Time Of Testing Research Articles

Lipid management among very-high-risk patients with atherosclerotic cardiovascular disease and type 2 diabetes

Abstract Background Patients with established atherosclerotic cardiovascular disease (ASCVD) and type 2 diabetes (DM2) often meet very-high-risk (VHR) criteria for recurrent ASCVD events and are recommended for aggressive low-density lipoprotein-cholesterol (LDL-C) lowering in guidelines. Purpose Our study aimed to evaluate the proportion of patients achieving guideline-based lipid goals and identify factors associated with achieving these goals among VHR patients with established ASCVD and DM2. Methods Electronic health record data were used to identify VHR patients with established ASCVD and DM2 across 14 large US healthcare systems between 1/1/2022-12/31/2022 with an available LDL-C measurement. We examined the percentage of patients achieving guideline-based lipid goals based on the 2018 AHA/ACC Multisociety Guideline, defined as either having an LDL-C <70 mg/dL or receiving maximal lipid-lowering therapy (i.e., on a PCSK9i monoclonal antibody (mAb)) at the time of the last LDL-C test, and performed multivariable logistic regression to evaluate factors associated with the achievement of those goals. Results Among 213,380 eligible VHR patients with ASCVD and DM2 (mean age 70.2 years, 42% women), 51.8% (110,452) patients achieved guideline-based lipid goals. This included 50.9% with an LDL-C <70 mg/dL and 1.7% on a PCSK9i mAb. Female sex (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.61-0.66), Black race (OR, 0.67; 95% CI, 0.63-0.72), Medicaid insurance (OR, 0.92; 95% CI, 0.86-0.97), and non-coronary artery disease forms of ASCVD including peripheral artery disease (OR, 0.67; 95% CI, 0.65-0.69) and cerebrovascular disease (OR, 0.80; 95% CI, 0.77-0.83) were associated with a lower likelihood of achieving guideline-based lipid goals. Conversely, having undergone percutaneous coronary intervention (OR, 1.31; 95% CI, 1.19-1.43) or coronary artery bypass graft (OR, 1.24; 95% CI, 1.06-1.45) in the previous year, and comorbidities including dialysis (OR, 1.38; 95% CI, 1.23-1.55), atrial fibrillation or flutter (OR, 1.09; 95% CI, 1.06-1.12), and systolic heart failure (OR, 1.11; 95% CI, 1.08-1.14) were associated with a higher likelihood of achieving these goals. Overall, 24.0% of patients were on no statin, 27.2% were on a low- or moderate-intensity statin, and only 5.8% were on a statin in combination with ezetimibe or a PCSK9i mAb. Conclusion Large gaps in care exist for VHR patients with ASCVD and DM2, particularly among women, Black individuals, and those with Medicaid. Targeted interventions are needed to improve the uptake of evidence-based secondary prevention therapies in these patients.

Long-Term Outcomes of Prostate-Specific Membrane Antigen–PET Imaging of Recurrent Prostate Cancer

Although prostate-specific membrane antigen positron emission tomography (PSMA-PET) has shown improved sensitivity and specificity compared with conventional imaging for the detection of biochemical recurrent (BCR) prostate cancer, the long-term outcomes of a widespread shift in imaging are unknown. To estimate long-term outcomes of integrating PSMA-PET into the staging pathway for recurrent prostate cancer. This decision analytic modeling study simulated outcomes for patients with BCR following initial definitive local therapy. Inputs used were from the literature and a retrospective cohort study conducted at 2 institutions. The base case analysis assumed modest benefits of earlier detection and treatment, and scenario analyses considered prostate-specific antigen (PSA) level at imaging and different outcomes of earlier vs delayed treatment. The analysis was performed between April 1, 2023, and May 1, 2024. (1) Immediate PSMA-PET imaging, (2) conventional imaging (computed tomography and bone scan [CTBS]) followed by PSMA-PET if CTBS findings were negative or equivocal, and (3) CTBS alone. The main outcomes were detection of metastases, deaths from prostate cancer, and life-years and quality-adjusted life-years (QALYs) gained. The model estimated that per 1000 simulated patients with BCR (assumed median age, 66 years), PSMA-PET is expected to diagnose 611 (95% uncertainty interval [UI], 565-656) patients with metastasis compared with 630 (95% UI, 586-675) patients diagnosed using CTBS followed by PSMA-PET and 297 (95% UI, 202-410) patients diagnosed using CTBS alone. Moreover, the estimated number of prostate cancer deaths was 512 (95% UI, 472-552 deaths) with PSMA-PET, 520 (95% UI, 480-559 deaths) with CTBS followed by PSMA-PET, and 587 (95% UI, 538-632 deaths) with CTBS alone. Imaging with PSMA-PET yielded the highest number of QALYs, which were 824 (95% UI, 698-885) higher than CTBS. These results differed by PSA level at the time of testing, with the highest incremental life-years and QALYs and lowest number of deaths from prostate cancer among patients with PSA levels of at least 5.0 ng/mL. Finally, the estimates were sensitive to the expected benefit of initiating therapy for recurrent prostate cancer earlier in the disease course. The results of this decision-analytic model suggest that upfront PSMA-PET imaging for the evaluation of BCR is expected to be associated with reduced cancer mortality and gains in life-years and QALYs compared with the conventional imaging strategy, assuming modest benefits of earlier detection and treatment.

Nasal obstruction during development leads to defective synapse elimination, hypersynchrony, and impaired cerebellar function

Nasal respiratory disorders are linked to craniofacial anomalies and systemic dysfunctions. However, the implications of nasal respiratory disorders on brain development and their subsequent impact on brain functionalization remain largely unknown. Here, we describe that nasal obstruction from postnatal developmental stages in mice precipitates deficits in cerebellum-associated behaviors and compromised refinement and maturation of neural circuits in the cerebellum. We show that mice with nasal obstruction during developmental phases exhibit marked impairments in motor function and exhibit increased immobility time in forced swimming test. Additionally, we identified critical periods during which nasal respiration is essential for optimizing motor function and preserving mental health. Our study also reveals that nasal obstruction in mice disrupts the typical developmental process of synapse elimination in the cerebellum and hinders the normal transition of activity patterns in cerebellar Purkinje cell populations during development. Through comparing activity patterns in mouse models subjected to nasal obstruction at various stages, we suggest that the maturation of specific activity pattern among Purkinje cell populations is fundamental to the functional integrity of the cerebellum. Our findings highlight the indispensable role of adequate nasal respiration during development for the establishment and functional integrity of neural circuits, thereby significantly affecting brain function.

Access and models of obstructive sleep apnea care: a cross-national comparison of Canadian and Australian patient survey data.

To describe similarities and differences in OSA care pathways and their impact on patients in Australia and Canada, including among urban versus rural participants. In this secondary data analysis of patient surveys exploring OSA care in Australia and Canada, we recruited adults with a prior diagnosis of OSA from market research companies, social media, and patient-facing medical associations. Residential postal codes were used to classify participants as urban or rural. Survey domains included wait times and travel distances for care, providers, and treatments. Data from 589 Canadians (21% rural; 42% female, mean [SD] age = 57 [13] years) and 412 Australians (38% rural; 45% female, mean [SD] age = 58 [14] years) with OSA were included. Participants in both countries most commonly sought initial care for suspected OSA from a primary care practitioner. Canadian participants waited longer to seek care than Australian participants (37% vs 51% within 12 months of symptom onset). Wait times for diagnostic testing were longer in Canada (59% vs 76% within 3 months of initial assessment), especially in urban settings (58% vs 78%). In both countries, >80% of participants were offered positive airway pressure (PAP) therapy. Overall, a greater variety of treatments were offered and used by Australian participants. Greater access to diagnostic testing and a greater variety of treatments were found in Australia compared to Canada. Further research is needed to determine if reduced diagnostic wait times and presentation of increased therapy options found in Australia translate into better patient outcomes.

The administration of a phentolamine infusion into the basolateral amygdala enhances long-term memory and diminishes anxiety-like behavior in stressed rats.

The basolateral amygdala (BLA) contains adrenergic receptors, which are known to be involved in stress, anxiety, and memory. The objective of this study was to explore whether inhibition of α-adrenergic receptors (by phentolamine, an α-adrenergic receptor antagonist) in the BLA can reduce foot-shock stress-induced anxiety-like behavior, memory deficits, and long-term potentiation (LTP) deficits within the CA1 region of the rat hippocampus. Forty male Wistar rats were assigned to the intact, control, stress (Str), Phent (phentolamine), and Phent + Str groups. Animals were subjected to six shocks on 4 consecutive days, and phentolamine was injected into BLA 20 min before the animals were placed in the foot-shock stress apparatus. Results from the elevated plus maze test (EPM) revealed a reduction in anxiety-like behaviors (by an increased number of entries into the open arm, percentage of time spent in the open arm, and rearing and freezing) among stressed animals upon receiving injections of phentolamine into the BLA. The open-field test results (increased rearing, grooming, and freezing behaviors) were consistent with the EPM test results. Phentolamine infusion into the BLA enhanced spatial memory, reducing errors in finding the target hole and decreasing latency time in the Barnes maze test for stress and nonstress conditions. Injecting phentolamine into the BLA on both sides effectively prevented LTP impairment in hippocampal CA1 neurons after being subjected to foot-shock stress. It has been suggested that phentolamine in the BLA can effectively improve anxiety-like behaviors and memory deficits induced by foot-shock stress.

Impaired Sleep-Dependent Memory Consolidation in Pediatric Narcolepsy Type 1.

Disrupted nighttime sleep (DNS) is common in pediatric Narcolepsy type 1, yet its cognitive impact is unknown. As N2 sleep spindles are necessary for sleep-dependent memory consolidation, we hypothesized that Narcolepsy Type 1 impairs memory consolidation via N2 sleep fragmentation and N2 sleep spindle alterations. We trained 28 pediatric Narcolepsy Type 1 participants and 27 healthy controls (HC) on a spatial declarative memory task before a nocturnal in-lab polysomnogram and then gave them a cued recall test upon awakening in the morning. We extracted wake and sleep stage bout numbers and N2 spindle characteristics from the polysomnogram and conducted mixed model analysis of sleep-dependent memory consolidation to identify group differences. Narcolepsy Type 1 participants had shorter N2 bout durations and associated shorter N2 spindles vs. HC, but other N2 spindle features were similar. Narcolepsy Type 1 participants had worse memory performance post-sleep than HCs after adjusting for age and gender (mean memory consolidation HC: -3.1% ± 18.7, NT1: -15.6 ± 24.8, main effect group x time of testing F=5.3, p=0.03). We did not find significant relationships between sleep-dependent memory consolidation and N2 spindle characteristics. Notably, increased N1% was associated with worse sleep-dependent memory consolidation with results driven by the Narcolepsy Type 1 group. Sleep-dependent memory consolidation is mildly impaired in youth with Narcolepsy Type 1 and findings may be attributed to increases in N1 sleep. Further studies are needed to determine if these findings are generalizable and reversible with sleep-based therapies.

Refinement of Hy's Law using the Drug-Induced Liver Injury Network Database.

Hyman Zimmerman observed that hepatocellular (HC) drug-induced liver injury (DILI) with jaundice had a mortality rate of ≥10% (Hy's Law). Hy's Law does not specify the timing of liver tests nor the definition of HC DILI versus cholestatic or mixed (C/M) DILI. We aimed to assess the validity of Hy's Law in the prospective Drug-Induced Liver Injury Network (DILIN) cohort. Drugs with ≥10 confirmed DILI cases with jaundice were analyzed. Four permutations of Hy's Law were applied: R≥ 5 using initial (1) or peak (2) ALT, AST and Alk P levels, and the FDA associated criteria of ALT or AST ≥ 3x ULN with Alk P ≤ 2x ULN using initial (3) or peak values (4). Mortality was death or liver transplant adjudicated to be due to DILI. Using initial R values, mortality was 11.1% for HC vs 2.0% for C/M (p<0.001); using peak R values, mortality was 10.3% vs 1.6% (p<0.001). Using FDA associated definition, mortality was 7.9% vs 3.9% (p=0.04) using initial values and 7.9% vs 3.0% (p=0.01) using peak values. Using initial R values, drugs that frequently caused HC injury generally had mortality rates ≥ 10%; while drugs that typically caused C/M injury all had rates <10%. Occasional agents that caused HC injury with jaundice were associated with low mortality. Initial R values were the most reliable means of identifying Hy's Law cases. There were some drugs that caused HC injury with jaundice but with mortality rates <10%. Refinement of Hy's Law is warranted.

Diurnal variation of psychomotor, cognitive and physical performances in schoolchildren: sex comparison

BackgroundThe present study investigated the effect of time of day (08h00 vs. 11h00 vs. 14h00 vs. 17h00) and sex (girls vs. boys) on physical (i.e., five jump test (5JT), push-ball test and 5 m shuttle run test (5mSRT)), cognitive (i.e., attention) and mental (i.e., mental flexibility) performances.MethodsThirty schoolchildren, equally divided in girls (n = 15; age: 9.60 ± 0.51 years) and boys (n = 15; age: 9.40 ± 0.51 years) performed the digit cancellation test, the trail making test, the 5JT, the 2 kg push-ball test and the 5mSRT in a counterbalanced and cross over study design at 08h00, 11h00, 14h00 and 17h00 with 48 h of rest in between. Additionally, rating of perceived exertion (RPE) was determined after each repetition of the 5mSRT and the average of the score (i.e., sum of RPE scores divided by 6) was determined.ResultsResults showed that RPE at the end of the test was significantly higher at 11h00 compared to 08h00 (p = 0.02) and 14h00 (p = 0.001) and average RPE was higher at 11h00 compared to 08h00 (p = 0.001). Likewise, attention was significantly higher at 08h00 compared to 17h00 (p = 0.001) before and after the 5mSRT test only in girls. However, 5JT performance was significantly lower at 17h00, both in girls and boys, compared to at 08h00 (p = 0.02 and p = 0.001 respectively), 11h00 (p = 0.004 and p = 0.001 respectively) and 14h00 (p = 0.001 and p = 0.001 respectively). However, push-ball (p = 0.086) and 5mSRT performances [best distance (p = 0.173), total distance (p = 0.306), mean distance (p = 0.29), fatigue index (p = 0.06)] were time of day independent. Mental flexibility was significantly higher at 08h00, 11h00 and 14h00 compared to 17h00 (p = 0.001).ConclusionMental flexibility, attention and jump performances were time of day dependent and push-ball test and 5mSRT performances did not change according to the time of day. Also, no clear sex effect was found on the diurnal variation of mental, cognitive and physical performances.

Carbazole-Based Dual-Band Electrochromic Polymers: The Effect of Linkage Sites on Electrochromic Performance.

Dual-band electrochromic (EC) materials are expected to be utilized as building materials for energy saving, but their cycle stability is still an obstacle. Here, two D-A conjugated polymers, PDPPCz36 and PDPPCz27, based on diketopyrrolopyrrole and carbazole linked with different sites, are synthesized. Both of them exhibit dual-band EC behaviors with a dark blue color in the neutral state and high absorption in the near-infrared (NIR) region when oxidized. However, PDPPCz36 exhibits better cycle stability and a shorter response time than PDPPCz27. In the visible (VIS) region, the PDPPCz36 film exhibits an initial light modulation range (ΔT) of 43.0% and that of the PDPPCz27 film is 41.3%. After 100 cycles of redox, the ΔT of the PDPPCz36 film declines by 32%, while that of PDPPCz27 attenuates by more than 50%. A similar tendency is evident in the NIR region. Moreover, PDPPCz36 shows subsecond colored switch times both in the VIS (0.4 s) and NIR (0.7 s) regions, while those of PDPPCz27 are 2.1 and 1.6 s, respectively. Further research suggests that 3,6-linked carbazoles in PDPPCz36 simultaneously inhibit the side reaction and film aggregation, which leads to better redox stability and shorter response time in both EC tests and devices.

Plasma Cell-free DNA Metagenomic Next-Generation Sequencing in Immunocompromised Children

Abstract Background Plasma cell-free DNA metagenomic next-generation sequencing (mNGS) is a novel diagnostic tool for infectious diseases [1]. Data suggests that plasma mNGS may be useful in immunocompromised adults, changing management in up to 60% of the patients [2]. A prospective study evaluating utility of plasma mNGS for pneumonia in immunocompromised adults concluded that mNGS provided an additive diagnostic value of 12.1% [3]. A similar study in adults with febrile neutropenia reported a sensitivity and specificity of 85 and 100%, respectively [4]. However, there is limited data evaluating the utility of mNGS in immunocompromised children. Methods We retrospectively reviewed all pediatric immunocompromised patients who had plasma mNGS testing performed from December 2018 to July 2023 at St. Jude Children’s Research Hospital. Electronic medical records were reviewed to extract relevant clinical data and microbiologic data including results of mNGS, contemporaneous cultures, and related antimicrobial treatment. Descriptive statistics are presented as frequencies and medians (interquartile range, IQR). Comparisons were performed using Fisher’s exact test or Wilcoxon rank-sum test, as appropriate, using R version 3.6.3. Results A total of 18 immunocompromised children underwent plasma mNGS testing. Acute lymphoblastic leukemia was the most common malignancy (33.3%), followed by acute myeloid leukemia (22.2%). Two patients (11.1%) had undergone hematopoietic cell transplant, both allogeneic. At the time of testing, 16 patients (88.9%) had fever and 10 (55.6%) had an absolute neutrophil count of &amp;lt;500/mm3. All except one were on antimicrobial therapy at the time of testing, with a median duration of 8 days (IQR=12.25). Only 9 (50%) patients had a positive mNGS result. A positive mNGS resulted in broadening or extending antibiotics course in 4 patients (22.2%); negative mNGS results did not lead to changes in management in any of the cases. There were no significant differences in age, sex, days of fever, neutropenia, gastrointestinal (GI) symptoms, and days of fever before testing between those with positive versus negative results. However, a higher frequency of GI symptoms at the time of testing among those with positive results was observed. Clinical characteristics and impact on management in patients with positive and negative results are summarized in Table 1. Conclusion Plasma mNGS had a limited impact on the management of immunocompromised children at our institution. Negative results did not lead to de-escalation of therapy, and positive results led to additional exposure to antibiotics. Further research is needed to determine the role of mNGS in this population, and the interpretation of positive testing in the setting of gastrointestinal disease.

A Leakage Safety Discrimination Model and Method for Saline Aquifer CCS Based on Pressure Dynamics

The saline aquifer CCS is a crucial site for carbon storage. Safety monitoring is a key technology for saline aquifer CCS. Current CO2 leakage detection methods include microseismic, electromagnetic, and well-logging techniques. However, these methods face challenges, such as difficulties in determining CO2 migration fronts and predicting potential leakage events; as a result, the formulation of test timing and methods for these safety monitoring techniques are somewhat arbitrary. This study establishes a gas–water two-phase seepage model and solves it using a semi-analytical method to obtain the injection pressure and the derivative curve characteristics of the injection well. The pressure derivative curve can reflect the physical properties of the reservoir through which CO2 flows underground, and it can also be used to determine whether CO2 leakage has occurred, as well as the timing and amount of leakage, based on boundary responses. This study conducted sensitivity analyses on eight parameters to determine the impact of each parameter on the bottom-hole pressure and its derivatives, thereby obtaining the influence of its parameters on different flow stages. The research indicates that, when a steady-state flow characteristic appears at the outer boundary, CO2 leakage will occur. Additionally, the leakage location can be determined by calculating the distance from the injection well. This can guide the placement and measurement of safety monitoring methods for saline aquifer CCS. The method proposed in this paper can effectively monitor the timing, location, and amount of leakage, providing a technical safeguard for promoting CCS technology.

Risk Factors Associated With Exaggerated Blood Pressure Response At The Time Of Exercise Treadmill Stress Test.

Exaggerated blood pressure response (EBPR) to exercise stress testing (EST) may be a marker of future hypertension and carry valuable information for the prediction of cardiovascular events. We sought to evaluate the clinical and resting EST parameters associated with increased likelihood to EBPR. The records of 14073 patients (mean age: 55±11 years) without known cardiovascular disease who underwent a treadmill EST were analysed. The overall prevalence of arterial hypertension was 44%. A considerable proportion (24%) of patients exhibited EBPR. Multivariate analysis of the entire study population showed that middle-aged individuals (40-60 years old), resting systolic BP>130mmHg and/or diastolic BP>80 mmHg, known arterial hypertension, current cigarette smoking and family history of premature coronary artery disease are all independent risk factors for EBPR (all P<0.001). Although the presence of arterial hypertension increased the likelihood of EBPR in the analysis of the entire population, the relevant association in subjects above 60 years old is statistically non-significant (P=0.120). Notably, the pre-test systolic BP>130mmHg and/or diastolic BP>80 mmHg level increased significantly the likelihood to manifest EBPR in all age categories (<40, 40-60 and >60 years old) independent of hypertension presence and in all hypertensive patients independently of antihypertension treatment intake (all P<0.001). Considering the diagnostic and prognostic utility of EBPR during treadmill EST the clinical and resting haemodynamic parameters that increase the likelihood to EBPR are targets for interventions and preventive measures to modify lifestyle risk behaviours and reduce hypertension and cardiovascular risk factors in the early stages.

Is there enough evidence supporting the clinical adoption of clear cell likelihood score (ccLS)? An updated systematic review and meta-analysis

ObjectiveTo review the evidence for clinical adoption of clear cell likelihood score (ccLS) for identifying clear cell renal cell carcinoma (ccRCC) from small renal masses (SRMs).MethodsWe distinguished the literature on ccLS for identifying ccRCC via systematic search using PubMed, Embase, Web of Science, China National Knowledge Infrastructure, and Wanfang Data until 31 March, 2024. The risk of bias and concern on application was assessed using the modified quality assessment of diagnostic accuracy studies (QUADAS-2) tool. The level of evidence supporting the clinical adoption of ccLS for identifying ccRCC was determined based on meta-analyses.ResultsEight MRI studies and three CT studies were included. The risk of bias and application were mainly related to the index test and flow and timing, due to incomplete imaging protocol, unclear rating process, and inappropriate interval between imaging and surgery. The diagnostic odds ratios (95% confidence intervals) of MRI and CT ccLS were 14.69 (9.71–22.22; 6 studies, 1429 SRM, 869 ccRCC), and 5.64 (3.34–9.54; 3 studies, 296 SRM, 147 ccRCC), respectively, for identifying ccRCC from SRM. The evidence level for clinical adoption of MRI and CT ccLS were both rated as weak. MRI ccLS version 2.0 potentially has better diagnostic performance than version 1.0 (1 study, 700 SRM, 509 ccRCC). Both T2-weighted-imaging with or without fat suppression might be suitable for MRI ccLS version 2.0 (1 study, 111 SRM, 82 ccRCC).ConclusionccLS shows promising diagnostic performance for identifying ccRCC from SRM, but the evidence for its adoption in clinical routine remains weak.Critical relevance statementAlthough clear cell likelihood score (ccLS) demonstrates promising performance for detecting clear cell renal cell carcinoma, additional evidence is crucial to support its routine use as a tool for both initial diagnosis and active surveillance of small renal masses.Key PointsClear cell likelihood score is designed for the evaluation of small renal masses.Both CT and MRI clear cell likelihood scores are accurate and efficient.More evidence is necessary for the clinical adoption of a clear cell likelihood score.Graphical

Gaps in HIV Pre-exposure Prophylaxis Acceptance: Findings from an Outpatient HIV Testing Service in Italy

Background: The aim of this study is to assess the acceptability of HIV pre-exposure prophylaxis (PrEP) among individuals eligible for prophylaxis. Setting: Retrospective study of individuals receiving their first HIV test at the Infectious Diseases Unit of IRCCS San Raffaele Scientific Institute, Milan, Italy. Methods: People i) who received their first HIV test (baseline date) between January 2018 (availability of PrEP in Italy) and December 2023 (data lock), ii) with an indication for PrEP based on condomless sex were included; those already on PrEP were excluded. Individuals with a negative HIV test result were offered PrEP counselling and prescription according to guidelines. Characteristics of people who accepted or declined HIV PrEP were compared using Mann-Whitney or Chi-square tests, as appropriate. Results: A total of 2627 people were tested for HIV: 175 (6.6%) were diagnosed with HIV. Of the 2452 people with negative HIV test results, 2165 (88.3%) were men; median age was 34.3 years (interquartile range, IQR=28.7-42.4). Sexually transmitted infections (STIs) were detected in 478/2452 (19.5%), most commonly gonorrhoea (206/2452, 8.4%). Overall, 982/2452 (40.0%) people accepted PrEP, including only three women. Non-acceptance was higher among women (p&lt;0.001) and non-Caucasians (p&lt;0.001). Of those who did not accept PrEP, 260 (17.7%) were diagnosed with at least one STI at the time of HIV testing. Conclusion: Low PrEP acceptance was observed, particularly among women and people of non-Caucasian origin. Non-acceptance of PrEP was also observed among individuals diagnosed with an STI.

Different peripheral nerve blocks for patients undergoing total knee arthroplasty: a network meta-analysis of randomized controlled trials.

To comprehensively compare the effect of different peripheral nerve blocks for patients undergoing total knee arthroplasty (TKA). PubMed, Embase, Cochrane Library, and Web of Science were comprehensively searched. The outcomes included postoperative pain, postoperative function, adverse events, oral morphine equivalent (OME), and perioperative indicators. Network plots, forest plots, league tables and rank probabilities were drawn for all outcomes. Totally 30 studies were included. For postoperative pain, continuous adductor canal block (cACB) + genicular nerve block (GNB) was most likely to be the most effective block regarding rest pain score at 24h; cACB + GNB was most likely to result in the lowest rest pain score at 48h; patients undergoing cACB + infiltration between the popliteal artery and the capsule of the knee (IPACK) + GNB was most likely to have the lowest motion pain score at 24h; patients undergoing cACB + GNB was most likely to have the lowest motion pain score at 48h. For postoperative function, patients undergoing cACB + IPACK + GNB had the highest likelihood to exhibit the shortest time in Timed Up and Go test (TUG); cACB + tibial nerve block (TNB) was most likely to be the most effective block in terms of range of motion (ROM); cACB + IPACK was most likely to be the optimal block concerning the ambulation distance. cACB combined with IPACK/GNB may be the most favorable block after TKA, continuous blocks may be better than single-shot blocks, and combined blocks may be better than separate blocks.

Multitasking, subtitles, and product placement effectiveness: an analysis of multitasking influencing the effectiveness of product placement and being influenced by audiovisual translation formats

ABSTRACT Placing brands and products in movies and series has significantly increased in recent years, leading to more research on the subject being undertaken. Little of this research has so far focused on the relationship between multitasking by audiences and the effectiveness of product placement. This study tests time the correlation between levels of multitasking and brand recall of placements in programs. The second objective of the study is to investigate if there is any link between the version of a program watched (i.e. original, dubbed, or subtitled), and levels of multitasking. The experimental online survey showed no difference in brand recall among viewers engaging in secondary activities while watching a program for up to 5 minutes in a 20-minute episode. The addition of subtitles increased screen attention, and viewers did not multitask as much. An innovative out-of-lab method consisting of in-home video observation produced high-precision time data on viewers’ multi-tasking behavior and enabled cross-checking with the survey answers for false-positives. The main outcome of this study is that multitasking while watching shows or movies should not be a concern for advertisers investing in product placement.

6917 Multiple Red Herrings Complicating the Diagnosis of Cyclic Cushing’s Syndrome

Abstract Disclosure: A. Grover: None. R. McGlotten: None. L.K. Nieman: None. Introduction: Cyclic Cushing’s syndrome (CCS) is a rare disorder characterized by intermittent hypercortisolemia. It may be caused by pituitary tumor (Cushing disease), ectopic ACTH tumor secretion (EAS), or primary adrenal disease. We present a case of CCS with multiple red herrings complicating the diagnosis. Case: A 57-year-old Cushingoid appearing woman presented elsewhere with weight gain, brain fog, weakness, hypertension, worsening diabetes, and OSA. Screening tests showed more than three episodes of hypercortisolism with interval eucortisolism: salivary and 24-urine cortisol (UFC) ranged from 0.06-0.34 µg/dL (reference range, RR, ≤0.09 µg/dL) and 59.7-137.1 µg/24 h (RR 4-50 µg/24 h) respectively. The patient was symptomatic throughout. Differential diagnosis was CCS vs a physiologic non-neoplastic condition. As she had no clear etiology for the latter, further testing was performed. ACTH was indeterminate (23-27 pg/mL, RR &amp;lt;46). Pituitary MRI showed a left 7 mm lesion. Inferior petrosal sinus sampling (IPSS) with Corticotropin Releasing Hormone (CRH) administration showed peripheral baseline ACTH levels of 9.0 and 10.0 pg/mL, suggesting that she had cycled out of a hypercortisolemic phase. The left petrosal baseline values were low (9 pg/mL,16 pg/mL), suggesting poor catheterization, which was confirmed by a low prolactin-normalized ACTH ratio. The petrosal levels were lower than expected (maximum 767 pg/ml), due to suppression of normal corticotropes vs poor tumor response. However, a central:peripheral step-up was consistent with Cushing's disease (CD) or pseudo-CS. She was referred to us for re-evaluation. A low FSH, LH, low normal TSH, and UFC of 160 µg/24h supported a diagnosis of CS. ACTH was 14.6 pg/mL. Pituitary MRI showed a 1.3 cm x 0.8 cm mass extending into the left cavernous sinus. She did not suppress cortisol during a dexamethasone suppression test (DST). After CRH administration ACTH levels doubled. Based on the macroadenoma and CRH response, CD was established; IPSS was not repeated. After transsphenoidal hypophysectomy, pathology revealed ACTH positive adenoma. Post-operative adrenal insufficiency required hydrocortisone replacement. Conclusion: CCS can pose a diagnostic challenge due to unpredictable duration and frequency of hypercortisolism. Intermittently elevated cortisol levels with CS symptoms should raise suspicion for CCS. In our case, low peripheral ACTH levels further suggested this possibility. DST may give spurious results in CCS owing to spontaneous falls or rises in cortisol at the time of testing. Prolonged hypercortisolism is required in all patients to ensure suppression of normal corticotropes, which if not complete, may confound results in patients with EAS. Finally, inadequate catheterization may affect accuracy of lateralization in any patient with CS and is ideally evaluated both by venography and prolactin measurement. Presentation: 6/1/2024

Design, synthesis and biological evaluation of arylpropylamine derivatives as potential multi-target antidepressants

In this study, a series of novel arylpropylamine derivatives were designed, synthesized and evaluated as potential multi-target antidepressants. Among them, compound (R)-13j displayed unique pharmacological features, exhibiting excellent inhibitory potency against serotonin and noradrenaline transporters (SERT/NET) and high affinity for 5-HT2A/2C receptor, and showing low affinity for histamine H1, adrenergic α1 receptors and hERG channels (to reduce QT interval prolongation). Molecular docking studies provided a rational binding model of (R)-13j in complex with SERT and 5-HT2A/2C receptor. In animal models, compound (R)-13j dose-dependently reduced the immobility time in the tail suspension test (TST) and the forced swimming test (FST) in mice, with higher efficacy when compared to duloxetine, and showed no stimulatory effect on the locomotor activity. Moreover, compound (R)-13j significantly shortened the immobility time in the ACTH-induced rat model of treatment-resistant depression (TRD). Furthermore, compound (R)-13j also exhibited a higher threshold for acute toxicity than duloxetine. In addition, compound (R)-13j possessed a favorable pharmacokinetic profile in mice. Taken together, compound (R)-13j may constitute a novel class of drugs for the treatment of depression.

A-016 Can You Believe Your Troponin? Using Laboratory Automation and Programmed Rules to Reduce Non-Repeatable False Positive Troponin Results

Abstract Background Cardiac troponin is currently the standard biomarker for evaluating patients with suspected acute coronary syndrome. Like all immunoassays, troponin testing is susceptible to non-repeatable positive results. Because this can cause a clinical challenge, we assessed our false positive rate by manipulating the timing and conditions of repeat troponin testing. Methods A prospective observational study established the repeatability failure (RF) rate in three scenarios, where a suspicious initial result prompts a repeat test. Protocol 1: We programed our middleware (Remisol, Beckman Coulter) to route the specimen to online storage after initial testing. After a 120-minute delay, the specimen was automatically retrieved from storage and tested again. Protocol 2: We programmed DxI 800 systems (Beckman Coulter) to aspirate a specimen reserve volume sufficient for two test replicates simultaneously. Protocol 3: We restricted repeat testing to 18-50 ng/L where the majority of RF occurred. To analyze RF in 4 and 18 ng/L interval (limit of reporting and URL, respectively), an absolute 3.5 ng/L bias was considered an RF. For specimens &amp;gt;18 ng/L, a difference of ±4.0 SD difference between replicates with a CV of 7% was a RF, equating to a relative difference of 28% (Method 1). Method 2 used a relative difference of 35% for RF. Method 3 defined RF as a critical difference of z×√2×SDanalytical where z=3.5 and SD=1.8 for results &amp;lt;19 ng/L and SD for results ≥19 ng/L were calculated from a fixed 7% CV for each result. A z-value of 3.5 represents a probability of 0.0005 (5 in 10,000). Results Using Protocol 1, RF rate was significantly higher in delayed repeat testing (1.6%, CI 1.5-1.8, n=23,525) compared to immediate repeat testing (0.4%, CI 0.4-0.5, n=14,880, p&amp;lt;0.0001) in two-tailed analysis. Because the first result was more commonly larger than the second (77.7% v. 52.2%, respectively), one-tailed analysis was used and found RF in delayed repeat testing was 0.9% (CI 0.8-1.0) v. immediate repeat testing (0.4%, CI 0.3-0.4, p&amp;lt;0.0001). A similar percentage of results were found in the 18-50 ng/L range in delayed testing (88.6%) v. immediate repeat (86.8%). Protocol 2 (with one-tailed analysis) yielded similar RF rates: 0.8%, CI 0.8-1.0 v. 0.3%, CI 0.3-0.4, delayed and immediate repeat testing, respectively. Protocol 3 yielded RF rate of 0.6%, CI 0.5-0.7 v. 0.2%, CI 0.2-0.3, delayed and immediate repeat testing, respectively, with all p-values &amp;lt;0.0001. Conclusions By programming auto-repeating hsTnI testing only in the 18-50 ng/L range, we found &amp;gt;80% of specimens with potential RF results could be retested using either the delayed- or immediate-repeat protocols. This suggests automated protocols could repeat testing with potential RFs without staff intervention or increasing container movement on the automation line. Reagent usage because of repeat testing could be conserved by limiting repeat testing to specimens most likely to create provider confusion. Rules to automate selected retesting of hsTnI in testing systems and/or middleware can enhance quality of results without human intervention and subsequent burden on staff, reduce reagent waste and enhance provider decision making in a critical population.

A quality initiative in BRCA testing and timing of BRCA test prior to surgery in HER2- early stage breast cancer.

287 Background: The University of Pittsburgh Medical Center (UPMC) collaborated with Integra Connect PrecisionQ (IC) on a quality initiative to improve BRCA 1/2 (BRCA) testing in patients (pts) with early-stage (I-III) human epidermal growth factor receptor negative (HER2-) breast cancer (BC). The project involved developing a baseline of BRCA testing, reviewing the results with leadership, conducting a focus group with physicians to identify improvements, and then monitoring the results of BRCA testing thereafter during a post-baseline period. The project sought to improve the identification of pts who may be eligible for olaparib given the updated approval on March 11, 2022, for early-stage high-risk germline BRCA mutated pts. We aim to show the improvement in BRCA testing and timing of test in relation to surgery among HER2- BC pts at UPMC. Methods: Using the de-identified IC PrecisionQ database, 202 UPMC pts with early-stage HER2- BC were selected for medical chart curation as baseline group. Pts in the baseline group received surgery between 7/1/2021 to 6/30/2022. The baseline data was reviewed with UPMC clinical leadership and findings were discussed among a focus group of 8 physicians on 7/17/2023. Following the meeting, UPMC practices performed genetic testing at the office as opposed to sending pts to directly to genetic counseling. Post-baseline, we evaluated 70 pts who underwent surgery between 8/1/2023 to 1/31/2024 to assess BRCA rates and timing of BRCA testing in relation to surgery. Descriptive analyses were performed and proportions were compared using a chi-squared test. Results: Among the baseline cohort of 202 pts, 72% were hormone receptor positive (HR+) and 28% were hormone receptor negative (HR-). Among the post-baseline cohort of 70 pts, 77% were HR+ and 23% were HR-. The rate of BRCA testing at baseline was 44% compared to 56% post-baseline (p 0.05). Among HR+ pts, BRCA testing increased from 38% to 50% and among HR- pts, BRCA testing increased from 67% to 81%. The rate of BRCA testing prior to surgery at baseline was 58% (N= 88) compared to 80% (N=40) post-baseline (p &lt;0.01). Among HR+ pts age &lt;65, BRCA testing at baseline was 46% (N=54) compared to 51% (N=35) post-baseline. Among HR- pts age &lt;65 BRCA testing at baseline was 84% (N=25) compared to 100% (N=9) post-baseline. Conclusions: The quality initiative at UPMC that focused on BRCA testing among HER2- BC pts led to an improvement from 44% to 56% of pts being tested. Among those who were tested, there was an increase from 58% to 80% tested prior to surgery. Given the recent updates on January 4 th , 2024 by ASCO and SSO recommending BRCA1/2 testing to all women younger than age 65 with breast cancer, such QIs can be a useful tool to align a practice’s approach to new standards of care.