Recommendations on the Use of Multiple Labels in Human Mass Balance Studies.

The administration of radiolabeled drug candidates is considered the gold standard in absorption, distribution, metabolism, and excretion studies for small-molecule drugs since it allows facile and accurate quantification of parent drug, metabolites, and total drug-related material independent of the compound structure. The choice of the position of the radiolabel, typically 14C or 3H, is critical to obtain relevant information. Sometimes, a biotransformation reaction may lead to cleavage of a part of the molecule. As a result, only the radiolabeled portion can be followed, and information on the fate of the nonlabeled metabolite may be lost. Synthesis and administration of two or more radiolabeled versions of the parent drug as a mixture or in separate studies may resolve this issue but comes with additional challenges. In this paper, we address the questions that may be considered to help make the right choice whether to use a single or multiple radiolabel approach and discuss the pros and cons of different multiple-labeling strategies that can be taken as well as alternative methods that allow the nonlabeled part of the molecule to be followed. SIGNIFICANCE STATEMENT: Radiolabeled studies are the gold standard in drug metabolism research, but molecules can undergo cleavage with loss of the label. This often results in discussions around potential use of multiple labels, which seem to be occurring with increased frequency since an increasing proportion of the small-molecule drugs are tending towards larger molecular weights. This review provides insight and decision criteria in considering a multiple-label approach as well as pros and cons of different strategies that can be followed.

The Hammersmith Score Optimises Patient Selection and Predicts for Overall Survival in Early-Phase Cancer Trial Participants Independent of Tumour Burden.

INTRODUCTION: As tumour response rates are increasingly demonstrated in early-phase cancer trials (EPCT), optimal patient selection and accurate prognostication are paramount. Hammersmith Score (HS), a simple prognostic index derived on routine biochemical measures (albumin <35 g/L, lactate dehydrogenase >450 IU/L, sodium <135 mmol/L), is a validated predictor of response and survival in EPCT participants. HS has not been validated in the cancer immunotherapy era. METHODS: We retrospectively analysed characteristics and outcomes of unselected referrals to our early-phase unit (12/2019-12/2022). Independent predictors for overall survival (OS) were identified from univariable and multivariable models. HS was calculated for 66 eligible trial participants and compared with the Royal Marsden Score (RMS) to predict OS. Multivariable logistic regression and C-index was used to compare predictive ability of prognostic models. RESULTS: Of 212 referrals, 147 patients were screened and 82 patients treated in EPCT. Prognostic stratification by HS identifies significant difference in median OS, and HS was confirmed as a multivariable predictor for OS (HR: HS 1 vs. 0 2.51, 95% CI: 1.01-6.24, p = 0.049; HS 2/3 vs. 0: 10.32, 95% CI: 2.15-49.62, p = 0.004; C-index 0.771) with superior multivariable predictive ability than RMS (HR: RMS 2 vs. 0/1 5.46, 95% CI: 1.12-26.57, p = 0.036; RMS 3 vs. 0/1 6.83, 95% CI: 1.15-40.53, p < 0.001; C-index 0.743). CONCLUSIONS: HS is a validated prognostic index for patients with advanced cancer treated in the context of modern EPCTs, independent of tumour burden. HS is a simple, inexpensive prognostic tool to optimise referral for EPCT.

Factors Influencing Recovery From Pediatric Stroke Based on Discussions From a UK-Based Online Stroke Community: Qualitative Thematic Study.

BACKGROUND: The incidence of stroke in children is low, and pediatric stroke rehabilitation services are less developed than adult ones. Survivors of pediatric stroke have a long poststroke life expectancy and therefore have the potential to experience impairments from their stroke for many years. However, there are relatively few studies characterizing these impairments and what factors facilitate or counteract recovery. OBJECTIVE: This study aims to characterize the main barriers to and facilitators of recovery from pediatric stroke. A secondary aim was to explore whether these factors last into adulthood, whether they change, or if new factors impacting recovery emerge in adulthood. METHODS: We performed a qualitative thematic analysis based on posts from a population of participants from a UK-based online stroke community, active between 2004 and 2011. The analysis focused on users who talked about their experiences with pediatric stroke, as identified by a previous study. The posts were read by 3 authors, and factors influencing recovery from pediatric stroke were mapped into 4 areas: medical, physical, emotional, and social. Factors influencing recovery were divided into short-term and long-term factors. RESULTS: There were 425 posts relating to 52 survivors of pediatric stroke. Some survivors of stroke posted for themselves, while others were talked about by a third party (mostly parents; 31/35, 89% mothers). In total, 79% (41/52) of survivors of stroke were aged ≤18 years and 21% (11/52) were aged >18 years at the time of posting. Medical factors included comorbidities as a barrier to recovery. Medical interventions, such as speech and language therapy and physiotherapy, were also deemed useful. Exercise, particularly swimming, was deemed a facilitator. Among physical factors, fatigue and chronic pain could persist decades after a stroke, with both reported as a barrier to feeling fully recovered. Tiredness could worsen existing stroke-related impairments. Other long-standing impairments were memory loss, confusion, and dizziness. Among emotional factors, fear and uncertainty were short-term barriers, while positivity was a major facilitator in both short- and long-term recovery. Anxiety, grief, and behavioral problems hindered recovery. The social barriers were loneliness, exclusion, and hidden disabilities not being acknowledged by third parties. A good support network and third-party support facilitated recovery. Educational services were important in reintegrating survivors into society. Participants reported that worrying about losing financial support, such as disability allowances, and difficulties in obtaining travel insurance and driving licenses impacted recovery. CONCLUSIONS: The lived experience of survivors of pediatric stroke includes long-term hidden disabilities and barriers to rehabilitation. These are present in different settings, such as health care, schools, workplaces, and driving centers. Greater awareness of these issues by relevant professional groups may help ameliorate them.

Absorption, Distribution, Metabolism, and Excretion of [14C]iptacopan in Healthy Male Volunteers and in In Vivo and In Vitro Studies.

Iptacopan (LNP023) is an oral, small-molecule, first-in-class, highly potent proximal complement inhibitor that specifically binds factor B and inhibits the alternative complement pathway. Iptacopan is currently in development as a targeted treatment of paroxysmal nocturnal hemoglobinuria and multiple other complement-mediated diseases. In this study, the absorption, distribution, metabolism, and excretion (ADME) of iptacopan was characterized in six healthy volunteers after a single 100 mg oral dose of [14C]iptacopan. This was supplemented with an in vivo rat ADME study and metabolite exposure comparisons between human, rat, and dog, in addition to in vitro assays, to better understand the clearance pathways and enzymes involved in the metabolism of iptacopan. The fraction of [14C]iptacopan absorbed was estimated to be about 71%, with a time to maximum concentration of 1.5 hours and elimination half-life from plasma of 12.3 hours. Following a single dose of [14C]iptacopan, 71.5% of the radioactivity was recovered in feces and 24.8% in urine. [14C]iptacopan was primarily eliminated by hepatic metabolism. The main biotransformation pathways were oxidative metabolism via CYP2C8, with M2 being the major oxidative metabolite, and acyl glucuronidation via UGT1A1. The two acyl glucuronide metabolites in human plasma, M8 and M9, each accounted for ≤ 10% of the total circulating drug-related material; systemic exposure was also observed in toxicology studies in rat and dog, suggesting a low risk associated with these metabolites. Binding of iptacopan to its target, factor B, in the bloodstream led to a concentration-dependent blood:plasma distribution and plasma protein binding of [14C]iptacopan. SIGNIFICANCE STATEMENT: We characterized the pharmacokinetics, excretion, metabolism and elimination of [14C]iptacopan (an oral, selective small-molecule inhibitor of factor B) in healthy human subjects. [14C]iptacopan was primarily eliminated by metabolism. The primary biotransformation pathways were oxidative metabolism via CYP2C8 and acyl glucuronidation via UGT1A1. Direct secretion of iptacopan into urine and potentially bile represented additional elimination mechanisms. Binding of iptacopan to its target, factor B, in the bloodstream led to a concentration-dependent blood:plasma distribution and plasma protein binding of [14C]iptacopan.

Assessment of routine same-day discharge surgery for robot-assisted radical prostatectomy.

INTRODUCTION: It is important for robotic surgery to be cost-effective, especially by reducing the length of stay (LOS). Therefore, we developed a protocol for day-case robot-assisted radical prostatectomy (RARP). This study aimed to validate this as a safe practice of care and to assess the potential benefits to the hospital and patient. METHODS: In this single-centre study, all patients booked for RARP between April 2022 and October 2022 were screened for suitability for day case. All tumour types were included. Exclusion criteria were a history of complex abdominal surgeries, salvage prostatectomy, body mass index (BMI) > 35 and patient living alone or > 150 km away from the hospital. All day-case RARPs were performed as a morning case with a protocol for review throughout the day with evening discharge if mobilising independently and eating/drinking well. The primary outcome of the study was success rate of discharge home on day of surgery (DOS) with secondary outcomes of readmissions and complications. A patient questionnaire was completed at home including both visual analogue scale (VAS) for pain and satisfaction rating. RESULTS: Forty-five patients underwent day-case RARP over a 6-month period with minimum of 30 days of follow-up. 41/45 (91%) had successful DOS discharge home. The four admissions overnight were due to dizziness, low oxygen saturation, intraoperative complications and a diagnosis of COVID-19. There were no readmissions and no 30-day complications. The most common issues at home were catheter discomfort and constipation with low mean VAS pain score and low nausea reported. The overall patient satisfaction rating was very high at 4.8/5, and 97% said they would recommend to a family member. The cost saving for the hospital was 400 pounds per patient. CONCLUSION: Day-case procedure is a viable, safe and efficient pathway for appropriately selected and counselled patients undergoing RARP.

Evaluating the Effectiveness of Tethered Bis(urazolyl) Diradicals as Molecular Building Blocks for Dynamic Covalent Chemistry.

Dynamic covalent chemistry (DCvC) is a powerful means by which to rapidly prepare complex structures from simple molecular building blocks. Effective DCvC behavior is contingent upon the reversibility of covalent bond formation. Stabilized radical species, therefore, have been effectively used for these applications. In earlier work we demonstrated that properly substituted 1-arylurazolyl radicals showed promise as oxygen-insensitive heterocyclic N-centered radicals with a propensity for reversible bond formation. In this work we have synthesized several tethered bis(urazolyl) diradicals, varying by the type and length of connectivity between the urazole rings, and tested them for DCvC behavior. We have found that when the two aryl rings to which the urazolyl radical sites are attached are tethered by a chain of five or more carbons, equilibrium mixtures of monomeric and dimeric species are formed by N-N bond formation between two radical sites. DCvC behavior is observed that is sensitive to changes in temperature, concentration, and (to a lesser extent) solvent. In general, the dimer species is favored at lower temperatures and higher concentrations.

Optimization of the Hemolysis Assay for the Assessment of Cytotoxicity.

In vitro determination of hemolytic properties is a common and important method for preliminary evaluation of cytotoxicity of chemicals, drugs, or any blood-contacting medical device or material. The method itself is relatively straightforward, however, protocols used in the literature vary substantially. This leads to significant difficulties both in interpreting and in comparing the obtained values. Here, we examine how the different variables used under different experimental setups may affect the outcome of this assay. We find that certain key parameters affect the hemolysis measurements in a critical manner. The hemolytic effect of compounds tested here varied up to fourfold depending on the species of the blood source. The use of different types of detergents used for generating positive control samples (i.e., 100% hemolysis) produced up to 2.7-fold differences in the calculated hemolysis ratios. Furthermore, we find an expected, but substantial, increase in the number of hemolyzed erythrocytes with increasing erythrocyte concentration and with prolonged incubation time, which in turn affects the calculated hemolysis ratios. Based on our findings we propose an optimized protocol in an attempt to standardize future hemolysis studies.

The impact of a guided paced breathing audiovisual intervention on anxiety symptoms in Palestinian children: a pilot randomized controlled trial.

BACKGROUND: Children in Palestine may be at high risk for anxiety symptoms. However, access to mental health services is limited. Therefore, the objective of this study was to conduct a pilot randomized controlled trial to examine whether a guided audiovisual paced breathing intervention was feasible, acceptable, and improved anxiety symptoms in Palestinian children. METHODS: Students (6-10 years old) in an after-school program in Palestine were randomly assigned to the intervention or control condition. All participants completed a pre- and post-intervention measure of anxiety using the Revised Children's Manifest Anxiety Scale. Participants in the intervention completed 24 sessions over 8 weeks and rated breathing ease as well as pre- and post-session relaxation on a 5-point Likert scale. To examine condition differences in post-intervention anxiety, four analyses of covariance were conducted, adjusting for age, sex, and pre-intervention anxiety. RESULTS: A total of 144 participants (65.3% girls; Mage  = 7.5 ± 1.2; 50% per condition) enrolled in the study. There were no differences in demographics or baseline anxiety between the two conditions (ps > .05). Participants reported that it was easy to breathe during the sessions (Ms = 4.1-4.7, SDs = 0.5-1.1). For all but the first session, participants reported being more relaxed after the breathing session than before (ps < .003). Post-intervention, participants in the intervention reported fewer anxiety symptoms compared to participants in the control condition (ps < .01). CONCLUSION: A guided paced breathing audiovisual intervention was feasible and had a significant positive impact on anxiety symptoms in Palestinian children compared to a control condition. Future research should examine whether the audiovisual guided breathing intervention significantly improves long-term outcomes.

Insights into the Chemistry of Iodine New Particle Formation: The Role of Iodine Oxides and the Source of Iodic Acid.

Iodine chemistry is an important driver of new particle formation in the marine and polar boundary layers. There are, however, conflicting views about how iodine gas-to-particle conversion proceeds. Laboratory studies indicate that the photooxidation of iodine produces iodine oxides (IxOy), which are well-known particle precursors. By contrast, nitrate anion chemical ionization mass spectrometry (CIMS) observations in field and environmental chamber studies have been interpreted as evidence of a dominant role of iodic acid (HIO3) in iodine-driven particle formation. Here, we report flow tube laboratory experiments that solve these discrepancies by showing that both IxOy and HIO3 are involved in atmospheric new particle formation. I2Oy molecules (y = 2, 3, and 4) react with nitrate core ions to generate mass spectra similar to those obtained by CIMS, including the iodate anion. Iodine pentoxide (I2O5) produced by photolysis of higher-order IxOy is hydrolyzed, likely by the water dimer, to yield HIO3, which also contributes to the iodate anion signal. We estimate that ∼50% of the iodate anion signals observed by nitrate CIMS under atmospheric water vapor concentrations originate from I2Oy. Under such conditions, iodine-containing clusters and particles are formed by aggregation of I2Oy and HIO3, while under dry laboratory conditions, particle formation is driven exclusively by I2Oy. An updated mechanism for iodine gas-to-particle conversion is provided. Furthermore, we propose that a key iodine reservoir species such as iodine nitrate, which we observe as a product of the reaction between iodine oxides and the nitrate anion, can also be detected by CIMS in the atmosphere.

Primary tumour immune response and lymph node yields in colon cancer.

BACKGROUND: The mechanism underlying improved survival in non-metastatic colon cancer with higher lymph node (LN) yield is unknown. This study aimed to identify whether molecular features in the primary tumour were predictive of LN yield. METHODS: Clinical, genomic, transcriptomic, proteomic and methylation data of non-metastatic, colon cancers studied in The Cancer Genome Atlas were interrogated for associations with LN yield. Based on maximal survival effects, patients were segregated into high (>15) and low (≤15) LN yield. Gene set enrichment analysis was performed on transcriptomic changes to identify biological processes associated with LN yield. Correlations were validated in an independent set of Stage II colon cancers. RESULTS: High LN yield was found predictive of overall and disease-free survival. There was no association of higher LN yield and increasing nodal positivity. High LN yield was strongly linked with gene expression changes associated with the adaptive and dendritic cell immune response. This association was most prominent in node-negative cancers. Analogous findings were reproduced in the validation dataset. CONCLUSION: The study shows a strong association of an activated immune response in tumours with a high LN yield. Immunogenic tumours have a better prognosis, likely explaining the survival benefit with higher LN yields.

Innate immunity in latent autoimmune diabetes in adults.

Latent autoimmune diabetes in adults (LADA) is an autoimmune disease that shares some genetic, immunological and clinical features with both type 1 diabetes and type 2 diabetes. Immune cells including CD4+ T cells, CD8+ T cells, B cells, macrophages and dendritic cells (DCs) have been detected in the pancreas of patients with LADA and a rat model of LADA. Therefore, similar to type 1 diabetes, the pathogenesis of LADA may be caused by interactions between islet ß-cells and innate and adaptive immune cells. However, the role of the immunity in the initiation and progression of LADA remains largely unknown. In this review, we have summarized the potential roles of innate immunity and immune-modulators in LADA development. Furthermore, we have examined the evidence and discussed potential innate immunological reasons for the slower development of LADA compared with type 1 diabetes. More in-depth mechanistic studies are needed to fully elucidate the roles of innate immune-associated genes, molecules and cells in their contributions to LADA pathogenesis. Undertaking these studies will greatly enhance the development of new strategies and optimization of current strategies for the diagnosis and treatment of the disease.

RNA metabolism and links to inflammatory regulation and disease.

Inflammation is vital to protect the host against foreign organism invasion and cellular damage. It requires tight and concise gene expression for regulation of pro- and anti-inflammatory gene expression in immune cells. Dysregulated immune responses caused by gene mutations and errors in post-transcriptional regulation can lead to chronic inflammatory diseases and cancer. The mechanisms underlying post-transcriptional gene expression regulation include mRNA splicing, mRNA export, mRNA localisation, mRNA stability, RNA/protein interaction, and post-translational events such as protein stability and modification. The majority of studies to date have focused on transcriptional control pathways. However, post-transcriptional regulation of mRNA in eukaryotes is equally important and related information is lacking. In this review, we will focus on the mechanisms involved in the pre-mRNA splicing events, mRNA surveillance, RNA degradation pathways, disorders or symptoms caused by mutations or errors in post-transcriptional regulation during innate immunity especially toll-like receptor mediated pathways.

Supporting the implementation of new healthcare technologies by investigating generalisability of pilot studies using area-level statistics.

BACKGROUND: Implementation of new technologies into national health care systems requires careful capacity planning. This is sometimes informed by data from pilot studies that implement the technology on a small scale in selected areas. A critical consideration when using implementation pilot studies for capacity planning in the wider system is generalisability. We studied the feasibility of using publicly available national statistics to determine the degree to which results from a pilot might generalise for non-pilot areas, using the English human papillomavirus (HPV) cervical screening pilot as an exemplar. METHODS: From a publicly available source on population indicators in England ("Public Health Profiles"), we selected seven area-level indicators associated with cervical cancer incidence, to produce a framework for post-hoc pilot generalisability analysis. We supplemented these data by those from publicly available English Office for National Statistics modules. We compared pilot to non-pilot areas, and pilot regimens (pilot areas using the previous standard of care (cytology) vs. the new screening test (HPV)). For typical process indicators that inform real-world capacity planning in cancer screening, we used standardisation to re-weight the values directly observed in the pilot, to better reflect the wider population. A non-parametric quantile bootstrap was used to calculate 95% confidence intervals (CI) for differences in area-weighted means for indicators. RESULTS: The range of area-level statistics in pilot areas covered most of the spectrum observed in the wider population. Pilot areas were on average more deprived than non-pilot areas (average index of multiple deprivation 24.8 vs. 21.3; difference: 3.4, 95% CI: 0.2-6.6). Participants in HPV pilot areas were less deprived than those in cytology pilot areas, matching area-level statistics. Differences in average values of the other six indicators were less pronounced. The observed screening process indicators showed minimal change after standardisation for deprivation. CONCLUSIONS: National statistical sources can be helpful in establishing the degree to which the types of areas outside pilot studies are represented, and the extent to which they match selected characteristics of the rest of the health care system ex-post. Our analysis lends support to extrapolation of process indicators from the HPV screening pilot across England.

Electrospun fibre diameter and its effects on vascular smooth muscle cells.

Bypass grafting is a technique used in the treatment of vascular disease, which is currently the leading cause of mortality worldwide. While technology has moved forward over the years, synthetic grafts still show significantly lower rates of patency in small diameter bypass operations compared to the gold standard (autologous vessel grafts). Scaffold morphology plays an important role in vascular smooth muscle cell (VSMC) performance, with studies showing how fibre alignment and surface roughness can modulate phenotypic and genotypic changes. Herein, this study has looked at how the fibre diameter of electrospun polymer scaffolds can affect the performance of seeded VSMCs. Four different scaffolds were electrospun with increasing fibre sizes ranging from 0.75 to 6 µm. Culturing VSMCs on the smallest fibre diameter (0.75 µm) lead to a significant increase in cell viability after 12 days of culture. Furthermore, interesting trends were noted in the expression of two key phenotypic genes associated with mature smooth muscle cell contractility (myocardin and smooth muscle alpha-actin 1), whereby reducing the fibre diameter lead to relative upregulations compared to the larger fibre diameters. These results showed that the smallest (0.75 µm) fibre diameter may be best suited for the culture of VSMCs with the aim of increasing cell proliferation and aiding cell maturity.

The impact of public health messaging and personal experience on the acceptance of mask wearing during the COVID-19 pandemic.

Face coverings have been shown to slow the spread of COVID-19, yet their use is not universal and remains controversial in the United States. Designing effective nudges for widespread adoption is important when federal mandates are politically or legally infeasible. We report the results from a survey experiment in which subjects were exposed to one of three video messages from President Trump, and then indicated their preference for wearing a mask. In the first video, the President simply recited the Centers for Disease Control and Prevention (CDC) guidelines. In the second, the President additionally emphasized that wearing a mask is optional. In the third video, the President added that he will not personally wear a mask. We find that exposure to presidential messages can increase the stated likelihood of wearing a mask-particularly among the President's supporters. We also explore experiential effects of COVID-19, and find that people (especially supporters of the President) are more likely to support wearing a mask if they know someone who has tested positive for COVID-19. These results offer guidance to policy makers and practitioners interested in understanding the factors that influence viral risk mitigation strategies.

Crosstalk between circadian rhythms and the microbiota.

Circadian rhythms influence daily molecular oscillations in gene/protein expression and aspects of biology and physiology, including behaviour, body temperature and sleep-wake cycles. These circadian rhythms have been associated with a number of metabolic, immune and microbial changes that correlate with health and susceptibility to disease, including infection. While light is the main inducer of circadian rhythms, other factors, including the microbiota, can have important effects on peripheral rhythms. The microbiota have been of significant interest to many investigators over the past decade, with the development of molecular techniques to identify large numbers of species and their function. These studies have shown microbial associations with disease susceptibility, and some of these have demonstrated that alterations in microbiota cause disease. Microbial circadian oscillations impact host metabolism and immunity directly and indirectly. Interestingly, microbial oscillations also regulate host circadian rhythms, and the host circadian rhythms in turn modulate microbial composition. Thus, it is of considerable interest and importance to understand the crosstalk between circadian rhythms and microbiota and especially the microbial influences on the host. In this review, we aim to discuss the role of circadian microbial oscillations and how they influence host immunity. In addition, we discuss how host circadian rhythms can also modulate microbial rhythms. We also discuss potential connections between microbes and circadian rhythms and how these may be used therapeutically to maximize clinical success.

Inference of the Neutron Star Equation of State from Cosmological Distances.

Finite-size effects on the gravitational wave signal from a neutron star merger typically manifest at high frequencies where detector sensitivity decreases. Proposed sensitivity improvements can give us access both to stronger signals and to a myriad of weak signals from cosmological distances. The latter will outnumber the former and the relevant part of the signal will be redshifted towards the detector's most sensitive band. We study the redshift dependence of information about neutron star matter and find that single-scale properties, such as the star radius or the postmerger frequency, are better measured from the distant weak sources from z∼1.

Integrating mental health and disaster preparedness in intervention: a randomized controlled trial with earthquake and flood-affected communities in Haiti.

BACKGROUND: Given the frequency of natural hazards in Haiti, disaster risk reduction is crucial. However, evidence suggests that many people exposed to prior disasters do not engage in disaster preparedness, even when they receive training and have adequate resources. This may be partially explained by a link between mental health symptoms and preparedness; however, these components are typically not integrated in intervention. METHODS: The current study assesses effectiveness of an integrated mental health and disaster preparedness intervention. This group-based model was tested in three earthquake-exposed and flood-prone communities (N = 480), across three time points, using a randomized controlled trial design. The 3-day community-based intervention was culturally-adapted, facilitated by trained Haitian lay mental health workers, and focused on enhancing disaster preparedness, reducing mental health symptoms, and fostering community cohesion. RESULTS: Consistent with hypotheses, the intervention increased disaster preparedness, reduced symptoms associated with depression, post-traumatic stress disorder, anxiety, and functional impairment, and increased peer-based help-giving and help-seeking. Mediation models indicated support for the underlying theoretical model, such that the effect of the intervention on preparedness was mediated by mental health, and that effects on mental health were likewise mediated by preparedness. CONCLUSIONS: The community-based mental health-integrated disaster preparedness intervention is effective in improving mental health and preparedness among community members in Haiti vulnerable to natural hazards. This brief intervention has the potential to be scaled up for use with other communities vulnerable to earthquakes, seasonal flooding, and other natural hazards.

SMG1 heterozygosity exacerbates haematopoietic cancer development in Atm null mice by increasing persistent DNA damage and oxidative stress.

Suppressor of morphogenesis in genitalia 1 (SMG1) and ataxia telangiectasia mutated (ATM) are members of the PI3-kinase like-kinase (PIKK) family of proteins. ATM is a well-established tumour suppressor. Loss of one or both alleles of ATM results in an increased risk of cancer development, particularly haematopoietic cancer and breast cancer in both humans and mouse models. In mice, total loss of SMG1 is embryonic lethal and loss of a single allele results in an increased rate of cancer development, particularly haematopoietic cancers and lung cancer. In this study, we generated mice deficient in Atm and lacking one allele of Smg1, Atm-/- Smg1gt/+ mice. These mice developed cancers more rapidly than either of the parental genotypes, and all cancers were haematopoietic in origin. The combined loss of Smg1 and Atm resulted in a higher level of basal DNA damage and oxidative stress in tissues than loss of either gene alone. Furthermore, Atm-/- Smg1gt/+ mice displayed increased cytokine levels in haematopoietic tissues compared with wild-type animals indicating the development of low-level inflammation and a pro-tumour microenvironment. Overall, our data demonstrated that combined loss of Atm expression and decreased Smg1 expression increases haematopoietic cancer development.

19F-NMR-based determination of the absorption, metabolism and excretion of the oral phosphatidylinositol-3-kinase (PI3K) delta inhibitor leniolisib (CDZ173) in healthy volunteers.

1. Leniolisib is a novel oral phosphatidylinositol-3-kinase (PI3K) delta inhibitor, currently in clinical development for the treatment of inflammatory and autoimmune diseases. 2. We investigated the absorption, metabolism, and excretion of leniolisib in healthy subjects after a single oral 400 mg dose as part of a first-in-human clinical study. The parent drug and metabolites were quantified by 19F-NMR in plasma, urine and faeces after liquid chromatography separation, and structures were determined by liquid chromatography coupled to tandem mass spectrometry. 3. Drug-related material was mainly excreted as oxidative metabolites in urine and faeces, providing evidence that elimination occurs mainly by metabolism. No metabolites were abundant in plasma relative to the parent drug. An average mass balance of 66% was obtained, demonstrating that relatively extensive elimination/excretion data can be obtained by 19F-NMR in a first in human clinical study without the use of a radiolabeled drug.