The objective of this retrospective study was to evaluate and compare the safety characteristics of patients with chronic low back pain (cLBP) without a recent positive history of opioid use disorder (OUD). This study was conducted using the Merative MarketScan® database (January 2019-December 2023). The first date of Belbuca®, buprenorphine patch, or oral schedule II (CII) opioid prescription was designated as the index date. The observational period covered a 6-month preindex period and a follow-up period that lasted until the end of index treatment or continuous healthcare coverage. Patients were required to have two low back pain diagnoses and no OUD in the preindex period and continuous healthcare coverage during the observational period. The primary outcomes were serious treatment-emergent adverse event (TEAE) rates reported as incidence rate ratios (IRR) or absolute incidence rate difference (IRD) per 1,000 person-years for TEAEs occurring in one cohort. Propensity-score matching was employed to balance differences in patient characteristics and minimize their impact on study outcomes. There were no serious TEAEs associated with higher occurrence in the Belbuca® cohort compared with oral CII opioids. Belbuca® treatment was associated with a significantly lower rate of serious opioid abuse/dependence (IRD -33.76 per 1,000 person-years, p = 0.032), osteoarthritis (IRD -78.77 per 1,000 person-years, p = 0.001), urinary discomfort (IRD -146.28 per 1,000 person-years, p < 0.001), seizures (IRR 0.11, p = 0.019), dehydration (IRR 0.13, p = 0.003), abdominal pain (IRR 0.25, p < 0.001), and nausea/vomiting (IRR 0.30, p = 0.001). The subanalysis compared incidence rates of serious TEAEs between Belbuca® and buprenorphine patch cohorts. Belbuca® demonstrated higher rates of serious coronary artery disease (IRD 39.01 per 1,000 person-years, p = 0.035), cholecystitis (IRD 39.01 per 1,000 person-years, p = 0.035), and headache (IRD 39.01 per 1,000 person-years, p = 0.035). However, the buprenorphine patch cohort had higher incidence rates of serious QT prolongation (IRD -52.78 per 1,000 person-years, p = 0.009), opioid abuse/dependence (IRD -184.75 per 1,000 person-years, p < 0.001), confusion (IRR 0.10, p = 0.007), hypertension (IRR 0.22, p = 0.043), and cellulitis (IRR 0.41, p = 0.011). The study findings suggest that Belbuca® may have a favorable safety profile relative to oral CII opioids and buprenorphine patch treatments in cLBP patients without a positive history of OUD.
This Viewpoint reviews the case of sodium oxybate, a product of gamma-hydroxybutyrate (GHB), to illustrate how psychedelics and other Schedule I substances can proceed through a similar regulatory pathway.
Learning-based multi-view 3D reconstruction pipelines, such as transformer-based approaches, enable the accurate reconstruction of 3D scenes from multiple images, but their deployment across the edge-cloud continuum is challenging due to high computational demands and large intermediate data transfers. Effective pipeline scheduling in the continuum must therefore balance latency constraints with the cost of cloud resource usage. In this work, we address cost-aware scheduling under latency constraints for a multi-stage 3D reconstruction pipeline consisting of depth estimation, transformer-based multi-view fusion, and point cloud merging with export to a rendering-ready representation. We implement a service-oriented pipeline where each stage can be executed either on edge or cloud nodes, and we experimentally characterize its performance on representative hardware platforms. The results show a strong imbalance between the computational time and communication latency across platforms, mainly due to large intermediate data. Based on these insights, we propose an online scheduler that dynamically selects stage placements to minimize the cloud cost while satisfying latency constraints. The scheduler incorporates a top-K edge selection mechanism that reduces the decision complexity by jointly considering the network conditions and node utilization. Simulation results parameterized with real-system measurements show that the proposed approach effectively reduces cloud usage while meeting latency constraints, outperforming the baseline strategies based on single-node pipeline execution.
Background/Objectives: Sapropterin dihydrochloride is an established treatment option for individuals with phenylketonuria (PKU) who demonstrate responsiveness, but uncertainty persists regarding dosing frequency, timing relative to meals, the influence of dietary composition, and efficacy of different formulations. Despite widespread use in the UK, real-world administration behaviours have not previously been characterised. This study aimed to characterise sapropterin administration behaviours among people with PKU in the UK. Methods: A 31-item questionnaire was developed and disseminated via the National Society for Phenylketonuria website and social media channels. The survey captured demographic information, dosing schedules, formulation use, administration techniques, co-ingestion with food, and changes in natural protein tolerance following initiation of generic sapropterin. Results: 124 current sapropterin users completed the survey. Most respondents were caregivers of children or adolescents (68.5% aged 0-18 years). Once-daily dosing was most common (66.1%, n = 82), typically administered at breakfast, followed by twice-daily (32.3%, n = 40) and three-times-daily (1.6%, n = 2). Tablets were the predominant formulation (92.7%, n = 115); 50.4% (n = 58/115) swallowed tablets whole, while the remaining (49.6%, n = 57/115) crushed or dissolved them in water or juice. Nine respondents (7.3%, n = 9/124) used powder sachets. Most participants (75%, n = 93/124) took sapropterin with food, with both low-fat (36.6%, n = 34/93) and high-fat (26.9%, n = 24/93) meals reported. Over a third of participants (33.9%, n = 42/124) tolerated a natural protein intake >30 g/day when this was measured, and a further 15.3% (n = 19) were able to maintain a fully unrestricted protein intake without protein substitute supplementation. The magnitude of protein intake improvement was significantly greater among adults (p < 0.001), those with higher baseline natural protein intake (≥30 exchanges/day) (p < 0.001), and individuals who swallowed sapropterin tablets whole (p = 0.038). Although 71.8% (n = 89/124) were pleased with their increased natural protein allowance, many expressed a desire for further improvement. Conclusions: Substantial heterogeneity in dosing schedules, formulation handling, and co-ingestion practices highlights the absence of standardised guidance. These findings emphasise the need for clearer clinical recommendations to optimise treatment effectiveness and support consistent, equitable care.
Does progesterone-based embryo transfer timing achieve live birth rates comparable to LH-surge-based timing in true natural cycle frozen embryo transfer (NC-FET)? Progesterone-based embryo transfer timing was associated with live birth rates comparable to those achieved with LH surge-based timing in true NC-FET, with no evidence of an independent association between ovulation timing strategy and live birth after adjustment for potential confounders. In true NC-FET, embryo transfer timing is commonly scheduled according to the LH surge. However, identification of the LH surge may be challenging. Serum progesterone rise may reflect ovulation timing, yet its use as an alternative approach for scheduling embryo transfer in NC-FET cycles remains insufficiently investigated. This prospective cohort study included 490 true NC-FET cycles performed at a single tertiary IVF center between 2022 and 2025. Cycles were analyzed according to the ovulation timing strategy used for embryo transfer scheduling: progesterone-based timing (n = 286) or LH surge-based timing (n = 204). Ovulation was monitored using serial ultrasound and serum hormone measurements. Embryo transfer timing was scheduled according to either detection of the LH surge or the rise in serum progesterone concentrations. The primary outcome was live birth. Adjusted relative risks were estimated using modified Poisson regression with robust standard errors, adjusting for infertility duration and etiology, endometrial thickness at transfer, embryo quality, and number of embryos transferred. Adjusted absolute risk differences were calculated using marginal standardization. An exploratory threshold-based assessment was performed on the risk-difference scale. Live birth occurred in 162 of 286 progesterone-timed cycles (56.6%) and 106 of 204 LH-timed cycles (52.0%) (unadjusted RR 1.09, 95% CI 0.93-1.28). After adjustment, ovulation timing strategy showed no evidence of an independent association with live birth (adjusted RR 1.09, 95% CI 0.93-1.30; P = 0.264). The adjusted absolute risk difference was +4.9% (95% CI -3.8% to +13.6%). Clinical pregnancy, hCG positivity, and miscarriage rates were also comparable between groups. In exploratory analyses, follicle size measured 1 day before ovulation was positively correlated with progesterone levels on the embryo transfer day (Spearman r = 0.36, P < 0.001), and embryo-transfer-day progesterone levels were positively correlated with estradiol levels measured 1 day before ovulation (Spearman r = 0.29, P < 0.001). The observational design may introduce residual confounding despite statistical adjustment. The timing strategy was not randomized and reflected an evolving institutional protocol. In addition, the progesterone thresholds were derived and applied within a single-center assay environment, which may limit generalizability to other clinical settings and laboratory platforms. Progesterone-based timing may represent a feasible alternative to LH-based scheduling in true NC-FET, although confirmation in adequately powered multicenter studies is required. No external funding was received for this study. The authors declare no competing interests. N/A.
This descriptive cross-sectional study aimed to examine the professional belonging (PB) and psychological empowerment (PE) among midwives working in Türkiye. This study was conducted between March and June 2023 with 384 midwives recruited through voluntary online sampling. Data were collected using the Midwifery Belonging Scale (MBS) and Spreitzer Psychological Empowerment Scale (SPES). Midwives had a mean work experience of 12.04 years. The mean MBS and SPES scores were 92.96 and 69.76, respectively. A significant moderate positive correlation was found between PB and PE (r = 0.394, p < 0.001). PB was significantly higher among midwives who reported sufficient professional rights, engaged in independent midwifery practice, worked in delivery rooms, had higher educational attainment, chose the profession by personal choice, were employed in private hospitals, and who worked in shift-based schedules (p < 0.001). Developing a professional midwifery practice environment and enhancing PE may contribute to strengthening PB among midwives.
Background/Objectives: The aim of this study is to analyze outcomes in patients who underwent genicular artery embolization (GAE) with respect to pain, symptoms, physical activity, quality of life, and knee joint range of motion and muscle strength of the knee joint. The study will provide evidence of the treatment's effectiveness using both subjective and objective measurements. In addition, the study will examine the impact of the severity of radiological changes in the knee joint and the number of embolized vessels on the extent of improvement in outcomes following the procedure. Methods: Patients eligible for GAE who exhibited symptoms of chronic exudative knee arthritis, confirmed by USG and MRI with contrast, did not have laboratory markers of inflammation, nor did they respond effectively to standard non-surgical treatments. The analysis included 34 patients. Subjective parameters were assessed using the VAS and KOOS scales. Knee range of motion and muscle strength were assessed using an electronic dynamometer and goniometer. Measurements were performed according to the same schedule before GAE, and at 1, 3 and 6 months after the procedure. The results were subjected to statistical analysis. Results: In the analysis up to 6 months, a significant time effect was demonstrated for the VAS and all KOOS subscales. The improvement was visible after 1 month and continued after 3 and 6 months. No significant changes over time were demonstrated for objective parameters. Exploratory analysis demonstrated a relationship between increased knee extensor strength and pain reduction up to 3 months and increased range of motion up to 6 months after the GAE. There was no significant association between radiological changes and the number of embolized vessels with improved outcomes after GAE. Conclusions: GAE appears to be a promising minimally invasive treatment option for patients with chronic knee synovitis. Clinically meaningful improvements were observed in patient-reported outcomes.
This study was designed to assess associations between real-time sub-bandage pressure patterns and puncture-related complications after femoral artery puncture and explore determinants of initial compression effectiveness. This was a prospective study enrolling adults scheduled for transfemoral cerebral angiography. All participants were followed from the time of vascular access closure through the immediate post-procedural period. A novel miniature pressure sensor was adopted to continuously monitor the sub-bandage pressure after the procedure and pressure measurements were obtained at pre-set intervals in the complication (n=20) and the non-complication (n=182) groups.Regression analyses were performed to identify predictors of initial-to-occlusion pressure ratio. Patients with complications exhibited significantly higher initial bandaging pressure (median 6.1 N, IQR 4.4-7.9 N; p=0.045) and faster pressure attenuation in the first 0.5 h post-procedure (2.6N/h; p=0.018). The initial-to-occlusion pressure ratio was not significantly different between groups (z= -0.733, p=0.463). Pressure-time trajectories showed the greatest decline during the first 2 h, indicating a high-risk period for bandage loosening/displacement. Regression analysis indicated that systolic blood pressure, body habitus, and age were independent predictors for the initial-to-occlusion pressure ratio (p<0.05). Continuous real-time sub-bandage pressure monitoring indicates that elastic bandages provide effective initial bandaging following transfemoral cerebral angiography, but a rapid decline in pressure is associated with increased puncture-related complications. Compression should be individualized by systolic blood pressure, body habitus, and age.
Background/Objective: Preoperative frailty assessment before open radical nephrectomy for renal cell carcinoma (RCC) is underused, and prospective data on the 5-Factor Frailty Index (5-IFi) are limited. We examined the association between the preoperative 5-IFi score and postoperative complications at a private tertiary center in Khyber Pakhtunkhwa, Pakistan. Methods: In this prospective cohort study, 30 adults with suspected or confirmed RCC scheduled for elective open radical nephrectomy were enrolled after ethics approval. The 5-IFi was scored preoperatively from records and medication lists. The primary outcome was any Clavien-Dindo grade ≥ II complication during the index hospitalization; secondary outcomes were length of stay and 30-day unplanned readmission. Groups were compared using Mann-Whitney U and Fisher's exact tests. Associations were estimated by Firth penalized logistic regression with profile-likelihood confidence intervals (CIs) and receiver operating characteristic (ROC) analysis with bootstrapped CIs; adjusted models were exploratory given the sample size. Results: Fourteen patients (46.7%) developed a grade ≥ II complication, all grade II; nine (30.0%) were frail (5-IFi ≥ 2). The 5-IFi score was the only baseline variable significantly associated with the outcome (median 1.5 vs. 1.0; p = 0.030). Each 1-point increase was associated with higher odds (unadjusted OR 2.35, 95% CI 1.16-6.80; adjusted for age and creatinine, OR 2.10, 95% CI 1.00-5.91). Discrimination was moderate but imprecise (AUC 0.72, 95% CI 0.53-0.88). At the ≥2 threshold, frail patients had a higher complication rate than non-frail/pre-frail patients (77.8% vs. 33.3%; Fisher's exact p = 0.046; exact OR 6.5, 95% CI 0.92-80.65), with sensitivity 50.0% and specificity 87.5%; length of stay was marginally longer in frail patients (p = 0.035). No grade ≥ III complications or deaths occurred. Conclusions: In this small single-center cohort, a higher 5-IFi score was associated with grade ≥ II complications, consistent after limited adjustment. Given the small sample, imprecise estimates, and exclusively grade II events, these findings are preliminary and hypothesis-generating. Multicenter validation is required before the 5-IFi can guide preoperative risk stratification or prehabilitation triage.
Target-mediated drug distribution (TMDD) is typically classified by accelerated removal of drug after serum concentration drops below a critical level. Susceptible drugs would be dosed to a schedule that maintains exposure above this level, where concentration drops monoexponentially. Out-dosing TMDD often implies that target binding is saturated or degraded. T-cell engagers and other biologics are often given with low dosages which make out-dosing TMDD unrealistic, yet are also typically observed to have monoexponential elimination. It can be challenging to determine whether such a concentration-time relationship is due to TMDD or standard non-specific (intrinsic) routes of clearance, and more so to scale this clearance from preclinical settings, as TMDD-driven clearance may not scale allometrically like intrinsic clearance. In this work, we derived an algebraic expression for the proportion of clearance that is target-mediated or intrinsic, which requires only the intrinsic half-life and the target receptor's concentration, turnover rate and binding affinity for the drug. We further show that the typical transition from monoexponential decline of serum concentrations to accelerated, target-driven clearance occurs at concentrations given by two expressions in those same parameters. We apply the equations to published data for monoclonal antibodies and T-cell engagers, finding that we consistently characterize their clearance as expected. These expressions can be used to determine if a drug's clearance would be expected to be driven by target-mediated or non-specific routes at pharmacologically active concentrations, and hence how to accurately translate pharmacokinetic properties from preclinical species to human, a process that is essential for drug development.
Background/Objectives: Patients with relapsed/refractory multiple myeloma (RRMM) have poor survival outcomes and limited treatment options. The increasing utilization of multiagent therapies for earlier lines of treatment and novel drug classes including BCMA-targeting agents in subsequent lines of therapy has created a need for innovative treatment platforms in patients who have relapsed after or are refractory to these current standard-of-care approaches. Iopofosine I 131 is a 131iodide (131I)-phospholipid conjugate that exploits the selective uptake and retention of phospholipid ethers through lipid rafts to facilitate tumor delivery of 131I. Methods: The objective of this phase 1 dose-escalation study was to assess the safety and tolerability of single and fractionated dose schedules of iopofosine I 131 + low-dose dexamethasone in heavily pretreated patients with RRMM. Results: The most common AEs overall were cytopenias, notably thrombocytopenia (93.5%), lymphopenia (74.2%), anemia (71%), leukopenia (61.3%), and neutropenia (58.1%). All patients experiencing hematologic adverse events recovered from those events with median time of recovery 21 days post-nadir. Nonhematologic adverse events were mostly limited to Grade 1 and 2. Dose-limiting toxicities included four Grade 4 thrombocytopenia events lasting longer than 7 days, one Grade 4 neutropenia, and one Grade 3 insomnia. The DMC determined 31.25 mCi/m2 was the maximum tolerated dose in the single-dose group, and 20 mCi/m2 × 2 doses was the maximum tolerated dose in the fractionated-dose group. For patients monitored through 85 days following the first infusion, 22 of 26 (84.6%) achieved stable disease after treatment, and 4 of 26 (15.4%) achieved a partial response. Conclusions: A favorable safety and tolerability profile and preliminary clinical activity support further development of iopofosine I 131 in RRMM.
Radial artery cannulation is often more difficult in patients with obesity because arterial landmarks may be less reliable and the vessel may be deeper from the skin surface. Whether ultrasound guidance improves cannulation outcomes in this subgroup remains uncertain. In this prospective, single-center, randomized, assessor-blinded trial, adults with body mass index >30 kg/m2 scheduled for elective laparoscopic sleeve gastrectomy and requiring radial artery cannulation were assigned to ultrasound-guided cannulation using a short-axis out-of-plane technique or to palpation-guided cannulation. The primary outcome was first-attempt success at the initially selected radial artery. Secondary outcomes included need for a second attempt, two-attempt success, cannulation time, failure at the initially selected artery, and vascular complications. Of 130 patients assessed for eligibility, 126 were randomized and analyzed (63 per group). First-attempt success was higher with ultrasound guidance than with palpation guidance (57/63 (90.5%) vs 44/63 (69.8%); absolute risk difference, 20.6%; 95% CI, 6.7-33.9; p = 0.003). Fewer patients in the ultrasound group required a second attempt (6/63 (9.5%) vs 19/63 (30.2%); p = 0.003). Two-attempt success was also higher with ultrasound guidance (62/63 (98.4%) vs 52/63 (82.5%); absolute risk difference, 15.9%; 95% CI, 5.8-27.1; p = 0.002). Median cannulation time was longer with ultrasound guidance for first-attempt success (64.0 s (IQR, 45.0-98.5) vs 41.0 s (IQR, 26.1-58.0); p = 0.005). Overall vascular complications were less frequent in the ultrasound group (7/63 (11.1%) vs 21/63 (33.3%); absolute risk difference, -22.2%; 95% CI, -35.7 to -7.7; p = 0.003). Among patients with obesity undergoing sleeve gastrectomy, ultrasound-guided radial artery cannulation increased first-attempt and two-attempt success and reduced vascular complications, although cannulation time was modestly longer. These findings support preferential use of ultrasound guidance when reliable first-site radial artery cannulation is clinically important.
Although platelet concentrates are associated with substantial blood consumption, whether platelet products at physiological concentrations can achieve comparable efficacy in chronic wounds remains unclear. To determine if physiological concentration platelet fibrin plasma (PFP) is non-inferior to supra-physiological platelet-rich plasma (PRP) for diabetic wound healing. This single-center, non-inferior randomized controlled trial enrolled patients with diabetic wounds who, after wound-bed-preparation with corrected infection, ischemia, stasis, shear forces, were scheduled for debridement suture surgery (DSS). Participants received either PFP (1× baseline) or PRP (4× baseline) during DSS. The primary outcome was the 4-week healing rate. Subgroup analysis was based on ulcer location. 56 patients were enrolled (DFU: 66%, all neuro-ischemic type; other sites: 34%), groups were balanced (DFU: 65.5% vs 64.3%, P=0.922;). Non-inferiority was confirmed: 4-week healing was 78.6% (PFP) vs 71.4% (PRP) (one-sided 95% CI lower bound -12.4%, P=0.038). No significant differences emerged in 2-, 3-, 6-, and 8-week healing rates, mean healing time (30.1 vs 32.2 days) (all P>0.05). Single center with a relatively small sample size. Physiological PFP demonstrated similar efficacy to supra-physiological PRP. With simpler preparation and lower blood consumption, PFP offers a practical, equivalent alternative.
Background: Incidental malignancies on emergency department (ED) CT may go unrecognized, risking delayed diagnosis. We investigated their prevalence, recognition rate, and follow-up risk stratification. Methods: We retrospectively reviewed 15,347 CT reports from a tertiary ED (April 2016-March 2019). To determine whether missed diagnoses reflected inherent radiological difficulty or situational factors, ten board-certified emergency physicians completed a standardized 18-case interpretation test under off-duty conditions. Results: Incidental malignancies were identified in 25 patients (0.16%); lung carcinoma was most common (28%). Of 25 patients, 16 (64%) had malignancy recognized at the initial ED visit; 9 (36%) were missed. One discharged new patient without scheduled follow-up represented the highest-risk group for loss to follow-up. Diagnostic accuracy ranged from 0/10 to 9/10 (Cochran's Q test, p < 0.001). Cases 1, 4, and 7 were unidentified by all evaluators (p = 0.002 vs. Case 16, McNemar test with Bonferroni correction). No significant inter-physician difference was observed (p = 0.73, Friedman test). Conclusions: Incidental malignancies occurred in 0.16% of ED CT examinations, with 36% missed at initial presentation. Missed diagnoses reflected inherent radiological difficulty and systemic factors rather than individual expertise. Discharged new patients without scheduled follow-up represent the highest-risk group, underscoring the need for systems-based interventions.
New tuberculosis (TB) vaccines for adults and adolescents are crucial for achieving global control targets, and several candidates may be ready for introduction within 5 years. We conducted a convergent mixed-methods study in Lusaka, Zambia, among community members and healthcare workers (HCWs) to understand preliminary TB vaccine acceptance and potential factors influencing uptake to inform readiness activities critical for successful implementation. Adult community members were enrolled from randomly selected households within four communities with historically low COVID-19 vaccine coverage, and HCWs from 10 public healthcare facilities representing different care levels. Structured surveys evaluated participants' perspectives on new vaccines and mixed-effects Poisson regression was used to estimate the marginal probability of participants' intention to get a new TB vaccine. Qualitative in-depth interviews (IDIs; n=24) and focus group discussions (FGDs; n=9) were conducted and analysed using a hybrid approach to explore acceptable vaccine attributes, preferences and determinants of TB vaccine uptake and recommendations for rollout. Overall, 499 participants completed surveys (395 community members and 104 HCWs) with 62 additional participants across IDIs and FGDs. 77% of community members and 83% of HCWs expressed intention to get a TB vaccine. Perceived TB risk and severity concerns were the only significant drivers of vaccine intention. Participants pragmatically accepted the WHO's preferred vaccine specifications (50% efficacy, two-dose schedule, transient, mild side effects, at least 2 years' duration) though HCWs preferred higher efficacy thresholds due to occupational risk. Implementation preferences emphasised early community engagement (at least 3-6 months pre-rollout), diverse delivery approaches, including facility-based and community venues for adults, schools for adolescents and door-to-door campaigns, while addressing COVID-19-related scepticism through transparent, clear communication using trusted sources. This study reveals strong potential for a successful TB vaccine rollout in Zambia through proactive implementation strategies, including early community engagement, transparent communication and person-centred delivery approaches.
The global shortage of transplantable donor livers increases reliance on marginal grafts, creating an urgent need for workflow-compatible assessment during normothermic machine perfusion. However, current biochemical evaluation remains constrained by intermittent perfusate sampling, low temporal resolution and limited cholangiobiliary context. Here we report a clinically deployed dual-compartment biochemical monitoring (DCBM) platform for human liver perfusion. The system integrates dual-channel microfluidics, multiplexed electrochemical sensing, bile-compatible antifouling interfaces and wireless data transmission to enable automated in-line measurement of pH, lactate and glucose in both perfusate and bile. In seven human donor livers, the DCBM platform shows strong agreement with standard laboratory assays while resolving transient biochemical excursions not captured by scheduled hourly sampling, including bile lactate elevations associated with subsequent adverse perfusion trends in selected cases. Continuous dual-compartment measurements further enable an exploratory outcome-anchored framework linked to post-transplant clinical course. This platform establishes a clinically deployed architecture for dual-compartment biochemical monitoring and provides an initial translational bridge from continuous sensing to viability-associated graft assessment during ex situ liver perfusion.
Touchscreen-based cognitive tasks are widely used to assess learning and working memory in non-human primates (NHPs); however, systematic evaluations of training efficiency and factors influencing task acquisition remain limited, often resulting in prolonged training periods and substantial inter-individual variability. This study investigated cognitive task acquisition and performance in cynomolgus monkeys using a touchscreen-based training system. Monkeys were sequentially trained on two-choice discrimination (TCD), matching-to-sample (MTS), and delayed matching-to-sample (DMS) tasks with varying training frequencies. TCD performance showed considerable individual variability regardless of the schedule. In contrast, training frequency significantly influenced MTS acquisition, with faster learning observed in monkeys trained four to five times per week than those trained two times a week. There was a trend for older monkeys, which had previously been individually housed, to require more trials to reach the MTS learning criterion. All monkeys completed working memory assessment, revealing notable individual differences, with some monkeys tolerating delays of up to 300 s, whereas others declined after 20 s. In addition, adaptive task modification through the introduction of short delay intervals during MTS training facilitated learning in monkeys that initially struggled with task acquisition. These findings highlight the importance of training intensity and individual variability in cognitive training outcomes and address a methodological gap by providing empirical evidence for optimizing DMS training protocols, support the DMS task as a valuable tool for assessing non-human primate memory.
Lithium has a narrow therapeutic index and remains the first-line treatment for bipolar I and II disorders. Dosing this medication requires careful monitoring, and there is a risk of toxicity. This case follows a 43-year-old male with a medical history of alcohol use and bipolar I disorder, admitted to the hospital three days after an intentional lithium overdose. Initial management involved treating alcohol withdrawal with scheduled phenobarbital, lorazepam, and intravenous fluids. In the following days, he demonstrated a neurologic decline in the setting of subtherapeutic serum lithium levels. As the patient continued to worsen, hemodialysis was eventually initiated due to concern for lithium neurotoxicity. After completing three rounds of hemodialysis, the patient subsequently returned to a normal neurologic baseline. This case highlights the significance of clinical manifestations of lithium toxicity in the setting of subtherapeutic and down-trending serum lithium to manage lithium toxicity. Pre-existing tissue stores and rate of elimination contribute to the discrepancy between the severity of symptoms and serum levels in those with chronic lithium use.
Epiretinal membranes (ERM), a macular disorder affecting the vitreoretinal surface, lead to a decrease in visual acuity and increase in metamorphopsia. Peeling of ERM during vitrectomy has the potential for improvements of visual acuity and metamorphopsia. Nevertheless, starting membrane peeling displays a critical step, as membranes are often difficult to grasp and there are risks for retinal damage during grasping of the ERM at the starting location. Aim of the study was to analyze associations of instrument tissue interactions at the grasp site with possible thinning of superficial retinal layers, with special respect to the ganglion cell layer, when using two different ILM forceps. This randomized trial included patients scheduled for pars plana vitrectomy with membrane peeling due to an idiopathic ERM. Patients were allocated to either group A (ILM forceps with a laser-modified microstructure on the branches), or group B (conventional ILM forceps). Instrument tissue interactions were analysed from surgical video-documentation including continuous intraoperative optical coherence tomography (OCT) and associations to anatomical (OCT) and functional (microperimetry) outcomes were examined. Among 58 patients included into the study, there were no significant differences in the number of grasp attempts between both ILM forceps with a median number of 6 grasp attempts in group A and 4 grasp attempts in group B (p = 0.23, Mann Whitney U test). Dipping of the forceps into retinal tissue was comparable between both forceps, except for fewer incidences of dipping into retinal tissue in group A among patients with partly adherent ERMs. Associations between postsurgical defects at the superficial retinal layers and instrument tissue interactions during grasping could be found only for a minority of patients in the postsurgical OCTs, and there were no obvious associations of postsurgical retinal defects to functional changes in microperimetry. There were no significant differences in the number of grasp attempts between both ILM forceps, with a trend in favour of the conventional ILM forceps. However, the ILM forceps with a laser-modified microstructure on the branches led to fewer situations with dipping of the ILM forceps into retinal tissue.
The increase in precision oncology largely relies on the availability of high-quality, longitudinal, and multi-source, multi-purpose, and multidimensional corresponding data that integrate clinical, pathological, and molecular information. While new and advanced biomedical methods enable large-scale data generation, the operational challenges associated with data retrieval, harmonization, and quality control remain insufficiently described in scientific literature. In parallel, data incompleteness and heterogeneity in collection practices and coding standards are diminishing confidence in precision medicine programs. This methodological case study focused on the challenges of data harmonization within the Molecular Twin Research Umbrella Protocol at Cedars-Sinai Medical Center. This systematic four-stage process includes requirements for data access and assembly, processing for cleaning and harmonization, and quality verification before distribution. Pairwise comparisons have been made for each type of record, from electronic health records through cancer registration and biobanking. The demographics showed a very high concordance (>95%), whereas the clinically essential variables, such as tumor TNM stage, diagnostic specificity, and intervention schedules, showed moderate discordance (14.8%-17%). These discrepancies are a significant hindrance to the readiness of the cohorts for prediction models. Based on these results, we propose mitigation strategies aimed at improving the accuracy, completeness, and standardization of longitudinal oncology cohort datasets. This study provides key recommendations for long-term oncology cohorts and for the development of digital twin infrastructure for any institution, stressing that sound data quality infrastructure is a cornerstone of trustworthy precision oncology and translational research.