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1.
medRxiv ; 2024 Aug 11.
Article in English | MEDLINE | ID: mdl-39148847

ABSTRACT

Importance: Observational studies have demonstrated consistent protective effects of higher educational attainment (EA) on the risk of suffering mental health conditions (MHC). Determining whether these beneficial effects are causal is challenging given the potential role of dynastic effects and demographic factors (assortative mating and population structure) in this association. Objective: To evaluate to what extent the relationship between EA and various MHC is independent from dynastic effects and demographic factors. Design: Within-sibship Mendelian randomization (MR) study. Setting: One-sample MR analyses included participants' data from the Trøndelag Health Study (HUNT, Norway) and UK Biobank (United Kingdom). For two-sample MR analyses we used summary statistics from publicly available genome-wide-association-studies. Participants: 61 880 siblings (27 507 sibships). Exposure: Years of education. Main outcomes: Scores for symptoms of anxiety, depression and neuroticism using the Hospital Anxiety Depression Scale (HADS), the 7-item Generalized Anxiety Disorder Scale (GAD-7), the 9-item Patient Health Questionnaire (PHQ-9), and the Eysenck Personality Questionnaire, as well as self-reported consumption of psychotropic medication. Results: One standard deviation (SD) unit increase in years of education was associated with a lower symptom score of anxiety (-0.20 SD [95%CI: -0.26, -0.14]), depression (-0.11 SD [-0.43, 0.22]), neuroticism (-0.30 SD [-0.53, -0.06]), and lower odds of psychotropic medication consumption (OR: 0.60 [0.52, 0.69]). Estimates from the within-sibship MR analyses showed some attenuation, which however were suggestive of a causal association (anxiety: -0.17 SD [-0.33, -0.00]; depression: -0.18 SD [-1.26, 0.89]; neuroticism: -0.29 SD [-0.43, -0.15]); psychotropic medication consumption: OR, 0.52 [0.34, 0.82]). Conclusions and Relevance: Associations between EA and MHC in adulthood, although to some extend explained by dynastic effects and demographic factors, overall remain robust, indicative of a causal effect. However, larger studies are warranted to improve statistical power and further validate our conclusions.

2.
BMJ Open ; 14(8): e084770, 2024 Aug 17.
Article in English | MEDLINE | ID: mdl-39153784

ABSTRACT

OBJECTIVES: To evaluate changes in health outcomes between years 2 and 3 after discharge following COVID-19 and to identify risk factors for poor health 3-year post-discharge. DESIGN: This is a multicentre observational cohort study. SETTING: This study was conducted in two centres from Wuhan, China. PARTICIPANTS: Eligibility screening has been performed in 3988 discharged laboratory-confirmed adult COVID-19 patients. Exclusion criteria were refusal to participate, inability to contact and death before follow-up. The WHO COVID-19 guidelines on defining disease severity were adopted. RESULTS: 1594 patients participated in the 1-year, 2-year and 3-year follow-ups, including 796 (49.9%) male patients, and 422 (26.5%) patients were classified in the severe disease group. 3 years after discharge, 182 (11.4%) patients still complained of at least one symptom. The most common symptoms were fatigue, myalgia, chest tightness, cough, anxiety, shortness of breath and expectoration. Fatigue or myalgia, the most common symptom cluster, frequently coexisted with chest symptoms and anxiety. Symptom persistence between years 2 and 3 was reported in 70 patients (4.4%) for which intensive care unit (ICU) admission was a risk factor (p=0.038). Of the 1586 patients who completed the chronic obstructive pulmonary disease assessment test (CAT), 97 (6.1%) scored ≥10, with older age being associated with CAT ≥10 (p=0.007). CONCLUSIONS: Between years 2 and 3 after SARS-CoV-2 infection, most patients returned to an asymptomatic state, and only a few were still symptomatic. ICU admission was a risk factor for symptom persistence.


Subject(s)
COVID-19 , Patient Discharge , SARS-CoV-2 , Humans , COVID-19/epidemiology , Male , Female , China/epidemiology , Middle Aged , Patient Discharge/statistics & numerical data , Adult , Aged , Risk Factors , Cohort Studies , Severity of Illness Index , Intensive Care Units/statistics & numerical data
3.
Clin Cancer Res ; 2024 Aug 02.
Article in English | MEDLINE | ID: mdl-39093127

ABSTRACT

PURPOSE: Early detection of neurofibromatosis type 1 (NF1) associated peripheral nerve sheath tumors (PNST) informs clinical decision-making, enabling early definitive treatment and potentially averting deadly outcomes. Here, we describe a cell-free DNA (cfDNA) fragmentomic approach which distinguishes non-malignant, pre-malignant and malignant forms of PNST in cancer predisposition syndrome NF1. EXPERIMENTAL DESIGN: cfDNA was isolated from plasma samples of a novel cohort of 101 NF1 patients and 21 healthy controls and underwent whole genome sequencing. We investigated diagnosis-specific signatures of copy number alterations (CNA) with in silico size selection as well as well as fragment profiles. Fragmentomics were analyzed using complementary feature types: bin-wise fragment size ratios, end-motifs, and fragment non-negative matrix factorization (NMF) signatures. RESULTS: The novel cohort of NF1 patients validated that our previous cfDNA CNA-based approach identifies malignant peripheral nerve sheath tumor (MPNST) but cannot distinguish among benign and premalignant states. Fragmentomic methods were able to differentiate pre-malignant states including atypical neurofibromas (AN). Fragmentomics also adjudicated AN cases suspicious for MPNST, correctly diagnosing samples noninvasively, which could have informed clinical management. CONCLUSIONS: Novel cfDNA fragmentomic signatures distinguish atypical neurofibromas from benign plexiform neurofibromas and malignant peripheral nerve sheath tumors, enabling more precise clinical diagnosis and management. This study pioneers the early detection of malignant and premalignant peripheral nerve sheath tumors in NF1 and provides a blueprint for de-centralizing non-invasive cancer surveillance in hereditary cancer syndromes.

4.
Sci Transl Med ; 16(752): eadf0555, 2024 Jun 19.
Article in English | MEDLINE | ID: mdl-38896604

ABSTRACT

Despite decades of effort aimed at developing clinically effective cell therapies, including mixed population mononuclear cells, to revascularize the ischemic limb, there remains a paucity of patient-based studies that inform the function and fate of candidate cell types. In this study, we showed that circulating proangiogenic/arteriogenic monocytes (PAMs) expressing the FcγIIIA receptor CD16 were elevated in patients with chronic limb-threatening ischemia (CLTI), and these amounts decreased after revascularization. Unlike CD16-negative monocytes, PAMs showed large vessel remodeling properties in vitro when cultured with endothelial cells and smooth muscle cells and promoted salvage of the ischemic limb in vivo in a mouse model of hindlimb ischemia. PAMs showed a propensity to migrate toward and bind to ischemic muscle and to secrete angiogenic/arteriogenic factors, vascular endothelial growth factor A (VEGF-A) and heparin-binding epidermal growth factor. We instigated a first-in-human single-arm cohort study in which autologous PAMs were injected into the ischemic limbs of five patients with CLTI. Greater than 25% of injected cells were retained in the leg for at least 72 hours, of which greater than 80% were viable, with evidence of enhanced large vessel remodeling in the injected muscle area. In summary, we identified up-regulation of a circulatory PAM subpopulation as an endogenous response to limb ischemia in CLTI and tested a potentially clinically relevant therapeutic strategy.


Subject(s)
Hindlimb , Ischemia , Monocytes , Neovascularization, Physiologic , Humans , Monocytes/metabolism , Animals , Ischemia/pathology , Ischemia/metabolism , Ischemia/therapy , Hindlimb/blood supply , Receptors, IgG/metabolism , Mice , Male , Vascular Endothelial Growth Factor A/metabolism , Female , Aged , Middle Aged , Cell Movement , Heparin-binding EGF-like Growth Factor/metabolism
5.
Heart Rhythm ; 2024 Jun 25.
Article in English | MEDLINE | ID: mdl-38936446

ABSTRACT

BACKGROUND: Heart rate score (HRSc), the percentage of atrial depolarizations in the largest paced and sensed 10-beats/min histogram bin recorded in cardiac devices, is associated with several adverse outcomes, but it remains uncertain whether HRSc independently predicts atrial high-rate episodes (AHREs) in patients with sinus node dysfunction (SND) undergoing pacemaker (PM) implantation. OBJECTIVE: This study aimed to determine whether initial HRSc after PM implantation predicts new-onset AHREs in patients with SND. METHODS: Patients had Boston Scientific PMs implanted for SND from 2012 to 2021 at Cleveland Clinic, University of Occupational and Environmental Health, Japan, Kyushu Rosai Hospital, and JCHO Kyushu Hospital. Patients were excluded if they had atrial fibrillation before PM implantation or AHREs within 3 months after implantation. Subsequent AHREs after implantation were evaluated and correlated with HRSc. RESULTS: During 48.9 (interquartile range, 25.7-50.4) months, 130 consecutive PM patients (76 ± 10 years; 40% male) had a median initial HRSc of 74% (57%-86%). AHREs defined by >1%, >6 h/d burden, and atrial tachycardia response events >24 hours developed in 27 of 130 (21%), 15 of 130 (12%), and 9 of 130 (7%), respectively. For each definition, patients with HRSc ≥80% had higher occurrence of AHREs than those with HRSc <80% (both P = .008, log-rank test). After adjustment for age, race, comorbidities, left ventricular ejection fraction, left atrial diameter, and cumulative percentage of right atrial and right ventricular pacing, initial HRSc ≥80% (hazard ratio, 3.33; 95% CI, 1.35-8.18; P = .009) and male sex (hazard ratio, 2.59; 95% CI, 1.06-6.33; P = .04) independently predicted AHREs. CONCLUSION: HRSc ≥80% is associated with new-onset, device-determined AHREs for patients undergoing PM implantation for SND. HRSc may have prognostic and therapeutic implications.

6.
J Sports Sci ; 42(7): 621-628, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38739494

ABSTRACT

Change of direction deficit (CODD) offers valuable insights into a player's balance between linear and multidirectional speed. However, there are still no established reference values for CODD. The objectives of this study were to determine CODD thresholds for various change of direction angles in basketball players according to gender and analyse the relationships between CODD and execution time in speed tests. One hundred and thirty basketball players (46% female; age: 23.7 ± 5.29 years; height: 189.1 ± 11.1 cm; body mass: 84.3 ± 15.7 kg) undertook 10-m linear and change of direction speed test at 45º, 90º and 180º. A k-means cluster analysis was conducted to standardise CODD thresholds and a one-way analysis of variance to identify the differences between clusters. The results revealed angulation-specific CODD thresholds, ranging from 3% to 8%, 17% to 25% and 43% to 51% for 45º, 90º and 180º cutting angles, respectively for the pooled sample. Furthermore, differences inter-clusters (p < 0.05) were observed for execution time at all cutting angles for both genders. Therefore, strength and conditioning coaches are encouraged to assess CODD as a highly valid variable for evaluating change of direction performance and to use current CODD thresholds to tailor training programmes according to each athlete's needs.


Subject(s)
Athletic Performance , Basketball , Humans , Basketball/physiology , Male , Female , Young Adult , Athletic Performance/physiology , Adult , Sex Factors , Reference Values , Biomechanical Phenomena , Adolescent
7.
J Econ Entomol ; 117(4): 1356-1366, 2024 Aug 12.
Article in English | MEDLINE | ID: mdl-38728437

ABSTRACT

The Asian citrus psyllid (ACP), Diaphorina citri Kuwayama (Hemiptera: Psyllidae), is a major pest of citrus due to its role as the vector of the bacterium that causes huanglongbing. In commercial citrus, ACP control currently relies on the application of insecticides, which may not be sustainable long-term, nor practical in urban areas. The sterile insect technique (SIT) is an alternative strategy in which large numbers of pests are reared, sterilized using radiation, and then released into the field to compete with wild individuals for matings, suppressing population growth. As a fundamental step toward the development of SIT for ACP, this study sought to identify the optimum radiation dose required to sterilize ACP without affecting their survival and mating capacity. Virgin adult ACP of both sexes were subjected to doses of X-ray irradiation ranging from 40 to 480 Gy, then paired with a nonirradiated mate and allowed to produce offspring. Fecundity was estimated as the number of eggs laid, and fertility as the proportion of those eggs that hatched. Females were more radio-sensitive than males, exhibiting a major drop in fecundity at even the lowest dose and 100% sterility at 80 Gy. In contrast, a fivefold higher dose (400 Gy) did not achieve complete sterility in males, with around 5% offspring survival. However, F1 progeny of males exposed to 320 Gy or higher were subsequently found to be 100% sterile. This confirmation of inherited sterility suggests that balancing the sterilizing effects of radiation against its mortality-inducing effects may warrant further evaluation.


Subject(s)
Fertility , Hemiptera , Animals , Female , Fertility/radiation effects , Male , Pest Control, Biological , X-Rays , Longevity , Citrus , Insect Control/methods
8.
Sports Med Open ; 10(1): 29, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38561438

ABSTRACT

BACKGROUND: Change of direction (COD) movements are associated with non-contact anterior cruciate ligament (ACL) injuries in multidirectional sports. Females appear at increased risk compared to males, which could be attributable to whole body kinematic strategies and greater multiplanar knee joint loads (KJLs) during COD which can increase ACL loading. OBJECTIVE: The aim of this systematic review and meta-analysis was to examine and quantitatively synthesise the evidence for differences between males and females regarding KJLs and their biomechanical determinants (whole body kinematic strategies determining KJLs) during COD tasks. METHODS: Databases including SPORTDiscus, Web of Science, and PubMed were systematically searched (July 2021-June 2023) for studies that compared differences in knee joint loads and biomechanical determinants of KJLs during COD between males and females. Inclusion criteria were: (1) females and males with no prior history of ACL injury (18-40 years); (2) examined biomechanical determinants of KJLs and/ or KJLs during COD tasks > 20°; (3) compared ≥ 1 outcome measure between males and females. Studies published between 2000 and 2023 examining a cutting task > 20° with a preceding approach run that compared KJLs or the whole body multiplanar kinematics associated with them, between sexes, using three-dimensional motion analysis. RESULTS: This meta-analysis included 17 studies with a pooled sample size of 451 participants (227 males, 224 females). Meta-analysis revealed females displayed significantly less peak knee flexion during stance (SMD: 0.374, 95% CI 0.098-0.649, p = 0.008, I2: 0%); greater knee abduction at initial contact (IC) (SMD: 0.687, 95% CI 0.299-1.076, p = 0.001, I2: 55%); less hip internal rotation (SMD: 0.437, 95% CI 0.134-0.741, p = 0.005, I2: 34%) and hip abduction at IC (SMD: -0.454, 95% CI 0.151-0.758, p = 0.003, I2: 33%). No significant differences were observed between males and females for any internal or externally applied KJLs. All retrieved studies failed to control for strength, resistance training or skill history status. CONCLUSION: No differences were observed in KJLs between males and females despite females displaying greater knee abduction at IC and less peak knee flexion during the stance phase of CODs, which are visual characteristics of non-contact ACL injury. Further research is required to examine if this translates to a similar injury risk, considering morphological differences in strain characteristics of the ACL between males and females. This observation may in part explain the disproportionate ACL injury incidence in female multidirectional athletes. Further higher quality controlled research is required whereby participants are matched by skill training history, resistance training history and strength status to ensure an appropriate comparison between males and females.

9.
J Dent Educ ; 2024 Apr 22.
Article in English | MEDLINE | ID: mdl-38646852

ABSTRACT

OBJECTIVES: Health professionals' education presents unique challenges including clinical application of knowledge and interprofessional collaboration. Additionally, institutions suffer from faculty shortages while class sizes increase. Therefore, educators seek innovative andragogical techniques utilizing minimal resources. Several active learning methods have been introduced as a solution. The aim of this study is to assess the impact of lecture (LBL), case (CBL), and team (TBL) based learning on the students' satisfaction and knowledge attainment. METHODS: A total of 134 sophomore dental students are taught pediatric dentistry course using LBL, CBL, and TBL techniques. At the end of the course, students are invited to participate in a satisfaction survey. Statistical analysis is conducted using a two-sided chi-square goodness of fit test. Students' comments are used for qualitative analysis. Final exam analysis is administered via Examsoft software. RESULTS: A total of 98% of the students participated in the survey out of which 83% met the inclusion criteria (N = 110). Students chose LBL as the method that helped them learn in a comprehensive way, provided the most comfortable environment, and presented the overall highest satisfaction with statistically significant difference (p value = 0.001). LBL questions scored the highest point biserial and discrimination index. The percentage of correct answers and difficulty level was highest for TBL. CONCLUSION: Students preferred LBL over the other learning methods. Final exam psychometrics showed favorable results for LBL and TBL. Students could potentially benefit from combining both techniques. However, more research is needed to assess the effectiveness of various teaching methods on the short- and long-term learning outcomes.

10.
MethodsX ; 12: 102645, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38524303

ABSTRACT

Distributions of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and fecal viral biomarkers between solid and liquid phases of wastewater are largely unknown. Herein, distributions of SARS-CoV-2, Pepper Mild Mottle Virus (PMMoV), and F-RNA bacteriophage group II (FRNAPH-II) were determined by viral RNA RT-qPCR. Comparison of viral recovery using three conventional fractionation methods included membrane filtration, a combination of mid-speed centrifugation and membrane filtration, and high-speed centrifugation. SARS-CoV-2 partitioned to the solids fraction in greater abundance compared to liquid fractions in a combination of mid-speed centrifugation and membrane filtration and high-speed centrifugation, but not in membrane filtration method in a particular assay, while fecal biomarkers (PMMoV and FRNAPH-II) exhibited the reciprocal relationship. The wastewater fractionation method had minimal effects on the solids-liquids distribution for all viral and phage markers tested; however, viral RNA load was significantly greater in solid-liquid fractions viral RNA loads compared with the than whole-wastewater PEG precipitation. A RNeasy PowerWater Kit with PCR inhibitor removal resulted in greater viral RNA loads and lesser PCR inhibition compared to a QIAamp Viral RNA Mini Kit without PCR inhibitor removal. These results support the development of improved methods and interpretation of WBE of SARS-CoV-2. •Distribution of SARS-CoV-2 to liquid and solid portions was addressed.•Addressing PCR inhibition is important in wastewater-based epidemiology.•Fraction methods have minimal effect.

11.
Clin Neuropsychol ; : 1-24, 2024 Mar 05.
Article in English | MEDLINE | ID: mdl-38444068

ABSTRACT

OBJECTIVE: To examine cognitive intraindividual variability (IIV) dispersion as a predictor of everyday functioning and mortality in persons who are homeless or precariously housed. METHOD: Participants were 407 community-dwelling adults, followed for up to 13 years. Neurocognition was assessed at baseline and IIV dispersion was derived using a battery of standardized tests. Functional outcomes (social, physical) were obtained at baseline and last follow-up. Mortality was confirmed with Coroner's reports and hospital records (N = 103 deaths). Linear regressions were used to predict current social and physical functioning from IIV dispersion. Repeated measures Analysis of Covariance were used to predict long-term change in functioning. Cox regression models examined the relation between IIV dispersion and mortality. Covariates included global cognition (i.e. mean-level performance), age, education, and physical comorbidities. RESULTS: Higher IIV dispersion predicted poorer current physical functioning (B = -0.46 p = .010), while higher global cognition predicted better current (B = 0.21, p = .015) and change in social functioning over a period of up to 13 years (F = 4.23, p = .040). Global cognition, but not IIV dispersion, predicted mortality in individuals under 55 years old (HR = 0.50, p = .013). CONCLUSIONS: Our findings suggest that indices of neurocognitive functioning (i.e. IIV dispersion and global cognition) may be differentially related to discrete dimensions of functional outcomes in an at-risk population. IIV dispersion may be a complimentary marker of emergent physical health dysfunction in precariously housed adults and may be best used in conjunction with traditional neuropsychological indices.

12.
Chronic Obstr Pulm Dis ; 11(2): 144-154, 2024 Mar 26.
Article in English | MEDLINE | ID: mdl-38442134

ABSTRACT

Background: A previous longitudinal study of chronic obstructive pulmonary disease (COPD) Assessment Test (CAT) score changes suggested patients fall into 3 patterns: stable, improving, and worsening. This study assessed the evolution of CAT scores over time and its relationship to exacerbations. Methods: In total, 84 participants used a telemedicine platform to complete CAT weekly for 52 weeks. Completion rates, annualized change in CAT scores, and learning effects were measured, as well as CAT changes of >4 units during look-back periods of 4 and 8 weeks. In a subgroup of participants with at least a 25% completion rate (adherent group, n=68 [81%]), the relationship between change in CAT score and exacerbations at any time during the study was examined post hoc. Results: Linear regression showed that 50%, 22%, and 28% of the adherent subgroup had CAT scores indicating worsening, stable, and improving health status, respectively. In the adherent subgroup, 70% (n=7/10) of participants who had an exacerbation during the study had worsening CAT scores, versus 47% (n=27/58) without an exacerbation. The hazard ratio association between CAT score increase and moderate exacerbation was 1.13 (95% confidence interval: 1.03-1.24). Most participants experienced at least one CAT score change of >4 units, and 7% showed an initial learning effect with a median of 2 weeks. Conclusion: Measuring trends in CAT scores may allow future studies to group patients into 3 defined categories of change over time and quantify CAT change trajectories to assess treatment response and potentially predict medium-term outcomes within individual patients.

13.
Pulm Ther ; 10(2): 183-192, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38446336

ABSTRACT

INTRODUCTION: Despite the proven benefits of inhaled corticosteroid (ICS)-containing triple therapy for chronic obstructive pulmonary disease (COPD), clinicians limit patient exposure to ICS due to the risk of pneumonia. However, there are multiple factors associated with the risk of pneumonia in patients with COPD. This post hoc analysis of IMPACT trial data aims to set the risks associated with ICS into a context of specific patient-related factors that contribute to the risk of pneumonia. METHODS: The 52-week, double-blind IMPACT trial randomized patients with symptomatic COPD and ≥1 exacerbation in the prior year 2:2:1 to once-daily fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI), FF/VI or UMEC/VI. Annual rate of on-treatment pneumonias in the intent-to-treat population associated with age, body mass index (BMI), percent predicted forced expiratory volume in 1 s (FEV1) and blood eosinophil count (BEC) was evaluated. RESULTS: This analysis revealed that the annual rate of pneumonia showed the lowest risk at the age of 50 years. The 95% confidence intervals (CI) between ICS-containing and non-ICS containing treatments diverged in ages > 63 years, suggesting a significantly increased ICS-related risk in older patients. In contrast, the annual rate of pneumonia rose in both groups below BMI of 22.5 kg/m2, but above that, there was no relationship to pneumonia rate and no differential effect between the two groups. The relationship between BEC and pneumonia was flat up to > 300/µL cells with ICS-containing treatment and then rose. In contrast, the rate of pneumonia with non-ICS containing treatment appeared to increase at a lower level of BEC (~ 200/µL). CONCLUSIONS: There was little evidence of a differential effect of older age, lower BMI, lower FEV1 and BEC on the pneumonia rate between ICS-containing and non-ICS containing treatments. This analysis points to the need for a balanced approach to risk versus benefit in the use of ICS-containing treatments in COPD. CLINICAL TRIAL REGISTRATION: IMPACT ClinicalTrials.gov number, NCT02164513.

14.
COPD ; 21(1): 2316594, 2024 12.
Article in English | MEDLINE | ID: mdl-38421013

ABSTRACT

Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with loss of lung function, poor quality of life, loss of exercise capacity, risk of serious cardiovascular events, hospitalization, and death. However, patients underreport exacerbations, and evidence suggests that unreported exacerbations have similar negative health implications for patients as those that are reported. Whilst there is guidance for physicians to identify patients who are at risk of exacerbations, they do not help patients recognise and report them. Newly developed tools, such as the COPD Exacerbation Recognition Tool (CERT) have been designed to achieve this objective. This review focuses on the underreporting of COPD exacerbations by patients, the factors associated with this, the consequences of underreporting, and potential solutions.


Subject(s)
Pulmonary Disease, Chronic Obstructive , Humans , Quality of Life , Disease Progression , Hospitalization
15.
J Med Chem ; 67(4): 2349-2368, 2024 Feb 22.
Article in English | MEDLINE | ID: mdl-38299539

ABSTRACT

ATR is a key kinase in the DNA-damage response (DDR) that is synthetic lethal with several other DDR proteins, making it an attractive target for the treatment of genetically selected solid tumors. Herein we describe the discovery of a novel ATR inhibitor guided by a pharmacophore model to position a key hydrogen bond. Optimization was driven by potency and selectivity over the related kinase mTOR, resulting in the identification of camonsertib (RP-3500) with high potency and excellent ADME properties. Preclinical evaluation focused on the impact of camonsertib on myelosuppression, and an exploration of intermittent dosing schedules to allow recovery of the erythroid compartment and mitigate anemia. Camonsertib is currently undergoing clinical evaluation both as a single agent and in combination with talazoparib, olaparib, niraparib, lunresertib, or gemcitabine (NCT04497116, NCT04972110, NCT04855656). A preliminary recommended phase 2 dose for monotherapy was identified as 160 mg QD given 3 days/week.


Subject(s)
Neoplasms , Humans , Ataxia Telangiectasia Mutated Proteins , Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Gemcitabine
16.
Health Promot Int ; 39(1)2024 Feb 01.
Article in English | MEDLINE | ID: mdl-38386901

ABSTRACT

Medication guides (MGs) provide patients with important information about certain prescription drugs to help them take these drugs safely. We surveyed US residents about their perceptions of MG readability and understandability. We randomly sampled 5204 US residents (age 18+) from Ipsos's KnowledgePanel to complete a two-part survey. Only respondents who reported receiving an MG with their prescription drugs (n = 3852) completed part 2, which included two key items: How easy to [(1)read/(2)understand] are the MGs that you have received from a pharmacy along with your prescription medicines? (1 = Very easy, 5 = Very difficult; reverse-coded). Health literacy (HL) and demographic data were also collected. After weighting our data, we found that 85% of respondents who reported receiving an MG perceived this information as 'very easy' (27.3%), 'somewhat easy' (28.3%) or 'about average' (29.3%) to read. Eighty-seven percent of respondents who reported receiving an MG perceived it as 'very easy' (27.6%), 'somewhat easy' (30.2%) or 'about average' (29.5%) to understand. ANOVAs revealed higher average perceived MG reading and comprehension ease scores among respondents presumed to have adequate versus inadequate HL (ps ≤ 0.0006). Younger or less-educated respondents and non-Hispanic Blacks perceived MGs as easier to read and understand, on average, than their counterparts (ps ≤ 0.0001). Many of these relationships remained intact in models predicting perceived MG reading and comprehension ease (ps ≤ 0.001). Adjusted R2 values across models were small, however (≤0.06). Our findings suggest most US residents (18+) who received MGs perceived them to be 'about average' to 'very easy' to read and understand.


Subject(s)
Health Literacy , Reading , Adult , Humans , Adolescent , Comprehension , Surveys and Questionnaires
17.
J Psychiatr Res ; 170: 290-296, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38185074

ABSTRACT

BACKGROUND: Studies have reported positive associations between drug-induced movement disorders (DIMDs) and symptoms of psychosis in patients with schizophrenia. However, it is not clear which subtypes of symptoms are related to each other, and whether one symptom precedes another. The current report assessed both concurrent and temporal associations between DIMDs and symptoms of psychosis in a community-based sample of homeless individuals. METHODS: Participants were recruited in Vancouver, Canada. Severity of DIMDs and psychosis was rated annually, allowing for the analysis of concurrent associations between DIMDs and Positive and Negative Syndrome Scale (PANSS) five factors. A brief version of the PANSS was rated monthly using five psychotic symptoms, allowing for the analysis of their temporal associations with DIMDs. Mixed-effects linear and logistic regression models were used to assess the associations. RESULTS: 401 participants were included, mean age of 40.7 years (SD = 11.2) and 77.4% male. DIMDs and symptoms of psychosis were differentially associated with each other, in which the presence of parkinsonism was associated with greater negative symptoms, dyskinesia with disorganized symptoms, and akathisia with excited symptoms. The presence of DIMDs of any type was not associated with depressive symptoms. Regarding temporal associations, preceding delusions and unusual thought content were associated with parkinsonism, whereas dyskinesia was associated with subsequent conceptual disorganization. CONCLUSIONS: The current study found significant associations between DIMDs and symptoms of psychosis in individuals living in precarious housing or homelessness. Moreover, there were temporal associations between parkinsonism and psychotic symptoms (delusions or unusual thought content), and the presence of dyskinesia was temporally associated with higher odds of clinically relevant conceptual disorganization.


Subject(s)
Dyskinesias , Ill-Housed Persons , Parkinsonian Disorders , Psychotic Disorders , Adult , Humans , Male , Female , Housing , Psychotic Disorders/epidemiology
18.
medRxiv ; 2024 Mar 11.
Article in English | MEDLINE | ID: mdl-38293154

ABSTRACT

Early detection of neurofibromatosis type 1 (NF1) associated peripheral nerve sheath tumors (PNST) informs clinical decision-making, potentially averting deadly outcomes. Here, we describe a cell-free DNA (cfDNA) fragmentomic approach which distinguishes non-malignant, pre-malignant and malignant forms of NF1 PNST. Using plasma samples from a novel cohort of 101 NF1 patients and 21 healthy controls, we validated that our previous cfDNA copy number alteration (CNA)-based approach identifies malignant peripheral nerve sheath tumor (MPNST) but cannot distinguish among benign and premalignant states. We therefore investigated the ability of fragment-based cfDNA features to differentiate NF1-associated tumors including binned genome-wide fragment length ratios, end motif analysis, and non-negative matrix factorization deconvolution of fragment lengths. Fragmentomic methods were able to differentiate pre-malignant states including atypical neurofibromas (AN). Fragmentomics also adjudicated AN cases suspicious for MPNST, correctly diagnosing samples noninvasively, which could have informed clinical management. Overall, this study pioneers the early detection of malignant and premalignant peripheral nerve sheath tumors in NF1 patients using plasma cfDNA fragmentomics. In addition to screening applications, this novel approach distinguishes atypical neurofibromas from benign plexiform neurofibromas and malignant peripheral nerve sheath tumors, enabling more precise clinical diagnosis and management.

19.
Am J Respir Crit Care Med ; 209(10): 1208-1218, 2024 05 15.
Article in English | MEDLINE | ID: mdl-38175920

ABSTRACT

Rationale: Chronic obstructive pulmonary disease (COPD) due to tobacco smoking commonly presents when extensive lung damage has occurred. Objectives: We hypothesized that structural change would be detected early in the natural history of COPD and would relate to loss of lung function with time. Methods: We recruited 431 current smokers (median age, 39 yr; 16 pack-years smoked) and recorded symptoms using the COPD Assessment Test (CAT), spirometry, and quantitative thoracic computed tomography (QCT) scans at study entry. These scan results were compared with those from 67 never-smoking control subjects. Three hundred sixty-eight participants were followed every six months with measurement of postbronchodilator spirometry for a median of 32 months. The rate of FEV1 decline, adjusted for current smoking status, age, and sex, was related to the initial QCT appearances and symptoms, measured using the CAT. Measurements and Main Results: There were no material differences in demography or subjective CT appearances between the young smokers and control subjects, but 55.7% of the former had CAT scores greater than 10, and 24.2% reported chronic bronchitis. QCT assessments of disease probability-defined functional small airway disease, ground-glass opacification, bronchovascular prominence, and ratio of small blood vessel volume to total pulmonary vessel volume were increased compared with control subjects and were all associated with a faster FEV1 decline, as was a higher CAT score. Conclusions: Radiological abnormalities on CT are already established in young smokers with normal lung function and are associated with FEV1 loss independently of the impact of symptoms. Structural abnormalities are present early in the natural history of COPD and are markers of disease progression. Clinical trial registered with www.clinicaltrials.gov (NCT03480347).


Subject(s)
Lung , Pulmonary Disease, Chronic Obstructive , Spirometry , Tomography, X-Ray Computed , Adult , Female , Humans , Male , Middle Aged , Young Adult , Disease Progression , Forced Expiratory Volume/physiology , Lung/physiopathology , Lung/diagnostic imaging , Pulmonary Disease, Chronic Obstructive/physiopathology , Pulmonary Disease, Chronic Obstructive/diagnostic imaging , Smokers/statistics & numerical data , Smoking/adverse effects , Smoking/physiopathology , Case-Control Studies
20.
Birth Defects Res ; 116(1): e2284, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38158745

ABSTRACT

INTRODUCTION: Seven gadolinium-based contrast agents (GBCAs), four linear and three macrocyclic, were evaluated for potential effects on development, including behavior of juvenile CD-1 mice. METHODS: The GBCAs were administered via intravenous injection once daily on postnatal day (PND) 9, 12, 15, 18, and 21 (PND 1 was the day of delivery) at doses up to twice the human equivalent clinical dose (i.e., 0.63 mmol Gd/kg for gadoxetate disodium and 2.5 mmol Gd/kg for the other GBCAs). Mice were bled for evaluation of exposure (plasma) to gadolinium (Gd) on PND 9, 12, and 70. At scheduled euthanasia, the liver, spleen, brain, skin (dorsal surface), bone (left femur), and kidneys were excised from up to six mice/sex/group on PND 10, 22, or 70 for the determination of Gd levels and histopathological analysis. All mice were monitored for toxicity, growth and survival, sexual maturation, and behavior. CONCLUSION: Gd was quantifiable in the brain tissues with levels declining over time. There was no long-term effect on the growth and development for mice exposed to any of the GBCAs. There was no impact on neurodevelopment as assessed by brain histology and validated neurobehavioral tests, including a functional observational battery, motor activity, and learning and memory as evaluated in the Morris water maze. For all GBCAs, the highest dose tested represented the no-observable-adverse-effect level in juvenile mice.


Subject(s)
Contrast Media , Organometallic Compounds , Mice , Humans , Animals , Contrast Media/pharmacology , Gadolinium/pharmacology , Organometallic Compounds/pharmacology , Magnetic Resonance Imaging , Brain
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