Mets and NETs: The Awakening Force.

In a recent study published in Science, Albrengues et al. (2018) unveil an intriguing mechanism whereby the release of neutrophil extra-cellular traps during chronic lung inflammation awakens dormant malignant cells and contributes to cancer progression.

The impact of preexisting psychiatric disorders and antidepressant use on COVID-19 related outcomes: a multicenter study.

Pre-existing mental disorders are linked to COVID-19-related outcomes. However, the findings are inconsistent and a thorough analysis of a broader spectrum of outcomes such as COVID-19 infection severity, morbidity, and mortality is required. We investigated whether the presence of psychiatric diagnoses and/or the use of antidepressants influenced the severity of the outcome of COVID-19. This retrospective cohort study evaluated electronic health records from the INSIGHT Clinical Research Network in 116,498 individuals who were diagnosed with COVID-19 between March 1, 2020, and February 23, 2021. We examined hospitalization, intubation/mechanical ventilation, acute kidney failure, severe sepsis, and death as COVID-19-related outcomes. After using propensity score matching to control for demographics and medical comorbidities, we used contingency tables to assess whether patients with (1) a history of psychiatric disorders were at higher risk of more severe COVID-19-related outcomes and (2) if use of antidepressants decreased the risk of more severe COVID-19 infection. Pre-existing psychiatric disorders were associated with an increased risk for hospitalization, and subsequent outcomes such as acute kidney failure and severe sepsis, including an increased risk of death in patients with schizophrenia spectrum disorders or bipolar disorders. The use of antidepressants was associated with significantly reduced risk of sepsis (p = 0.033), death (p = 0.026). Psychiatric disorder diagnosis prior to a COVID-19-related healthcare encounter increased the risk of more severe COVID-19-related outcomes as well as subsequent health complications. However, there are indications that the use of antidepressants might decrease this risk. This may have significant implications for the treatment and prognosis of patients with COVID-19.

Callous-unemotional traits and pre-ejection period in response to reward.

Callous-unemotional (CU) traits have important utility in distinguishing individuals exhibiting more severe and persistent antisocial behavior, and our understanding of reward processing and CU traits contributes to behavioral modification. However, research on CU traits often investigated reward alongside punishment and examined solely on average reward reactivity, neglecting the reward response pattern over time such as habituation. This study assessed individuals' pre-ejection period (PEP), a sympathetic nervous system cardiac-linked biomarker with specificity to reward, during a simple reward task to investigate the association between CU traits and both average reward reactivity and reward response pattern over time (captured as responding trajectory). A heterogeneous sample of 126 adult males was recruited from a major metropolitan area in the US. Participants reported their CU traits using the Inventory of Callous-Unemotional Traits and completed a simple reward task while impedance cardiography and electrocardiogram were recorded to derive PEP. The results revealed no significant association between average PEP reward reactivity and CU traits. However, CU traits predicted both linear and quadratic slopes of the PEP reactivity trajectory: individuals with higher CU traits had slower habituation initially, followed by a rapid habituation in later blocks. Findings highlight the importance of modeling the trajectory of PEP reward response when studying CU traits. We discussed the implications of individuals with high CU traits having the responding pattern of slower initial habituation followed by rapid habituation to reward and the possible mechanisms.

Breakthrough SARS-CoV-2 infections among recipients of tixagevimab-cilgavimab prophylaxis: A citywide real-world effectiveness study.

There are limited real-world data on the effectiveness of tixagevimab-cilgavimab as pre-exposure prophylaxis of COVID-19. We describe lessons learned when coordinating data collection and identifying breakthrough SARS-CoV-2 infections among patients across indications and institutions in a major US city. The Chicago Department of Public Health requested patient-level tixagevimab-cilgavimab administration data from all prescribing providers in Chicago, for treatments December 8, 2021 through June 30, 2022. Records were matched to COVID-19 vaccinations and laboratory-confirmed SARS-CoV-2 infections through December 31, 2022. Due to difficulty collecting data from all providers, targeted follow-up was conducted to improve completeness on key variables (demographics, vaccination status, clinical indication for prophylaxis). Over half of reported tixagevimab-cilgavimab administrations were to patients residing outside Chicago. Five hundred forty-four Chicago residents who received at least one dose of tixagevimab-cilgavimab were included in this analysis. Most were age 50 years or older (72%), Black non-Latinx (33%) or White non-Latinx (29%), and fully vaccinated (80%). Seventy-five patients (14%) had laboratory-confirmed COVID-19. Patients with and without breakthrough infections were demographically similar. Clinical indication was missing for >95% of cases, improved to 64% after follow-up; the most frequently specified was hematologic malignancy (10%). Severe outcomes were uncommon: 16% had documented COVID-19-related hospitalizations, one death was identified. Tixagevimab-cilgavimab recipients in Chicago had a lower rate of severe SARS-CoV-2 infection than reported among other untreated high-risk patients, including during predominance of non-neutralizing variants. Improving stakeholder collaboration is essential for generation of real-world effectiveness data, informing pandemic preparedness and optimizing use of medical countermeasures.

The Effect of Methylphenidate on Cognition in Patients with Comorbid Attention Deficit/Hyperactivity Disorder and Amphetamine Use Disorder: An Exploratory Single-Blinded within-Subject Study.

INTRODUCTION: Attention deficit/hyperactivity disorder (ADHD) with co-occurring substance use disorder (SUD) is associated with poor treatment outcomes. Two randomized controlled trials, utilizing robust doses of stimulants, demonstrated a significant effect on treatment outcomes in patients with ADHD/SUD. This study aimed to investigate differences in executive functioning and explore the dose-dependent effect of OROS-methylphenidate (MPH) in patients with comorbid ADHD and amphetamine use disorder (ADHD+AMPH) and patients with ADHD only. METHODS: Three groups (ADHD+AMPH, ADHD only, and healthy controls) were assessed repeatedly with a neuropsychological test battery. An exploratory within-subject single-blinded design was employed where the ADHD only group received a maximum dose of 72 mg OROS-MPH, the ADHD+AMPH group a maximum dose of 180 mg, whereas the healthy subjects did not receive any study medication. Both ADHD groups received the same dose titration up to 72 mg OROS-MPH. RESULTS: The ADHD+AMPH group demonstrated a significantly poorer motor inhibition and spatial working memory and reported more severe ADHD symptoms compared to the ADHD only group. 180 mg OROS-MPH was associated with a significant improvement in executive functioning in the dual diagnosis group. However, the exploratory study design and recruitment issues do not allow for any conclusion to be drawn regarding the effect of 180 mg OROS-MPH. CONCLUSION: Patients with ADHD+AMPH present with more severe neurocognitive deficits compared to ADHD only. The effect of 180 mg OROS-MPH on cognition in patients with ADHD+AMPH was inconclusive. Future studies should consider recruitment issues and high drop-out rates in this study population.

Unique and interactive effects of threat and deprivation on latent trait cortisol among emerging adults.

Though considerable work supports the Dimensional Model of Adversity and Psychopathology, prior research has not tested whether the dimensions-threat (e.g., abuse) and deprivation (e.g., neglect)-are uniquely related to salivary trait indicators of hypothalamic pituitary adrenal (HPA) axis activity. We examined the unique and interactive effects of threat and deprivation on latent trait cortisol (LTC)-and whether these effects were modified by co-occurring adversities. Emerging adults (n = 90; Mage = 19.36 years; 99.88% cisgender women) provided salivary cortisol samples four times a day (waking, 30 min and 45 min postwaking, bedtime) over three 3-day measurement waves over 13 weeks. Contextual life stress interviews assessed early adversity. Though the effects varied according to the conceptualization of early adversity, overall, threat-but not deprivation, nor other co-occurring adversities-was uniquely associated with the across-wave LTC. Specifically, the incidence and frequency of threat were each negatively related to the across-wave LTC. Threat severity was also associated with the across-wave LTC, but only among those with no deprivation. Finally, the effects of threat were modified by other co-occurring adversities. Findings suggest that threat has unique implications for individual differences in HPA axis activity among emerging adults, and that co-occurring adversities modify such effects.

Open Label Pilot of Lorcaserin (a serotonin 2C-receptor agonist) for Cannabis Use Disorder.

Background And Objective: Cannabis Use Disorder (CUD) has no FDA approved treatment. Serotonin-2c (5HT2c) agonists have preclinical and human laboratory evidence for potential efficacy for CUD. We assessed the tolerability and effects of lorcaserin (5HT2c agonist) on CUD. Methods: In a 10-week, open label, uncontrolled trial, the tolerability of lorcaserin was tested in outpatients with CUD. Adverse events (AE) were assessed weekly. Cannabis use was assessed twice weekly by the Timeline follow-back and quantitative urine metabolites. Results: 17 participants enrolled, and 14 received medication. Participants' average age was 35 years; majority were male (N=12). The medication was well tolerated in males. There were no serious adverse events (SAE). The most common AE's were headache/migraine (N=4, all females), anorexia (N=3), and irritability (N=2). Participants decreased their frequency of cannabis use significantly (p < 0.001), adjusted for baseline use. By the end of the trial, participants decreased by 1.76 (SE=0.47) cannabis using days/week. Average daily amount of cannabis and urine THC metabolite levels did not change significantly. Conclusions: Lorcaserin was well tolerated in males but not females suggesting possible sex differences. Future trials of other 5HT2c agonists (lorcaserin was withdrawn at the request of the FDA) should consider longer dose titration phases. Trial Registration: NCT02932215.

Comparison of Quantitative Mass Spectrometric Methods for Drug Target Identification by Thermal Proteome Profiling.

Thermal proteome profiling (TPP) provides a powerful approach to studying proteome-wide interactions of small therapeutic molecules and their target and off-target proteins, complementing phenotypic-based drug screens. Detecting differences in thermal stability due to target engagement requires high quantitative accuracy and consistent detection. Isobaric tandem mass tags (TMTs) are used to multiplex samples and increase quantification precision in TPP analysis by data-dependent acquisition (DDA). However, advances in data-independent acquisition (DIA) can provide higher sensitivity and protein coverage with reduced costs and sample preparation steps. Herein, we explored the performance of different DIA-based label-free quantification approaches compared to TMT-DDA for thermal shift quantitation. Acute myeloid leukemia cells were treated with losmapimod, a known inhibitor of MAPK14 (p38α). Label-free DIA approaches, and particularly the library-free mode in DIA-NN, were comparable of TMT-DDA in their ability to detect target engagement of losmapimod with MAPK14 and one of its downstream targets, MAPKAPK3. Using DIA for thermal shift quantitation is a cost-effective alternative to labeled quantitation in the TPP pipeline.

Cysteine-Selective Modification of Peptides and Proteins via Desulfurative C-C Bond Formation.

The site-selective modification of peptides and proteins facilitates the preparation of targeted therapeutic agents and tools to interrogate biochemical pathways. Among the numerous bioconjugation techniques developed to install groups of interest, those that generate C(sp3 )-C(sp3 ) bonds are significantly underrepresented despite affording proteolytically stable, biogenic linkages. Herein, a visible-light-mediated reaction is described that enables the site-selective modification of peptides and proteins via desulfurative C(sp3 )-C(sp3 ) bond formation. The reaction is rapid and high yielding in peptide systems, with comparable translation to proteins. Using this chemistry, a range of moieties is installed into model systems and an effective PTM-mimic is successfully integrated into a recombinantly expressed histone.

Racial differences in COVID-19 severity associated with history of substance use disorders and overdose: Findings from multi-site electronic health records in New York City.

Substance use disorders (SUD) are associated with increased risk of worse COVID-19 outcomes. Likewise, racial/ethnic minority patients experience greater risk of severe COVID-19 disease compared to white patients. Providers should understand the role of race and ethnicity as an effect modifier on COVID-19 severity among individuals with SUD. This retrospective cohort study assessed patient race/ethnicity as an effect modifier of the risk of severe COVID-19 disease among patients with histories of SUD and overdose. We used merged electronic health record data from 116,471 adult patients with a COVID-19 encounter between March 2020 and February 2021 across five healthcare systems in New York City. Exposures were patient histories of SUD and overdose. Outcomes were risk of COVID-19 hospitalization and subsequent COVID-19-related ventilation, acute kidney failure, sepsis, and mortality. Risk factors included patient age, sex, and race/ethnicity, as well as medical comorbidities associated with COVID-19 severity. We tested for interaction between SUD and patient race/ethnicity on COVID-19 outcomes. Findings showed that Non-Hispanic Black, Hispanic/Latino, and Asian/Pacific Islander patients experienced a higher prevalence of all adverse COVID-19 outcomes compared to non-Hispanic white patients. Past-year alcohol (OR 1.24 [1.01-1.53]) and opioid use disorders (OR 1.91 [1.46-2.49]), as well as overdose history (OR 4.45 [3.62-5.46]), were predictive of COVID-19 mortality, as well as other adverse COVID-19 outcomes. Among patients with SUD, significant differences in outcome risk were detected between patients of different race/ethnicity groups. Findings indicate that providers should consider multiple dimensions of vulnerability to adequately manage COVID-19 disease among populations with SUDs.

Early adversity and depressive symptoms among early adolescent girls: the mediating role of exposure to recent interpersonal acute stress.

Early adversity confers risk for depression in part through its association with recent (i.e., proximal) acute stress. However, it remains unresolved whether: a) early adversity predicts increases in recent acute stress over time; b) all - or only certain types - of recent events mediate the relationship between early adversity and depression; and c) early adversity places individuals at greater risk for depression via greater exposure to independent (i.e., fateful) interpersonal events or via greater generation of dependent (i.e., partially self-initiated) interpersonal events (i.e., stress generation) or both. These questions were examined in a 3-wave longitudinal study of early adolescent girls (N = 125; M = 12.35 years [SD = .77]) with no history of diagnosable depression using contextual life stress and diagnostic interviews. Path analyses indicated that increases in past-year acute interpersonal, but not non-interpersonal, stress mediated the link between early adversity and depressive symptoms. The mediating role of interpersonal events was limited to independent ones, suggesting increases in interpersonal event exposure, not interpersonal stress generation, acted as a mediator. Finally, findings support prior evidence that early adversity may not directly predict future depressive symptoms. Implications for understanding the role of recent stress in the association between early adversity and adolescent depression are discussed.

COVID-19 vaccination requirements, encouragement and hesitancy among non-health care, non-congregate workers in Chicago: results from the WEVax survey.

BACKGROUND: While frontline and essential workers were prioritized for COVID-19 vaccination in the United States, coverage rates and encouragement strategies among non-health care workers have not been well-described. The Chicago Department of Public Health surveyed non-health care businesses to fill these knowledge gaps and identify potential mechanisms for improving vaccine uptake. METHODS: The Workplace Encouragement for COVID-19 Vaccination in Chicago survey (WEVax Chicago) was administered using REDCap from July 11 to September 12, 2022, to businesses previously contacted for COVID-19 surveillance and vaccine-related outreach. Stratified random sampling by industry was used to select businesses for phone follow-up; zip codes with low COVID-19 vaccine coverage were oversampled. Business and workforce characteristics including employee vaccination rates were reported. Frequencies of requirement, verification, and eight other strategies to encourage employee vaccination were assessed, along with barriers to uptake. Fisher's exact test compared business characteristics, and Kruskal-Wallis test compared numbers of encouragement strategies reported among businesses with high (> 75%) vs. lower or missing vaccination rates. RESULTS: Forty-nine businesses completed the survey, with 86% having 500 or fewer employees and 35% in frontline essential industries. More than half (59%) reported high COVID-19 vaccination rates among full-time employees; most (75%) workplaces reporting lower coverage were manufacturing businesses with fewer than 100 employees. Verifying vaccination was more common than requiring vaccination (51% vs. 28%). The most frequently reported encouragement strategies aimed to improve convenience of vaccination (e.g., offering leave to be vaccinated (67%) or to recover from side effects (71%)), while most barriers to uptake were related to vaccine confidence (concerns of safety, side effects, and other skepticism). More high-coverage workplaces reported requiring (p = 0.03) or verifying vaccination (p = 0.07), though the mean and median numbers of strategies used were slightly greater among lower-coverage versus higher-coverage businesses. CONCLUSIONS: Many WEVax respondents reported high COVID-19 vaccine coverage among employees. Vaccine requirement, verification and addressing vaccine mistrust may have more potential to improve coverage among working-age Chicagoans than increasing convenience of vaccination. Vaccine promotion strategies among non-health care workers should target low-coverage businesses and assess motivators in addition to barriers among workers and businesses.

Sublingual dexmedetomidine (BXCL501) reduces opioid withdrawal symptoms: findings from a multi-site, phase 1b/2, randomized, double-blind, placebo-controlled trial.

Background: Like other alpha-2-adrenergic receptor agonists, dexmedetomidine may reduce the severity of opioid withdrawal but with fewer adverse cardiovascular effects.Objective: This study assessed the safety of sublingual dexmedetomidine (BXCL501) and its preliminary efficacy in treating opioid withdrawal (ClinicalTrials.gov: NCT04470050).Methods: Withdrawal was induced among individuals with physiological dependence on opioids via discontinuation of oral morphine (Days 1-5). Participants were randomized to receive placebo or active BXCL501: 30, 60, 90, 120, 180, and 240 µg twice daily (Days 6-12). Treatment-emergent adverse events (TEAEs) were the primary outcome measure. Secondary outcomes included the Clinical and Subjective Opiate Withdrawal Scales (COWS and SOWS-Gossop, respectively), and the Agitation and Calmness Evaluation Scale (ACES).Results: Of 225 participants enrolled, 90 discontinued during morphine stabilization. Post-BXCL501 randomization (Day 6) data were available from 135 participants (73% male), with 33% completing thru Day 12. In total, 36 subjects reported 1 or more TEAE. Higher doses of BXCL501 (i.e. 180 and 240 µg, twice daily) increased the frequency of: hypotension, orthostatic hypotension, and somnolence. TEAEs related to BXCL501 were mild or moderate in severity, except for one participant in the 120 µg condition whose orthostatic hypotension and bradycardia were classified as severe. Higher BXCL501 dose conditions (120, 180, and 240 µg) resulted in statistically significant reductions in COWS & SOWS scores. Mean ratings on the ACES were between 3 (mild), 4 (normal), and 5 (mild calmness), with few significant differences as a function of dose.Conclusions: These findings support the continued development of BXCL501 for the management of opioid withdrawal.

Open label trial of lofexidine-assisted non-opioid induction onto naltrexone extended-release injection for opioid use disorder.

Background: Opioid use disorder (OUD) continues to be major public health problem in the US and innovative medication strategies are needed. The extended-release injectable formulation of naltrexone (ER-NTX), an opioid receptor antagonist, is an effective treatment for OUD, but the need for an opioid-free period during the induction phase of treatment is a barrier to treatment success, particularly in the outpatient setting. Lofexidine, an alpha-2-adrenergic agonist, is an effective treatment for opioid withdrawal.Objectives: To evaluate the feasibility, safety, and tolerability of lofexidine for facilitating induction onto ER-NTX in the management of OUD.Methods: In an open-label, uncontrolled, 10-week outpatient clinical trial, 20 adults (four women) with OUD were treated with a fixed-flexible dosing strategy (maximum 0.54 mg 4×/daily) of lofexidine for up to 10 days to manage opioid withdrawal prior to receiving ER-NTX. The COVID-19 pandemic resulted in a modification of the study methods after enrolling 10 participants who attended all visits in person. The second group of 10 participants attended most induction period visits remotely.Results: Overall, 10 of the 20 participants (50%) achieved the primary outcome by receiving the first ER-NTX injection. Rates of induction success did not differ by the presence of fentanyl or remote visit attendance, although the small sample size provided limited statistical power. Six out of 20 participants (30%) initiated on lofexidine required dose adjustments. There were no study-related serious adverse events.Conclusions: This study provides preliminary evidence supporting the feasibility of inducting individuals with OUD onto ER-NTX using lofexidine.

The clinical course of comorbid substance use disorder and attention deficit/hyperactivity disorder: protocol and clinical characteristics of the INCAS study.

BACKGROUND: Substance use disorders (SUD) often co-occur with attention deficit hyperactivity disorder (ADHD). Although the short-term effects of some specific interventions have been investigated in randomized clinical trials, little is known about the long-term clinical course of treatment-seeking SUD patients with comorbid ADHD. AIMS: This paper presents the protocol and baseline clinical characteristics of the International Naturalistic Cohort Study of ADHD and SUD (INCAS) designed and conducted by the International Collaboration on ADHD and Substance Abuse (ICASA) foundation. The overall aim of INCAS is to investigate the treatment modalities provided to treatment-seeking SUD patients with comorbid ADHD, and to describe the clinical course and identify predictors for treatment outcomes. This ongoing study employs a multicentre observational prospective cohort design. Treatment-seeking adult SUD patients with comorbid ADHD are recruited, at 12 study sites in nine different countries. During the follow-up period of nine months, data is collected through patient files, interviews, and self-rating scales, targeting a broad range of cognitive and clinical symptom domains, at baseline, four weeks, three months and nine months. RESULTS: A clinically representative sample of 578 patients (137 females, 441 males) was enrolled during the recruitment period (June 2017-May 2021). At baseline, the sample had a mean age (SD) of 36.7 years (11.0); 47.5% were inpatients and 52.5% outpatients; The most prevalent SUDs were with alcohol 54.2%, stimulants 43.6%, cannabis 33.1%, and opioids 14.5%. Patients reported previous treatments for SUD in 71.1% and for ADHD in 56.9%. Other comorbid mental disorders were present in 61.4% of the sample: major depression 31.5%, post-traumatic stress disorder 12.1%, borderline personality disorder 10.2%. CONCLUSIONS: The first baseline results of this international cohort study speak to its feasibility. Data show that many SUD patients with comorbid ADHD had never received treatment for their ADHD prior to enrolment in the study. Future reports on this study will identify the course and potential predictors for successful pharmaceutical and psychological treatment outcomes. TRIAL REGISTRATION: ISRCTN15998989 20/12/2019.

Safety and tolerability of progesterone treatment for women with cocaine use disorder: a pilot treatment trial.

Background: Problematic cocaine use remains a significant public health issue, particularly among women. However, no concerted efforts have been made to target a pharmacological treatment option for women with cocaine use disorder (CUD) despite preclinical, human laboratory, and a limited number of clinical studies demonstrating that progesterone can attenuate the effects of cocaine to a greater extent in women than men.Objectives: To evaluate the safety, tolerability, and preliminary efficacy of progesterone for treating women with CUD.Methods: A 10-week double-blind randomized treatment trial was conducted. Prior to randomization, participants were required to achieve cocaine abstinence (1 week) before assignment to progesterone (up to 400 mg/day) or placebo. The primary efficacy outcomes were days to relapse and cocaine abstinence during the last 3 weeks of the trial. The frequency of side effects was also assessed.Results: 227 women were assessed for eligibility. Twenty-five women entered treatment and 21 were randomized to progesterone (n = 11) or placebo (n = 10). The majority of women relapsed in less than 4 days with no differences between the two groups. Further, there were no significant differences between the progesterone and placebo groups in terms of cocaine abstinence during the last 3 weeks of the trial (27% and 10% respectively). The most commonly reported side effects were headache and fatigue, but no group differences were noted.Conclusions: Progesterone was well tolerated and safe and supports further study is in a larger sample to determine if exogenous progesterone is an effective treatment option for women with CUD.(ClinicalTrials.gov Identifier: NCT00632099).

The Cognitive, Affective and Somatic Empathy Scales for Adults.

The Cognitive, Affective and Somatic Empathy Scales (CASES) assess three forms of empathy, each with subscales for positive and negative empathy. The present study extends this child instrument to adults and examines its factor structure and construct validity. A secondary aim is to investigate the under-researched area of positive empathy. Community samples totaling 2,604 adults completed the CASES for adults, together with scales assessing construct validity. Confirmatory factor analysis supported the three-factor cognitive-affective-somatic model and a two-factor positive-negative empathy model. Findings were replicated in a second independent sample. Internal reliabilities ranged from .80 to .92. Individuals with higher psychopathy and stimulation-seeking scores were less impaired in their empathic reactions to positive relative to negative valence events, suggesting that they are relatively capable of responding emotionally to rewarding events. Somatic empathy was most strongly associated with pleasure in affective touch and with female > male gender differences. While proactive aggression was associated with reduced cognitive and affective empathy, reactive aggression was associated with increased empathy. Findings provide initial support for the utility of CASES for assessing different forms of empathy and suggest that the balance between positive and negative empathy could provide new insights into psychological traits.

A Dual Role for FADD in Human Precursor T-Cell Neoplasms.

A reduction in FADD levels has been reported in precursor T-cell neoplasms and other tumor types. Such reduction would impact on the ability of tumor cells to undergo apoptosis and has been associated with poor clinical outcomes. However, FADD is also known to participate in non-apoptotic functions, but these mechanisms are not well-understood. Linking FADD expression to the severity of precursor T-cell neoplasms could indicate its use as a prognostic marker and may open new avenues for targeted therapeutic strategies. Using transcriptomic and clinical data from patients with precursor T-cell neoplasms, complemented by in vitro analysis of cellular functions and by high-throughput interactomics, our results allow us to propose a dual role for FADD in precursor T-cell neoplasms, whereby resisting cell death and chemotherapy would be a canonical consequence of FADD deficiency in these tumors, whereas deregulation of the cellular metabolism would be a relevant non-canonical function in patients expressing FADD. These results reveal that evaluation of FADD expression in precursor T-cell neoplasms may aid in the understanding of the biological processes that are affected in the tumor cells. The altered biological processes can be of different natures depending on the availability of FADD influencing its ability to exert its canonical or non-canonical functions. Accordingly, specific therapeutic interventions would be needed in each case.

Homeward bound: Exploring the motives of mothers who brought their offspring with intellectual disabilities home from residential settings during the COVID-19 pandemic.

BACKGROUND: At the start of the COVID-19 pandemic, some parents in the Netherlands decided to bring their offspring with intellectual disabilities, who normally live in residential care, home. The present study explored why the mothers decided to bring their offspring home. METHOD: Interviews were carried out with seven mothers of adults with intellectual disabilities. An interpretative phenomenological approach was used to establish in-depth accounts of the mothers' experiences. RESULTS: The analysis yielded three overarching themes: (a) Families are indispensable; (b) the complex role of being a mother of a child with intellectual disabilities; and (c) Who is looking out for our offspring during COVID-19? CONCLUSIONS: The mothers experienced a strong sense of wanting to do what was best for their offspring with intellectual disabilities during COVID-19. The study provides insight into why mothers remain involved in the care for their offspring and the complexity of navigating lifelong care responsibilities.

Site-Selective Installation of Nϵ -Modified Sidechains into Peptide and Protein Scaffolds via Visible-Light-Mediated Desulfurative C-C Bond Formation.

Post-translational modifications (PTMs) enhance the repertoire of protein function and mediate or influence the activity of many cellular processes. The preparation of site-specifically and homogeneously modified proteins, to apply as tools to understand the biological role of PTMs, is a challenging task. Herein, we describe a visible-light-mediated desulfurative C(sp3 )-C(sp3 ) bond forming reaction that enables the site-selective installation of Nϵ -modified sidechains into peptides and proteins of interest. Rapid, operationally simple, and tolerant to ambient atmosphere, we demonstrate the installation of a range of lysine (Lys) PTMs into model peptide systems and showcase the potential of this technology by site-selectively installing an Nϵ Ac sidechain into recombinantly expressed ubiquitin (Ub).