Abstract Purpose Dynamometers are commonly used to assess muscle force properties, with isokinetic dynamometers (IKD) considered the gold standard. However, their high cost and limited portability have led to the development of alternative devices. In this study, we investigated validity and reliability of a tension dynamometer (Tindeq) compared to an IKD and how different methods of determining peak torque and rate of torque development (RTD) influence measurement properties. Methods Twenty-eight healthy university students (23.14 ± 4.06 years) completed isometric knee extension (KE) and flexion (KF) testing. Validity and reliability of peak torque and RTD were assessed using ICC , minimal detectable change (MDC), correlation (R), and Bland Altman plots across three methods: average of three trials, highest of three trials, and a single trial. Results Peak torque demonstrated good validity ( ICC = 0.80–0.88) across all methods, only KF demonstrating minimal bias (< 2% of mean). Respectively, excellent and good reliability for peak torque was observed for KE ( ICC = 0.94–0.95, MDC = 24.90%–26.81%) and KF ( ICC = 0.80–0.82, MDC = 35.08%–35.79%). Most Tindeq RTD measures demonstrated poor-moderate validity and systematically underestimated RTD (bias: 9.6%–67.5% of mean), only KF average and highest methods RTD20%–80% performed good ( ICC = 0.80–0.84). RTD20%–80% methods performed moderately ( ICC = 0.70–0.75, MDC = 69.23%–91.60%), except for the first trial method which performed poorly ( ICC = 0.25–0.48, MDC = 112.44%–179.17%). Peak RTD methods demonstrated moderate-good reliability but with large MDC ( ICC = 0.73–0.88, MDC = 49.06%–75.63%). Conclusion Tindeq demonstrates strong validity and reliability for peak torque assessment, supporting it as a portable, low-cost alternative for knee strength testing. Tindeq RTD measurement properties were less consistent, likely stemming from differences in sampling rate and processing differences.

Introduction Ovarian reserve depicts the quality and quantity of oocytes remaining in the ovaries and gives an idea about ovarian function at a given time. Because of aging, ovarian reserve diminish physiologically. However, many women face a non-physiologic reduction of ovarian reserve, irrespective of age. To date, standard-of-care treatment options are not available to treat diminished ovarian reserve (DOR). Studies shows that DOR patients mostly undergo in vitro fertilization (IVF) with donor cycles. Hence, identifying effective treatment modalities for DOR is an area of great clinical relevance. This trial will investigate the role of an Ayurvedic treatment protocol in DOR patients prior to IVF. Reports suggest that the factors influencing oocyte maturation can be determined through multi-omics analysis of the follicular fluid. However, the impact of Ayurvedic interventions in improving therapeutic outcomes has yet to be explored in detail. Hence this study also aims to explore whether therapeutic targets can be identified through multi-omics analysis of the follicular fluid collected from the participants after Ayurvedic treatment. Materials and methods An open label single arm trial will be conducted to explore the role of an Ayurveda treatment protocol as a prerequisite for IVF in women with DOR. Forty women diagnosed with DOR satisfying eligibility criteria will be recruited to the study. Out of them, thirty participants will be undergoing Ayurveda treatment prior to their next IVF, and ten participants will be assigned to control group for follicular fluid analysis. Within subject change in serum anti-mullerian hormone and antral follicle count will be the primary outcomes evaluated. The multiomics analysis of follicular fluid will be done in 20 participants recruited to the study (treatment group 10 and control group 10). Discussion This multidisciplinary exploratory clinical trial will be the first study to explore the role of an Ayurvedic treatment protocol in managing DOR. The multi-omics approaches will be helpful in identifying potential biomarkers associated with treatment response. The information gained through the study might be useful in planning a safe and feasible pre-conception care for DOR patients undergoing IVF. Clinical trial registration ctri.nic.in , identifier CTRI/2023/11/059872.

Models of working memory make fundamentally different commitments to the architecture of individual memories. Information-sparse models conceptualize individual memories single point estimates agnostic to meta-cognitive variables such a uncertainty. In contrast, information-rich models propose memories re encoded s probability distributions over feature space that embed memory uncertainty in the shape of the distribution To distinguish these accounts, constructed probability distributions of memory from participant’s iterative reports of motion direction each trial. Remarkably, the idiosyncratic shape of these distributions (e.g., asymmetry) single trials matched the shape of neural probability distributions decoded from fMRI patterns measured from occipital and parietal cortex. Consistent with information-rich models, the neural representation of n individual memory encodes mor than the memorized feature; its variance (i.e., width and asymmetry) encodes idiosyncrasies whose read-out predicts memory behavior.

BackgroundAlcohol use disorder (AUD) remains a prevalent and challenging condition, with current behavioral and pharmaceutical treatments yielding limited success and high relapse rates. Non-invasive neuromodulation techniques, such as transcranial magnetic stimulation (TMS), offer promising therapeutic alternatives. TMS has demonstrated efficacy in modulating brain circuits associated with the limbic system and cognitive control, both critical in AUD pathology. While the dorsolateral prefrontal cortex (DLPFC) and medial prefrontal cortex (MPFC) have been identified as potential TMS targets, no studies have evaluated both sites against a sham condition in a single trial. This randomized, double-blind, sham-controlled clinical trial addresses this gap by evaluating the efficacy of multi-session intermittent theta burst stimulation (iTBS) applied to either the DLPFC or MPFC in reducing alcohol consumption, alcohol craving, and brain reactivity to alcohol cues.MethodsOne hundred and eighty individuals with AUD will be randomized to receive real iTBS to the MPFC, real iTBS to the DLPFC, or sham iTBS. Participants will complete 30 treatment sessions, administered in 15 daily sessions spread over 3 to 6 weeks, with pre- and post-treatment MRI scans and 3 months of follow-up.DiscussionBy evaluating two cortical targets and leveraging rigorous methodologies, this trial aims to generate insights that could inform future studies optimizing TMS for AUD treatment. Findings will contribute to developing standardized TMS protocols, with the potential to enhance treatment efficacy and support FDA approval, advancing TMS as an intervention for AUD.Trial registrationClinicalTrials.gov NCT04154111. Registered on November 6, 2019.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13063-025-09093-1.

Rivaroxaban Does Not Alter Carotid Plaque Echolucency, Volume, or Neovascularisation.

INTRODUCTION: In the Single Ventricle Reconstruction Trial, long-term follow up (SVRIII), morbidity and mortality compounded with age regardless of shunt type at Norwood procedure. AIMS: We aimed to describe SVRIII MRI findings by shunt type and determine associations between cardiac MRI and exercise performance. METHODS: Cardiac magnetic resonance imaging (CMR) and cardiopulmonary exercise testing (CPET) were performed at ages 10-14 years. Demographics and CMR parameters were compared by shunt type. An estimate of aortopulmonary collaterals (APC) and fenestration (Fen) flow was calculated by subtracting total vena cava flow from aorta flow. All SVR III, CMR, and demographics data were used to determine univariate and multivariable predictors of right ventricular function (RVEF %). CMR parameters were used to determine predictors of ventilatory efficiency (VE/VCO 2 ) and peak VO 2 (ml/min/kg). RESULTS: Among 237 participants enrolled in SVR III, 168 participants had complete CMR exams (79 mBTTS, 89 RVPAS, 33% female). RV volumes (BTTS 91.9 ml/m2 vs RVPAS 93.4 ml/m2, cardiac output (BTTS 42ml/beat vs RVPAS 46ml/beat), and APC+Fen flow were similar between shunt types, while the RVPAS group tended to have higher SVC flow (BTTS 16.1ml/beat vs RVPAS 18.3 ml/beat P=0.04). The mBTTS group had a slightly larger isthmus (13.8mm vs 12.8mm), but similar ascending aorta (AAO mm), and branch PA sizes. Table 1 shows CMR univariate predictors of RVEF, VE/VCO 2 and peak VO 2 . Both RVESVi (ml/m 2 ) and RVEDVi (ml/m 2 ) were negatively associated with RVEF. Despite a negative association between higher RPA:LPA flow balance and RVEF, there was also a weakly negative association between LPA size and RVEF. Higher total vena cava flow (ml/beat) and pulmonary blood flow were associated with improved VE/VCO 2 . Right ventricular volumes and mass were negatively associated with Peak VO 2 , while AAO and RVEF were positively associated with peak VO 2 . By multivariable analysis RV mass and AAO size explain approximately 11% of the variability in peak VO 2 ( Table 2 ). CONCLUSION: Chronic volume loading of the single right ventricle in the setting of low systemic blood flow and pulmonary flow imbalance are associated with RV dysfunction. CMR measures of RV size and systemic blood flow have a modest association with ventilatory efficiency and peak exercise performance. Higher Qs is associated with improved ventilatory efficiency, while larger AAO and lower RV mass are associated with improved peak VO 2 .

Zanubrutinib combined with anti-CD19 CAR-T cell therapy in relapsed and refractory B-cell lymphoma

Cognitive behavioral therapy for insomnia in people with schizophrenia: a systematic review and meta-analysis.

Multidimensional Motor Evoked Potentials (MultiMEP): Digging up buried information from single trials.

Abstract Background Acne vulgaris (AV) is common chronic inflammatory disorder of pilosebaceous unit. Although various mechanisms have been indicated in the etiopathogenesis of AV, the exact pathology is still unknown. There are numerous factors in the etiopathogenesis of AV. The main factors are Inflammation, abnormal keratinization, microbial flora changes, and increased sebum production. Aim of the Work The aim of this study is to evaluate the level of serum calprotectin in patients with moderate to severe AV before and after treatment with isotretinoin. Patients and Methods At Ain Shams University Hospitals’ dermatological outpatient clinic, patients were gathered, assessed, and given treatment. The investigation commenced in May 2023 and ended in October 2023. This study involved a single arm clinical trial with 40 individuals diagnosed with acne vulgaris and a case control comparison of 20 controls with 20 patients. Results Our study showed that there was no significant difference between both study groups as regard personal data (age, sex, and marital status). Our study showed that there was a highly significant difference between both study groups as regard serum Calprotectin before treatment with higher mean level among cases, similarly a highly statistically significant difference was found between calprotectin after treatment in cases group compared to calprotectin in control group. Among cases group, our study showed that there was no significant correlation between each of age, BMI, weight, GAGS grade and serum calprotectin before treatment. Using roc curve, our study showed that serum calprotectin can be used to differentiate cases from controls at a cutoff level of > 114.5, with sensitivity, specificity, PPV and NPV equal to 100% (AUC = 1.0 & p-value < 0.001). Conclusion Calprotectin levels in the blood are higher in acne vulgaris patients than in stable control groups suggesting that calprotectin may be used as a chemical biomarker to determine disease severity. Calprotectin levels were decreased after treatment with systemic isotretinoin may be due to its anti-inflammatory role.

Background Remote ischemic conditioning (RIC) is a simple, non‐invasive strategy proposed to enhance neuroprotection and vascular adaptation in ischemic stroke.Multiple randomized trials have assessed its utility in both acute management and secondary prevention, with mixed findings.While some studies demonstrated improved functional independence and reductions in recurrent ischemic events, others failed to show significant benefit.Despite its favorable safety profile and ease of application, current evidence remains inconsistent, highlighting the need for larger, well‐designed trials. Methods We systematically reviewed randomized controlled trials (RCTs) evaluating RIC in patients with acute ischemic stroke or symptomatic intracranial stenosis. Primary outcome was functional independence at 90 days (mRS 0‐1). Secondary outcomes included recurrent ischemic events, infarct growth, mortality, and safety. Random‐effects models were used for pooled analyses where appropriate. Results Six randomized controlled trials (RCTs; n≈6,296) were eligible for inclusion. In the acute stroke setting, the RICAMIS trial (n≈1,893) demonstrated improved functional independence (67.4% vs 62.0%; OR 1.27, 95% CI 1.05‐1.54), whereas the RESIST (n≈1,500) and RESCUE BRAIN (n=188) trials yielded neutral or nonsignificant findings. A pooled analysis of RICAMIS and RESCUE BRAIN indicated a modest benefit (RR 1.09, 95% CI 1.02‐1.17). For secondary prevention, the large RICA trial (n=3,033) showed no effect in the intention‐to‐treat analysis but reported a significant reduction in recurrent ischemic events among adherent patients (HR 0.76, 95% CI 0.59‐0.99). Infarct growth outcomes were inconsistent, while mortality and serious adverse events were comparable between remote ischemic conditioning (RIC) and control groups. The most common minor adverse effect was local limb discomfort. Conclusions RIC appears safe and may modestly improve functional outcomes in acute ischemic stroke, though results are largely driven by a single large trial. For intracranial stenosis, long‐term efficacy may depend on adherence. Current evidence highlights the potential of RIC but underscores the need for further large‐scale, rigorously controlled studies.

The direction and magnitude of conditioned pain modulation is dependent on test stimulus intensity in healthy participants but not in those with fibromyalgia.

Intraoperative methylene blue infusion reduces postoperative delirium in patients undergoing pancreatic surgery: A randomized controlled clinical trial.

Evidence-based practice relies on clinical guidelines, whose recommendations depend on the quality, relevance, and validity of supporting research. We evaluated the class/strength and level of evidence (LOE) or quality of evidence (QOE) supporting American Heart Association/American Stroke Association and European Stroke Organisation guideline recommendations, and examined temporal changes in LOE. Stroke guidelines from American Heart Association/American Stroke Association (1995-2025) and European Stroke Organisation (2014-2025) were identified through society websites and EMBASE/MEDLINE. Eligible documents contained recommendations with class/strength and LOE/QOE. Consensus statements were excluded. Since 2006, American Heart Association/American Stroke Association has classified LOE as A (multiple or large randomized-controlled trials), B (single trial or observational studies), or C (expert opinion). European Stroke Organisation applies the Grading of Recommendations Assessment, Development, and Evaluation system (high, moderate, low, and very low QOE). Across 1102 recommendations in 9 current American Heart Association/American Stroke Association stroke guidelines, 156 (14.2%) were supported by LOE A, 559 (50.7%) by LOE B, and 387 (35.1%) by LOE C. Of 407 class I recommendations (ie, should do), and 117 class III recommendations (ie, should not do), 116 (22.1%), 258 (49.2%), and 150 (28.6%) were supported by LOE A, B, and C, respectively. Although the number of recommendations increased across guideline updates (median, 22 [interquartile range, 25th-75th percentiles, 18.0-42.0]), the proportion supported by LOE A declined (median, -4.6% [interquartile range, -7.8 to -0.8]). Across 260 recommendations in 30 European Stroke Organisation guidelines, 19 (7.3%) were supported by high, 62 (23.8%) by moderate, 81 (31.2%) by low, and 98 (37.7%) by very low QOE. Among 90 strong recommendations, 18 (20.0%) were supported by high QOE, and 66.7% of guideline topics had no recommendations supported by high QOE. There was insufficient evidence to make recommendations for 123 (32.7%) clinical questions. Due to limited randomized data for many important clinical questions, most stroke guideline recommendations are based on low-to-moderate-quality evidence. These findings emphasize the need to improve the funding, design, and delivery of efficient, patient-focused clinical trials.

The aim is to evaluate the impact of cross-linked hyaluronic acid gel (HA) on the clinical outcomes of gingival depigmentation using scalpel or diode laser techniques. In this single blinded prospective randomized clinical trial, forty-four patients who had gingival pigmentation in the upper jaw were allocated into a test group (HA+) that had HA gel applied and a control group (HA-). Depigmentation was done using scalpel or a 940nm diode laser of 0.8w in a split-mouth design. The follow-up visits were at 3, 7, 14, and 30 days. Clinical measurements included wound healing index (WHI), digital measurement of the non-healed remaining area (NRA), pigmentation, pain, and bleeding index. At 30 days, WHI and NRA showed similar results in both HA- and HA+ groups (P > 0.05). In contrast, the diode laser had significantly improved WHI mean in the 7th and 14th day and NRA mean in the 3rd and 7th day (WHI = 1.55, 1.02), (NRA = 29%, 2.1%) in comparison to the scalpel (WHI = 1.70, 1.14), (NRA = 53%, 5%). The decrease in pigmentation intensity and distribution was highly significant (P < .001) and similar between the HA-, HA+, scalpel and laser groups at one-month (P > 0.05). The pain did not differ significantly between HA- and HA+ (P > 0.05). However, it was significantly less with diode laser than the scalpel (P < 0.05). Diode laser had significantly less bleeding than the scalpel (P < .001). HA did not confer additional benefits to promote wound healing and reduce pain in depigmentation. Diode laser is a convenient method of depigmentation that improves initial healing and decreases initial pain with reduced bleeding. Clinical relevance Gingival hyperpigmentation is a major aesthetic issue for many individuals. Laser and scalpel treatments produce equivalent aesthetic outcomes.

Abstract Background and Aims The elderly represent the most rapidly growing end stage kidney disease age group world-wide. The hemodialysis (HD) prescription that provides the best outcomes for this distinct population with reduced life expectancy is unknown. Observational data suggest that quality of life (QOL) could be improved with less frequent HD without increasing mortality in this unique population. The primary aim of the D-LITE pilot trial was to determine the feasibility and safety of conducting a trial designed to determine whether twice versus thrice weekly HD improves QOL in incident elderly HD patients. Method We conducted a pilot randomized open controlled single centre trial in Kingston, Canada. Eligible subjects were incident HD patients ≥ 70 years of age 3 months post HD initiation planning to continue in-centre HD. Forty subjects were randomized to twice weekly versus thrice weekly HD stratified by residual kidney function and were followed for 9 months. The primary outcomes were those of feasibility and safety. Secondary outcomes included patient-reported QOL assessments, hyperkalemic events, mortality and requirement for emergency dialysis. Results Figure 1 shows patient flow. Consent rate of eligible subjects was high (77%), adherence approached 100%, and 78% of randomized patients completed study. Subjects randomized to the twice weekly arm had similar pre-HD normokalemia rates (90%) to the thrice weekly arm and fewer than 10% of HD post weights exceeded prescribed target weight by 1.0 kg. Urgent HD treatments for hypervolemia and hyperkalemia was infrequent and similar between arms as were hospitalizations and death. Conclusion The results of this pilot randomized controlled study of twice and thrice weekly HD in an elderly incident HD population reveal that the study was both feasible and safe. These results will inform the design of a multi-center RCT with QOL and safety endpoints.

Abstract Background and Aims Atypical haemolytic uraemic syndrome (aHUS) is a rare disease which without treatment is associated with high morbidity and mortality. Eculizumab, a monoclonal complement inhibitor, is an effective treatment but the optimal way to use this high-cost medication has not been determined. The SETS aHUS trial aimed to establish the safety of eculizumab withdrawal and the effectiveness of a monitoring protocol to detect disease relapse and safe reintroduction of treatment if disease relapse occurs. Method The SETS aHUS multicentre, open label, prospective, single arm trial enrolled participants from 15 UK hospitals with embedded qualitative and health economic analyses. Patients over two years of age with aHUS who were receiving eculizumab therapy for at least six months were eligible to withdraw from treatment, replacing it with monitoring to assess disease activity with re-introduction of treatment if relapse occurred. The primary outcome measure was harm to a participant as a consequence of eculizumab withdrawal during the 2-year trial period. Participants met a primary outcome if there was a permanent reduction in estimated glomerular filtration rate (GFR), requirement for kidney replacement therapy or significant extra-renal manifestation of disease. The Bayes factor single arm binary model was used to monitor and analyse the trial data, applying pre-trial stopping rules. The trial is registered with the European Union Drug Regulating Authority (EudraCT 2017-003916-37). Results One of 28 participants (3.6%) who withdrew from treatment met a primary outcome. Four participants relapsed, all of whom had pathogenic genetic variants in complement proteins. Only participants with an identified cause of complement dysregulation relapsed. It was possible, by monitoring and rapid participant access, to successfully reintroduce eculizumab treatment. Based on the pre-trial analysis plan, withdrawal from treatment is not associated with a greater risk to patients compared to remaining on treatment. Most patients welcomed the opportunity to withdraw from treatment but identified concerns about monitoring and the risk of relapse, informed by initial experience at presentation. Withdrawing a patient from treatment saves £4.2 million in health care costs. Conclusion Withdrawal of eculizumab treatment with monitoring of disease activity was not associated with an increased risk of harm compared to continuation of eculizumab. The presence of an identifiable cause of complement dysregulation predicts a higher risk of relapse. This study adds to the growing evidence for time limited periods of anti-complement therapy in patients with aHUS.

Aims: Equine acupressure therapies possess an abundance of acclaimed anecdotal evidence; however, scientific validation remains limited. This investigation aimed to explore the effect of manual acupressure on the mechanical nociceptive thresholds (MNTs) of the equine epaxial musculature. Materials and Methods: The study design was a randomized, single crossover trial involving ten horses (five geldings and five mares) of various ages (16 ± 4.49 years). Horses were split into two groups and received a 10-minute acupressure or sham treatment. Nine acupressure points were selected and treated with 30 seconds of direct light pressure followed by six full circles. Each horse was assessed for points of sensitivity at three points bilaterally along the epaxial musculature, before, immediately after, and one day after the acupressure or sham treatment. A two-week washout period was implemented; the groups were reversed, and the protocol was repeated. Data were both parametric and nonparametric; therefore, to ascertain whether differences occurred in MNT values across the time points, a series of repeated measures ANOVAs and Friedman's analyses were undertaken. Where significant differences were found, post hoc Wilcoxon tests with Bonferroni correction identified how MNTs differed with time. Further paired t-tests or Wilcoxon rank tests determined whether differences occurred in the percentage of change between the treatment and control groups. Results: The results of the study suggest that acupressure elicits an immediate increase in MNTs in the epaxial musculature, most significantly at the thoracolumbar region. A decrease in this response could indicate lower sensitivity of the back, allowing better back kinematics and possibly improved performance.

Fragile X Syndrome (FXS) is a leading genetic cause of intellectual disability and autism-like behaviors. Glutamatergic mGluR5 receptors and matrix metalloproteinase-9 (MMP-9) are therapeutic targets to treat FXS, but clinical trials targeting each of these pathways have not been successful. Here, we tested if the electroencephalography (EEG) phenotypes associated with FXS are reversed with a novel combination of treatments affecting the two pathways. Fmr1 knockout (KO) mice were given 10 days of CTEP (mGluR5 antagonist) alone or in combination with minocycline (MMP-9 inhibitor). EEG was recorded during resting (no acoustic stimulation) and during sound presentations (to produce sound-evoked EEG) at 1 day and 10 days after the beginning of treatment administration to test acute effects and potential tachyphylaxis. In pre-treatment WT and KO mice comparisons, we replicated previously published Fmr1 KO mouse EEG phenotypes including elevated power in the resting gamma band, elevated single trial power, and reduced phase-locking to spectrotemporally dynamic auditory stimuli. We found that CTEP treatment alone did not show any benefit compared to vehicle in Fmr1 KO mice after either 1 or 10 days of treatment. CTEP + minocycline reduced resting gamma band power in the Fmr1 KO mice to a greater extent than vehicle at both treatment time points. There were no effects on sound-evoked responses. These data suggest that combined CTEP and minocycline treatment alters resting EEG measures while each treatment administered separately does not yield similar changes. High power in broadband gamma frequency correlates with irritability, stereotyped behaviors, and hyperactivity in FXS patients, suggesting a combination of drugs that reduce mGluR5 and MMP-9 activity may be beneficial in FXS.

To secure market authorization, the Food and Drug Administration requires that drug manufacturers demonstrate product safety and efficacy for an indicated use based on two adequate and well-controlled studies, known as pivotal clinical trials. A single pivotal trial may also be sufficient for product approval, however, if safety and efficacy is clearly and convincingly demonstrated, or if accompanied by confirmatory evidence. We examined all original drug and biologic indication approvals by the Food and Drug Administration between 2015 and 2023 to determine what proportion of those approved on the basis of a single pivotal trial were accompanied by confirmatory evidence, the type and strength of this evidence, and whether confirmatory evidence was cited more frequently after December 2019, when the Food and Drug Administration released draft guidance clarifying issues related to confirmatory evidence. Information was extracted from publicly available Food and Drug Administration documents, and we used descriptive statistics to characterize the sample and chi-square tests to compare the frequency with which confirmatory evidence was cited before and after December 2019. Overall, the Food and Drug Administration approved 441 original drug and biologic indications between 2015 and 2023; 40 of which were excluded. Of the remaining, 181 (41%) were based on 2 or more pivotal trials, 35 (7.9%) on a single pivotal trial with at least one clinical primary efficacy endpoint without orphan designation, and 185 (42%) on a single pivotal trial. Among the final category of approvals, the Food and Drug Administration explicitly referenced confirmatory evidence for 36 (19.5%) single pivotal trial approvals and implicitly referenced confirmatory evidence for 4 (2.2%) others. These 40 approvals referenced 99 unique sources of confirmatory evidence, most commonly pharmacodynamic/mechanistic (n = 49) and other (n = 32). Reference to confirmatory evidence was greater after the Food and Drug Administration issued clarifying guidance in December 2019 (pre: 7% vs post: 34%; p < 0.0001). Given the rising number of the Food and Drug Administration approvals based on a single pivotal trial, greater clarity on confirmatory evidence standards and communication of its use could be considered.