TARDBP Mutations in Facial-Onset Sensory and Motor Neuronopathy.

Objectives: Facial-onset sensory and motor neuronopathy (FOSMN) is a rare neuromuscular disorder characterized by progressive facial sensory impairment followed by motor dysfunction in a rostro-caudal distribution. FOSMN is clinically and pathologically associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). In contrast to ALS/FTD, the genetic profile of patients with FOSMN and the role of genetic testing are poorly defined. Methods: A 66-year-old woman was evaluated in our neuromuscular clinic for progressive facial pain, dysphagia, and dysarthria. Her diagnostic evaluation included brain and cervical MRI, nerve conduction studies and EMG, and an ALS/FTD next-generation sequencing panel. Results: The patient was diagnosed with FOSMN, and we identified a N390D variant in transactive response DNA-binding protein (TDP-43/TARDBP). This variant has never been reported in FOSMN but was previously reported in 2 cases of ALS, and a N390S variant was also previously reported in FOSMN. A review of the literature revealed that TARDBP mutations are overrepresented in patients with FOSMN compared with patients with ALS/FTD. By contrast, other common familial forms of ALS, including C9ORF72 or SOD1, are respectively absent or rare in FOSMN. Discussion: FOSMN is pathologically and genetically associated with TDP-43. Therefore, ALS genetic testing that includes specifically TARDBP should be considered in patients with FOSMN.

Malaria and other infections induce polyreactive antibodies that impact SARS-CoV-2 seropositivity estimations in endemic settings.

Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence is used to estimate the proportion of individuals within a population previously infected, to track viral transmission, and to monitor naturally and vaccine-induced immune protection. However, in sub-Saharan African settings, antibodies induced by higher exposure to pathogens may increase unspecific seroreactivity to SARS-CoV-2 antigens, resulting in false positive responses. To investigate the level and type of unspecific seroreactivitiy to SARS-CoV-2 in Africa, we measured immunoglobulin G (IgG), IgA, and IgM to a broad panel of antigens from different pathogens by Luminex in 602 plasma samples from African and European subjects differing in coronavirus disease 2019, malaria, and other exposures. Seroreactivity to SARS-CoV-2 antigens was higher in prepandemic African than in European samples and positively correlated with antibodies against human coronaviruses, helminths, protozoa, and especially Plasmodium falciparum. African subjects presented higher levels of autoantibodies, a surrogate of polyreactivity, which correlated with P. falciparum and SARS-CoV-2 antibodies. Finally, we found an improved sensitivity in the IgG assay in African samples when using urea as a chaotropic agent. In conclusion, our data suggest that polyreactive antibodies induced mostly by malaria are important mediators of the unspecific anti-SARS-CoV-2 responses, and that the use of dissociating agents in immunoassays could be useful for more accurate estimates of SARS-CoV-2 seroprevalence in African settings.

Do acting interns need residents? A comparison of acting intern experience on hospital medicine resident versus nonresident teams.

BACKGROUND: The clinical demands for hospitalist groups have grown at academic medical centers, without similar growth of teaching opportunities for faculty. Traditional resident teaching teams are often crowded with learners which can limit acting intern (or subintern) patient encounters. Medical students are often placed on nonresident teaching teams, although there are few studies on learner experience on a nonresident teaching team model. METHODS: To address these concerns, we created two nonresident teaching teams composed of one attending and two acting interns. We compared acting intern experience on the nonresident teaching teams to the traditional resident teams to determine if there were significant differences in student experience by reviewing course evaluation data on the two team models. RESULTS: Of the 276 students who completed the Internal Medicine Acting Internship from 2019 to 2023, 224 students (81%) completed the course evaluation. The course was highly rated, and the ratings were similar in both models demonstrating that the nonresident teaching team model is an effective option for acting interns. CONCLUSION: The nonresident teaching team model can offload crowded teaching teams, add additional acting intern experiences, and add teaching opportunities for hospital medicine attendings.

Psychological Status as an Effect Modifier of the Association Between Allergy Symptoms and Allergy Testing.

OBJECTIVE: Patient-reported outcome measures, while valuable, may not correlate with diagnostic test results. To better understand this potential discrepancy, our objective was to determine whether psychological health is an effect modifier of the association between patient-reported allergy outcome scores and allergy test results. STUDY DESIGN: Prospective outcomes study. SETTING: Tertiary care hospital and community-based clinic. METHODS: This study included 600 patients at least 18 years of age who presented for symptoms related to allergic rhinitis and completed the related sinonasal outcome test (SNOT), which includes validated nasal, allergy, and psychological domains. Stratified analyses of odds ratios and Spearman correlation coefficients were utilized to assess for effect modification by psychological status. RESULTS: Worse patient-reported allergic rhinitis symptoms were significantly associated with positive allergy test results (odds ratio [OR] 1.69, 95% confidence interval [CI] 1.22-2.34, P = .002) in patients with better psychological health. In contrast, there was no association in patients with worse psychological health (OR 1.06, 95% CI 0.36-3.10, P = .92). These findings were corroborated by assessments of correlation: allergy domain scores were positively correlated with allergy testing scores (Spearman rho 0.18, 95% CI 0.10-0.25, P < .001) in patients with better psychological health, while there was no correlation in patients with worse psychological health (-0.02, 95% CI -0.16-0.12, P = .77). CONCLUSIONS: Psychological status was an effect modifier of the association between allergy domain and allergy testing data. When assessing the relationship between subjective measures, such as sinonasal validated instruments, and objective measures, such as allergy test results, accounting for effect modifiers such as psychological state can provide clinical and research-related insights.

Development of Luminescent Biosensors for Calprotectin.

Calprotectin, a metal ion-binding protein complex, plays a crucial role in the innate immune system and has gained prominence as a biomarker for various intestinal and systemic inflammatory and infectious diseases, including inflammatory bowel disease (IBD) and tuberculosis (TB). Current clinical testing methods rely on enzyme-linked immunosorbent assays (ELISAs), limiting accessibility and convenience. In this study, we introduce the Fab-Enabled Split-luciferase Calprotectin Assay (FESCA), a novel quantitative method for calprotectin measurement. FESCA utilizes two new fragment antigen binding proteins (Fabs), CP16 and CP17, that bind to different epitopes of the calprotectin complex. These Fabs are fused with split NanoLuc luciferase fragments, enabling the reconstitution of active luciferase upon binding to calprotectin either in solution or in varied immobilized assay formats. FESCA's output luminescence can be measured with standard laboratory equipment as well as consumer-grade cell phone cameras. FESCA can detect physiologically relevant calprotectin levels across various sample types, including serum, plasma, and whole blood. Notably, FESCA can detect abnormally elevated native calprotectin from TB patients. In summary, FESCA presents a convenient, low-cost, and quantitative method for assessing calprotectin levels in various biological samples, with the potential to improve the diagnosis and monitoring of inflammatory diseases, especially in at-home or point-of-care settings.

Ambient light intensity affecting ultrasound operator detection of liver lesions in cine-clips.

INTRODUCTION: Ambient light (AL) is an important factor to improve ultrasound pathology detection. However, there are no established room AL levels recommended during an ultrasound examination. We aim to examine the diagnostic accuracy using different intensity of AL for the detection of liver lesions in anonymised pre-recorded cine-clips. METHODS: Eight ultrasound operators with 5-14 years' professional experiences were prospectively recruited to evaluate 51 randomised cine-clips directly from one ultrasound machine. These 15-s clips of the right lobe of the liver in longitudinal and transverse planes were meant to simulate the ultrasound examination. Operators reviewed all cine-clips and responded to two questions per cine-clip regarding their detection performance under 3 AL settings; 3, 15 and 25 lux, at one lighting per visit. A repeat visit under each AL was performed to assess for intra-operator variability. Each operator completed six visits in total, with at least a 2-day washout period. The operators' performance was compared against imaging reference standards from contrast CT/MRI for cine-clips with lesion and serial US for those without. RESULTS: AL with highest degree of diagnostic accuracy was found to be at 25 lux. Results from 8 operators revealed sensitivity ranged from 79% to 100%, specificity ranged from 94% to 100%. Positive and negative predictive values were up to 100% with AL at 25 lux. Both intra-and interrater reliability were excellent at 0.85-1.0 (0.79-0.98) and 0.98 (0.97, 0.99) respectively, with AL at 25 lux. CONCLUSION: This study proved that ambient light intensity affects the ultrasound operator detection of liver lesions on cine-clips. IMPLICATIONS FOR PRACTICE: Identifying suitable AL levels will influence future ultrasound room construct.

The excitatory-inhibitory balance as a target for the development of novel drugs to treat schizophrenia.

The intricate balance between excitation and inhibition (E/I) in the brain plays a crucial role in normative information processing. Dysfunctions in the E/I balance have been implicated in various psychiatric disorders, including schizophrenia (SCZ). In particular, abnormalities in GABAergic signaling, specifically in parvalbumin (PV)-containing interneurons, have been consistently observed in SCZ pathophysiology. PV interneuron function is vital for maintaining an ideal E/I balance, and alterations in PV interneuron-mediated inhibition contribute to circuit deficits observed in SCZ, including hippocampus hyperactivity and midbrain dopamine system overdrive. While current antipsychotic medications primarily target D2 dopamine receptors and are effective primarily in treating positive symptoms, novel therapeutic strategies aiming to restore the E/I balance could potentially mitigate not only positive symptoms but also negative symptoms and cognitive deficits. This could involve, for instance, increasing the inhibitory drive onto excitatory neurons or decreasing the putative enhanced pyramidal neuron activity due to functional loss of PV interneurons. Compounds targeting the glycine site at glutamate NMDA receptors and muscarinic acetylcholine receptors on PV interneurons that can increase PV interneuron drive, as well as drugs that increase the postsynaptic action of GABA, such as positive allosteric modulators of α5-GABA-A receptors, and decrease glutamatergic output, such as mGluR2/3 agonists, represent promising approaches. Preventive strategies aiming at E/I balance also represent a path to reduce the risk of transitioning to SCZ in high-risk individuals. Therefore, compounds with novel mechanisms targeting E/I balance provide optimism for more effective and tailored interventions in the management of SCZ.

Azithromycin for Pediatric Critical Asthma: A Multicenter Retrospective Cohort Study.

OBJECTIVES: To characterize the prescribing trends and clinical outcomes related to azithromycin (AZI) among children hospitalized for critical asthma (CA). METHODS: We performed a multicenter, retrospective cohort study using the Pediatric Health Information Systems registry of children 3 to 17 years of age hospitalized in a PICU for CA from January 2011 to December 2022. We excluded for alternative indications for AZI (eg, atypical pneumonia, B. pertussis infection, acute otitis media, acute sinusitis, pharyngitis/tonsillitis, and urethritis). The primary outcome was AZI prescribing rate by hospital and calendar year (trends assessed by Joinpoint regression). Cohorts with and without AZI exposure were further characterized by demographics, CA treatments, and inpatient outcomes using descriptive and comparative (ie, χ2 and Wilcoxon rank tests) statistics. RESULTS: Of the 47 797 children studied, 9901 (20.7%) were prescribed AZI with a downward annual trend noted from 34.7% in 2011% to 12.4% in 2022 (-1.7% per year, R2 = 0.91). Median institutional AZI prescribing rate was 19.2% (interquartile range [IQR] 11.7%-28%; total range 5.6%-60%). Compared with children not prescribed AZI, those prescribed AZI were older (median 8.3 [IQR 5.7-11.6] vs 7.3 [4.9-10.8] years, P < .001) and experienced a more severe clinical trajectory with greater rates of bilevel positive airway pressure ventilation (19.7% vs 12.6%, P < .001), invasive ventilation (22.1% vs 13.5%, P < .001), extracorporeal life support (0.8% vs 0.1%, P < .001), and median length of stay (4 [IQR 3-6] vs 3 [IQR 2-4] days, P < .001). CONCLUSIONS: Between 2011 and 2022, 20.7% of children hospitalized for CA were prescribed AZI notwithstanding the absence of trial-derived efficacy or safety data for this indication and population.

Solutes unmask differences in clustering versus phase separation of FET proteins.

Phase separation and percolation contribute to phase transitions of multivalent macromolecules. Contributions of percolation are evident through the viscoelasticity of condensates and through the formation of heterogeneous distributions of nano- and mesoscale pre-percolation clusters in sub-saturated solutions. Here, we show that clusters formed in sub-saturated solutions of FET (FUS-EWSR1-TAF15) proteins are affected differently by glutamate versus chloride. These differences on the nanoscale, gleaned using a suite of methods deployed across a wide range of protein concentrations, are prevalent and can be unmasked even though the driving forces for phase separation remain unchanged in glutamate versus chloride. Strikingly, differences in anion-mediated interactions that drive clustering saturate on the micron-scale. Beyond this length scale the system separates into coexisting phases. Overall, we find that sequence-encoded interactions, mediated by solution components, make synergistic and distinct contributions to the formation of pre-percolation clusters in sub-saturated solutions, and to the driving forces for phase separation.

Performance and Return to Play After Surgery for Thoracic Outlet Syndrome in Professional Baseball Players: A Matched Cohort Analysis.

BACKGROUND: Thoracic outlet syndrome (TOS) remains a rare diagnosis but is being recognized as a cause of upper extremity dysfunction in professional baseball players. PURPOSE/HYPOTHESIS: The purpose was to determine performance and return-to-play (RTP) outcomes in professional baseball players after surgical treatment of TOS. The hypothesis was that there would be a high RTP rate in professional baseball players after TOS surgery with no statistical differences in performance between pitchers who had TOS surgery and matched controls. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: All professional baseball players who underwent surgical treatment of TOS between 2010 and 2017 were identified using the Major League Baseball Health and Injury Tracking System database. Demographic and performance data (before and after surgery) for each player were recorded. Performance variables were then compared between players who underwent TOS surgery and matched controls. The matching criteria were no history of previous surgeries on affected arm, age at time of surgery, throwing side, level of play (Major or Minor League Baseball), and years of experience playing professional baseball. RESULTS: Overall, 52 players underwent surgery for TOS, of whom 46 (88%) were pitchers. The type of TOS was neurogenic in 69% and venous in 29%. One player had arterial TOS. After TOS surgery, 79% of players returned to play at the same or higher level (RTSP) by 9.5 months and played ≥3 years after surgery. No differences were found in RTSP rate based on the type of TOS. No statistical difference was found in RTP rates between major and minor league players. Pitchers had a 76% RTSP, which was similar to the natural attrition for control pitchers (P = .874). After TOS surgery, pitchers saw a decline in several performance metrics, but these declines were not different from those of control pitchers, indicating that the decline in performance after TOS surgery was no faster than is seen in healthy professional pitchers as they age. CONCLUSION: The rate of RTSP after surgery for TOS in professional baseball players was 79%. There was no difference in RTP based on the type of TOS. Pitchers who underwent surgery for TOS had no significant differences in pitching performance metrics after surgery compared with matched controls.

Noninvasive assessment of organ-specific and shared pathways in multi-organ fibrosis using T1 mapping.

Fibrotic diseases affect multiple organs and are associated with morbidity and mortality. To examine organ-specific and shared biologic mechanisms that underlie fibrosis in different organs, we developed machine learning models to quantify T1 time, a marker of interstitial fibrosis, in the liver, pancreas, heart and kidney among 43,881 UK Biobank participants who underwent magnetic resonance imaging. In phenome-wide association analyses, we demonstrate the association of increased organ-specific T1 time, reflecting increased interstitial fibrosis, with prevalent diseases across multiple organ systems. In genome-wide association analyses, we identified 27, 18, 11 and 10 independent genetic loci associated with liver, pancreas, myocardial and renal cortex T1 time, respectively. There was a modest genetic correlation between the examined organs. Several loci overlapped across the examined organs implicating genes involved in a myriad of biologic pathways including metal ion transport (SLC39A8, HFE and TMPRSS6), glucose metabolism (PCK2), blood group antigens (ABO and FUT2), immune function (BANK1 and PPP3CA), inflammation (NFKB1) and mitosis (CENPE). Finally, we found that an increasing number of organs with T1 time falling in the top quintile was associated with increased mortality in the population. Individuals with a high burden of fibrosis in ≥3 organs had a 3-fold increase in mortality compared to those with a low burden of fibrosis across all examined organs in multivariable-adjusted analysis (hazard ratio = 3.31, 95% confidence interval 1.77-6.19; P = 1.78 × 10-4). By leveraging machine learning to quantify T1 time across multiple organs at scale, we uncovered new organ-specific and shared biologic pathways underlying fibrosis that may provide therapeutic targets.

Mitigation of Effect Modification by Psychological Status in Patients with Hearing Loss.

Importance: Although patient-reported outcomes provide valuable insights, these subjective data may not align with objective test results. Hearing loss is a pervasive problem, such that concordance between subjective perceptions of hearing ability and objective audiogram assessments would be beneficial. Objectives: To determine (1) whether psychological status is an effect modifier of the association between subjective patient reports of hearing ability and objective audiometry results, and (2) whether any effect modification observed in standard static questionnaires would be either mitigated or exacerbated by adaptive testing based on Item Response Theory analyses. Design, Setting, and Participants: This diagnostic study at a tertiary care center and community-based practice included consecutive adults who presented with queries related to hearing loss. Participants were recruited and enrolled and data analyses occurred from 2022 to 2024. Exposures: Participants prospectively reported their hearing-specific abilities through either a standard static or adaptive version of the Inner Effectiveness of Auditory Rehabilitation (EAR) scale, alongside validated measures of their mental health and audiometry. Word recognition scores (WRS) and pure tone averages (PTA) were used to analyze audiometric testing. Main Outcomes and Measures: The association between subjective Inner EAR results and audiometry was evaluated. Stratified analyses were used to assess for effect modification by psychological status. The results of standard static and adaptive testing were compared. Results: In this study of 395 patients (mean [range] age, 55.9 [18-89] years; 210 [53.2%] female), standard static Inner EAR mean scores were appropriately higher in patients with higher (better) WRS (50.7, 95% CI, 46.4-54.9), compared with patients with lower (worse) WRS (34.7, 95% CI, 24.3-45.1). However, among patients with worse mental health, there was no association between standard static Inner EAR scores and WRS. In contrast, adaptive Inner EAR mean scores were significantly higher for those with better WRS, regardless of mental health status. Thus, effect modification was observed in standard static assessments, whereas adaptive testing remained durably associated with audiometry, regardless of mental health. Conclusions and Relevance: Psychological status was an effect modifier of the association between standard Inner EAR scale scores and audiometry, with a positive association observed only in those with better mental health. Adaptive testing scores, however, remained significantly associated with audiometry, even when mental status was worse. Adaptive testing may stabilize the association between subjective and objective hearing outcomes.

Structural and molecular basis of choline uptake into the brain by FLVCR2.

Choline is an essential nutrient that the human body needs in vast quantities for cell membrane synthesis, epigenetic modification and neurotransmission. The brain has a particularly high demand for choline, but how it enters the brain remains unknown1-3. The major facilitator superfamily transporter FLVCR1 (also known as MFSD7B or SLC49A1) was recently determined to be a choline transporter but is not highly expressed at the blood-brain barrier, whereas the related protein FLVCR2 (also known as MFSD7C or SLC49A2) is expressed in endothelial cells at the blood-brain barrier4-7. Previous studies have shown that mutations in human Flvcr2 cause cerebral vascular abnormalities, hydrocephalus and embryonic lethality, but the physiological role of FLVCR2 is unknown4,5. Here we demonstrate both in vivo and in vitro that FLVCR2 is a BBB choline transporter and is responsible for the majority of choline uptake into the brain. We also determine the structures of choline-bound FLVCR2 in both inward-facing and outward-facing states using cryo-electron microscopy. These results reveal how the brain obtains choline and provide molecular-level insights into how FLVCR2 binds choline in an aromatic cage and mediates its uptake. Our work could provide a novel framework for the targeted delivery of therapeutic agents into the brain.

Interactions of cumulative load with biomarkers of cartilage turnover predict knee cartilage change over 2 years: data from the osteoarthritis initiative.

The purpose was to investigate relationships of cumulative load and cartilage turnover biomarkers with 2-year changes in cartilage in knee osteoarthritis. From participants with Kellgren-Lawrence (KL) grades of 1 to 3, cartilage thickness and transverse relaxation time (T2) were computed from 24-month (baseline) and 48-month magnetic resonance images. Cumulative load was the interaction term of the Physical Activity Scale for the Elderly (PASE) and body mass index (BMI). Serum cartilage oligomeric matrix protein (COMP) and the nitrated form of type II collagen (Coll2-1 NO2) were collected at baseline. Multiple regressions (adjusted for baseline age, KL grade, cartilage measures, pain, comorbidity) evaluated the relationships of cumulative load and biomarkers with 2-year changes. In 406 participants (63.7 (8.7) years), interactions of biomarkers with cumulative load weakly predicted 2-year cartilage changes: (i) COMP × cumulative load explained medial tibia thickness change (R2 increased 0.062 to 0.087, p < 0.001); (ii) Coll2-1 NO2 × cumulative load explained central medial femoral T2 change (R2 increased 0.177 to 0.210, p < 0.001); and (iii) Coll2-1 NO2 × cumulative load explained lateral tibia T2 change (R2 increased 0.166 to 0.188, p < 0.001). Moderate COMP or Coll2-1 NO2 at baseline appeared protective. High COMP or Coll2-1 NO2, particularly with high BMI and low PASE, associated with worsening cartilage. Moderate serum concentrations of cartilage turnover biomarkers, at high and low physical activity, associated with maintained cartilage outcomes over 2 years. In conclusion, high concentrations of cartilage turnover biomarkers, particularly with high BMI and low physical activity, associated with knee cartilage thinning and increasing T2 over 2 years. Key Points • Higher quality cartilage may be better able to tolerate a larger cumulative load than poor quality cartilage. • Among participants enrolled in the Osteoarthritis Initiative Biomarkers Consortium Project, a representation of cumulative load exposure and its interaction with cartilage turnover biomarkers were weakly related with 2-year change in knee cartilage. • These findings suggest that cartilage turnover is a factor that modifies the relationship between loading exposure and cartilage loss in knee OA.

Prospective benchmarking of an observational analysis in the SWEDEHEART registry against the REDUCE-AMI randomized trial.

Prospective benchmarking of an observational analysis against a randomized trial increases confidence in the benchmarking process as it relies exclusively on aligning the protocol of the trial and the observational analysis, while the trials findings are unavailable. The Randomized Evaluation of Decreased Usage of Betablockers After Myocardial Infarction (REDUCE-AMI, ClinicalTrials.gov ID: NCT03278509) trial started recruitment in September 2017 and results are expected in 2024. REDUCE-AMI aimed to estimate the effect of long-term use of beta blockers on the risk of death and myocardial following a myocardial infarction with preserved left ventricular systolic ejection fraction. We specified the protocol of a target trial as similar as possible to that of REDUCE-AMI, then emulated the target trial using observational data from Swedish healthcare registries. Had everyone followed the treatment strategy as specified in the target trial protocol, the observational analysis estimated a reduction in the 5-year risk of death or myocardial infarction of 0.8 percentage points for beta blockers compared with no beta blockers; effects ranging from an absolute reduction of 4.5 percentage points to an increase of 2.8 percentage points in the risk of death or myocardial infarction were compatible with our data under conventional statistical criteria. Once results of REDUCE-AMI are published, we will compare the results of our observational analysis against those from the trial. If this prospective benchmarking is successful, it supports the credibility of additional analyses using these observational data, which can rapidly deliver answers to questions that could not be answered by the initial trial. If benchmarking proves unsuccessful, we will conduct a "postmortem" analysis to identify the reasons for the discrepancy. Prospective benchmarking shifts the investigator focus away from an endeavour to use observational data to obtain similar results as a completed randomized trial, to a systematic attempt to align the design and analysis of the trial and the observational analysis.

Evaluation of Protein Identification and Quantification by the diaPASEF Method on timsTOF SCP.

Accurate and precise quantification is crucial in modern proteomics, particularly in the context of exploring low-amount samples. While the innovative 4D-data-independent acquisition (DIA) quantitative proteomics facilitated by timsTOF mass spectrometers gives enhanced sensitivity and selectivity for protein identification, the diaPASEF (parallel accumulation-serial fragmentation combined with data-independent acquisition) parameters have not been systematically optimized, and a comprehensive evaluation of the quantification is currently lacking. In this study, we conducted a thorough optimization of key parameters on a timsTOF SCP instrument, including sample loading amount (50 ng), ramp/accumulation time (140 ms), isolation window width (20 m/z), and gradient time (60 min). To further improve the identification of proteins in low-amount samples, we utilized different column settings and introduced 0.02% n-dodecyl-ß-d-maltoside (DDM) in the sample reconstitution solution, resulting in a remarkable 19-fold increase in protein identification at the single-cell-equivalent level. Moreover, a comprehensive comparison of protein quantification using a tandem mass tag reporter (TMT-reporter), complement TMT ions (TMTc), and diaPASEF revealed a strong correlation between these methods. Both diaPASEF and TMTc have effectively addressed the issue of ratio compression, highlighting the diaPASEF method's effectiveness in achieving accurate quantification data compared to TMT reporter quantification. Additionally, an in-depth analysis of in-group variation positioned diaPASEF between the TMT-reporter and TMTc methods. Therefore, diaPASEF quantification on the timsTOF SCP instrument emerges as a precise and accurate methodology for quantitative proteomics, especially for samples with small amounts.

Association of time spent on social media with youth cigarette smoking and e-cigarette use in the UK: a national longitudinal study.

BACKGROUND: Social media may influence children and young people's health behaviour, including cigarette and e-cigarette use. METHODS: We analysed data from participants aged 10-25 years in the UK Household Longitudinal Study 2015-2021. The amount of social media use reported on a normal weekday was related to current cigarette smoking and e-cigarette use. Generalised estimating equation (GEE) logistic regression models investigated associations of social media use with cigarette smoking and e-cigarette use. Models controlled for possible confounders including age, sex, country of UK, ethnicity, household income and use of cigarette/e-cigarettes by others within the home. RESULTS: Among 10 808 participants with 27 962 observations, current cigarette smoking was reported by 8.6% of participants for at least one time point, and current e-cigarette use by 2.5% of participants. In adjusted GEE models, more frequent use of social media was associated with greater odds of current cigarette smoking. This was particularly apparent at higher levels of use (eg, adjusted odds ratio (AOR) 3.60, 95% CI 2.61 to 4.96 for ≥7 hours/day vs none). Associations were similar for e-cigarettes (AOR 2.73, 95% CI 1.40 to 5.29 for ≥7 hours/day social media use vs none). There was evidence of dose-response in associations between time spent on social media and both cigarette and e-cigarette use (both p<0.001). Analyses stratified by sex and household income found similar associations for cigarettes; however, for e-cigarettes associations were concentrated among males and those from higher household income groups. CONCLUSIONS: Social media use is associated with increased risk of cigarette smoking and e-cigarette use. There is a need for greater research on this issue as well as potential policy responses.

Implementing Maximum Fair Price Without Hurting Pharmacies.

This Viewpoint discusses challenges pharmacies may face under the Inflation Reduction Act and steps that can be taken to prevent unintended consequences.

Considerations for first field trials of low-threshold gene drive for malaria vector control.

Sustainable reductions in African malaria transmission require innovative tools for mosquito control. One proposal involves the use of low-threshold gene drive in Anopheles vector species, where a 'causal pathway' would be initiated by (i) the release of a gene drive system in target mosquito vector species, leading to (ii) its transmission to subsequent generations, (iii) its increase in frequency and spread in target mosquito populations, (iv) its simultaneous propagation of a linked genetic trait aimed at reducing vectorial capacity for Plasmodium, and (v) reduced vectorial capacity for parasites in target mosquito populations as the gene drive system reaches fixation in target mosquito populations, causing (vi) decreased malaria incidence and prevalence. Here the scope, objectives, trial design elements, and approaches to monitoring for initial field releases of such gene dive systems are considered, informed by the successful implementation of field trials of biological control agents, as well as other vector control tools, including insecticides, Wolbachia, larvicides, and attractive-toxic sugar bait systems. Specific research questions to be addressed in initial gene drive field trials are identified, and adaptive trial design is explored as a potentially constructive and flexible approach to facilitate testing of the causal pathway. A fundamental question for decision-makers for the first field trials will be whether there should be a selective focus on earlier points of the pathway, such as genetic efficacy via measurement of the increase in frequency and spread of the gene drive system in target populations, or on wider interrogation of the entire pathway including entomological and epidemiological efficacy. How and when epidemiological efficacy will eventually be assessed will be an essential consideration before decisions on any field trial protocols are finalized and implemented, regardless of whether initial field trials focus exclusively on the measurement of genetic efficacy, or on broader aspects of the causal pathway. Statistical and modelling tools are currently under active development and will inform such decisions on initial trial design, locations, and endpoints. Collectively, the considerations here advance the realization of developer ambitions for the first field trials of low-threshold gene drive for malaria vector control within the next 5 years.

Management of immune-mediated necrotizing myopathy.

The immune-mediated necrotizing myopathies (IMNM) are autoimmune myositides clinically characterized by proximal predominant weakness and elevated creatine kinase (CK). They may be associated with autoantibodies (anti-HMGCR, anti-SRP), triggered by statin use (e.g., anti-HMGCR myopathy), associated with cancer, or may be idiopathic. Immunotherapy is required to improve strength and decrease the CK level, but no therapies are currently approved by the U.S. Food and Drug Administration for the treatment of IMNM. The optimal treatment strategy for IMNM is currently unknown and wide practice variation exists in the management of this condition. However, observational studies and expert opinion suggest that certain therapies may be more effective for the different serological subtypes of IMNM. HMGCR IMNM often responds favorably to intravenous immunoglobulin (IVIG) even as monotherapy. Signal recognition peptide and seronegative IMNM typically require combination immunotherapy, most often consisting of an oral immunosuppressant, corticosteroids, and IVIG or rituximab. Patients often remain on immunotherapy for years and relapse is common during tapering of immunotherapy. Further studies are needed to guide the optimal management of these patients.