recovery-15 scores were significantly higher in the same group during 0–24 h observation period (P = 0.018 and 0.005, respectively). Conclusions The triple combination of fosaprepitant, palonosetron, and dexamethasone was superior in the prevention of PONV after gynecologic surgery in high-risk patients. We suggest that for high-risk patients, a triple combination therapy may be a better choice. Trial registration Registered at the Chinese Clinical Trial Registry (https://www.chictr.org.cn/showproj.html?proj=171741) with No. ChiCTR2200060890 on June 13, 2022. Principal investigator: Jingdun Xie.

Abstract PR007: Screening early detection of HPV-associated oropharynx cancers with multi-feature HPV whole genome sequencing liquid biopsy

Abstract Early detection of HPV-associated oropharyngeal cancer (HPV+OPSCC), the most common HPV cancer in the United States, could reduce disease-related morbidity, yet currently there are no screening tests. Circulating tumor HPV DNA (ctHPVDNA) is a sensitive and specific biomarker for HPV+OPSCC at diagnosis. It was previously unknown if ctHPVDNA is detectable prior to HPV+OPSCC diagnosis, and thus it’s potential as a screening test. We recently reported (2023 AACR-AHNS Head and Neck Cancer Conference) detection of ctHPVDNA with 79% overall sensitivity at 100% specificity in a case-control cohort of HPV+OPSCC patients with plasma samples collected 1-11 years prior to diagnosis (n=28) and age- and sex-matched controls (n=28) from the MassGeneralBrigham Biobank (MGBB) using a custom multi-feature HPV whole genome sequencing liquid biopsy, termed HPV-DeepSeek, demonstrating for the first time, the feasibility of blood-based screening for HPV+OPSCC. Here, we extend and validate these finding in a second independent cohort and generate combined metrics for estimating HPV+OPSCC screening accuracy by HPV-DeepSeek. We conducted a blinded case-control study nested within the NCI PLCO Screening Trial. PLCO enrolled 155,000 healthy participants from November 1993-July 2001 with plasma sample collected at multiple time points. All patients were followed for cancer outcomes. PLCO participants who were diagnosed with OPSCC >6 months after blood sample contribution were identified and matched 1:2 with controls based on smoking status, sex, race, year of blood collection, and year of birth. 400ul of plasma was retrieved, blinded, and transferred for testing. After quality control, the cohort included 72 OPSCC cases and 144 controls. Samples had previously underdone HPV E6 antibody testing which was used as a marker of HPV status. All samples were run on HPV- DeepSeek using pre-defined cut points and results were returned to NCI CDAS where case- control status was unblinded. 32 OPSCC cases were HPV E6 antibody positive and thus regarded as HPV16+OPSCC. 20/32 were ctHPVDNA positive and 12/32 were ctHPVDNA negative (overall sensitivity 63%). Specificity was 99%. The mean lead time of positive cases was 6.3 years, and the maximum lead time was 11.3 years. Sensitivity was highest closest to diagnosis and declined further from diagnosis (100% within 3 years of cancer diagnosis, 58% from 3-9 years, 20% from 9-12 years; p<0.001). Four additional samples were positive for non- HPV16 genotypes (31, 33, 33, 39) in the overall cohort. When combined with the MGBB cohort, overall screening sensitivity was 70% and specificity was 99%. Sensitivity within 3 years of cancer diagnosis was 100%. ctHPVDNA can be detected in the blood up to 11 years prior to diagnosis with HPV+OPSCC, with ≥99% specificity, and an overall screening sensitivity of 70% in a cohort of 100 OPSCC cases and 172 controls using a multi-feature HPV WGS liquid biopsy. ctHPVDNA detection alone, or in combination with previously identified serological biomarkers, may be a feasible approach to screening for HPV+OPSCC. Citation Format: Krystle Kuhs, Hilary Robbins, Dipon Das, Michael Bryan, Ling Aye, Yana Al-Inaya, Shun Hirayama, Viktor Adalsteinsson, Michael Lawrence, Tim Waterboer, Daniel L Faden. Screening early detection of HPV-associated oropharynx cancers with multi-feature HPV whole genome sequencing liquid biopsy [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr PR007.

Efficacy and safety of tozorakimab in moderate-to-severe atopic dermatitis: A Phase 2a randomized controlled trial (FRONTIER-2).

Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by intense pruritus and eczematous lesions. Tozorakimab is a high-affinity human monoclonal antibody that neutralizes interleukin-33, a broad-acting alarmin cytokine that is over-expressed in keratinocytes of patients with AD. This Phase 2a study (FRONTIER-2; NCT04212169) evaluated the safety and efficacy of tozorakimab in adults with moderate-to-severe AD. FRONTIER-2 was a randomized, placebo-controlled, parallel-group, double-blind study conducted from 9 December 2019 to 20 September 2022 at 32 centres across six countries. Patients were randomized 3:1:1:3 to receive placebo, tozorakimab 60 mg, tozorakimab 300 mg or tozorakimab 600 mg by subcutaneous injection once every 4 weeks for four doses. The primary endpoint was percentage change from baseline to Week 16 in the Eczema Area and Severity Index (EASI) score in patients treated with tozorakimab versus placebo. Secondary outcomes included EASI-75 responders (patients achieving ≥75% reduction from baseline in EASI score), Investigator's Global Assessment (IGA) responders (patients achieving an IGA score of 0 or 1), pharmacokinetics, immunogenicity and safety. Overall, 148 patients were randomized. There was no statistically significant difference in the primary endpoint (60 mg difference of 1.3 [90% confidence interval (CI): -13.7, 16.2], p = 0.888; 300 mg: difference of 5.9 [90% CI: -10.4, 22.1], p = 0.549; 600 mg: difference of - 1.7 [90% CI: -13.4, 10.0], p = 0.807). The proportion of EASI-75 and IGA 0/1 responders at Week 16 was numerically higher in the tozorakimab 600 mg group than in the placebo group (EASI-75: 18.2% vs. 7.1%, p = 0.094; IGA 0/1: 9.1% vs. 1.8%, p = 0.113). Serum pharmacokinetics were dose-dependent, immunogenicity incidence was low and tozorakimab was well tolerated. FRONTIER-2 did not show a statistically significant difference in the primary endpoint for tozorakimab compared with placebo. However, numerical increases in responder rates were observed.

Will a patient information brochure increase acceptance of Omani women with varicose veins to be examined by a male surgeon ?- A prospective randomized single blinded study.

Varicose veins are not uncommon among Omani women. As currently there are no female vascular surgeons, it has been noticed in our outpatient clinic that a number of them are reluctant to be examined by a male vascular surgeon, have a duplex ultrasound done and therefore a management plan cannot be made in this subset. This study is a first of its kind in Oman, looking at the impact of a patient information booklet about varicose veins etiology, symptoms, signs, assessment and management, on the attitude of a female patient's acceptance towards examination by a male surgeon in the presence of a chaperone.

Rocatinlimab Improves Patient-Reported Outcomes in Adults with Moderate-to-Severe Atopic Dermatitis: Results from a Double-Blind Placebo-Controlled Phase2b Study.

In adults with moderate-to-severe atopic dermatitis (AD), rocatinlimab demonstrated significant and progressive improvement in clinical measures of disease severity compared with placebo. This post hoc analysis of a phase2b study was undertaken to understand the disease burden and to assess the impact of rocatinlimab on patient-reported outcomes (PROs). This analysis used baseline data from a multicenter, randomized, double-blind study of adults with moderate-to-severe AD, who completed a Worst Pruritus numerical rating scale (NRS), Sleep Disturbance NRS, and the Dermatology Life Quality Index (DLQI). A mixed model for repeated measures was used to estimate changes in PRO scores from baseline; scores were also compared with clinically meaningful change benchmarks. The analysis included 267 subjects, mean (SD) age 37.9 (14.7) years, 40.8% female; 55.1% grade3 and 44.9% grade4 Investigator Global Assessment for AD. Mean (SD) scores were: Worst Pruritus NRS 7.5 (1.9), Sleep Disturbance NRS 5.5 (2.9), DLQI total score 12.6 (7.1). Worst Pruritus and Sleep NRS scores had low positive correlations with SCORing AD (SCORAD) score (r = 0.44, r = 0.45 respectively) and negligible correlations with Eczema Area and Severity Index (EASI) score and area affected (r < 0.30). DLQI score varied by sex, study country, race, age, longer disease duration, disease severity (EASI and SCORAD), presence of asthma, and Worst Pruritus NRS, Sleep disturbance NRS, and DLQI scores. Rocatinlimab showed benefit on all three PROs, with significant improvements from baseline at the end of the double-blind period (week18) and active treatment extension (week36). Benefits were maintained over 20weeks' post-treatment follow-up. The benefit of rocatinlimab treatment on PROs is rapid and maintained for at least 20weeks following treatment completion. This analysis demonstrates the importance of characterizing the burden of moderate-to-severe AD from the patient's perspective, alongside clinical disease measures, to develop a fuller picture of treatment benefit. ClinicalTrials.gov identifier, NCT03703102.