Error-Corrected Deep Targeted Sequencing of Circulating Cell-Free DNA from Colorectal Cancer Patients for Sensitive Detection of Circulating Tumor DNA.

Circulating tumor DNA (ctDNA) is a promising biomarker, reflecting the presence of tumor cells. Sequencing-based detection of ctDNA at low tumor fractions is challenging due to the crude error rate of sequencing. To mitigate this challenge, we developed ultra-deep mutation-integrated sequencing (UMIseq), a fixed-panel deep targeted sequencing approach, which is universally applicable to all colorectal cancer (CRC) patients. UMIseq features UMI-mediated error correction, the exclusion of mutations related to clonal hematopoiesis, a panel of normal samples for error modeling, and signal integration from single-nucleotide variations, insertions, deletions, and phased mutations. UMIseq was trained and independently validated on pre-operative (pre-OP) plasma from CRC patients (n = 364) and healthy individuals (n = 61). UMIseq displayed an area under the curve surpassing 0.95 for allele frequencies (AFs) down to 0.05%. In the training cohort, the pre-OP detection rate reached 80% at 95% specificity, while it was 70% in the validation cohort. UMIseq enabled the detection of AFs down to 0.004%. To assess the potential for detection of residual disease, 26 post-operative plasma samples from stage III CRC patients were analyzed. From this we found that the detection of ctDNA was associated with recurrence. In conclusion, UMIseq demonstrated robust performance with high sensitivity and specificity, enabling the detection of ctDNA at low allele frequencies.

A novel referral strategy to enhance the enrollment of patients with heart failure in cardiac rehabilitation: A feasibility study.

Background and Aims: Rehabilitation targeting patients with cardiac conditions are evident and acknowledged in clinical guidelines. However, participation rates remain suboptimal, with only 50% of all patients with cardiac conditions participating in these programs across Europe. Considering the well-documented effects of rehabilitation, increasing the referral rate to cardiac rehabilitation would be desirable. This study aimed to evaluate the feasibility of a novel referral strategy that could potentially enhance enrollment in cardiac rehabilitation for patients with heart failure. Methods: This prospective feasibility study incorporating both quantitative and qualitative methods was conducted in an outpatient heart failure clinic and a municipal health care center. 106 patients with heart failure were referred to the heart failure clinic from September 2021 through July 2022. A 15-20 min face-to-face physiotherapy consultation was incorporated into usual care, evaluating patients' habitual and actual level of functioning, disability, and physical activity and assessing their potential need and motivation for cardiac rehabilitation. Three predefined quantitative feasibility outcomes: reach, referral rate, and data completeness were assessed. Additionally, semi-structured interviews explored acceptability among patients and health care professionals at the municipal health care center and the hospital. Finally, the potential effect was assessed based on the enrollment rate. Results: Physiotherapy consultations were offered to 86% of eligible patients; of these, 52% were referred to cardiac rehabilitation. Ninety-one percent data completeness was achieved. The intervention was well-accepted by patients and health care professionals. The enrollment rate reached 79%. Conclusion: The novel referral strategy proved feasible concerning reach and data completeness, although the referral rate suggested that further refinements are required before a full-scale trial. The novel referral strategy was well-accepted, and enrollment rate approached an acceptable level.

Growing pains in Danish preschool children: a descriptive study.

This study provides a detailed description of growing pains in young Danish children as standardized diagnostic criteria are needed to avoid misclassifications of other musculoskeletal diagnoses. The study is nested in a cohort study of Danish preschool children. At baseline, parents completed a questionnaire with sociodemographic information. During the study, the parents received a text message every two weeks inquiring about musculoskeletal pain in the child. If pain was reported, a telephone interview about pain characteristics was conducted. The present study includes data from 2016 to 2019 with 777 children, aged 3-6 years of age at baseline. The prevalence of growing pains was 24-43%, depending on the definition. The pain occurred most frequently 1-3 times per week and most commonly in the lower legs, could be unilateral or bilateral and was usually without consequences. The prevalence increased with age, and there were no consistent associations with socio-economic factors. We suggest using Evan's criteria with the addition of unilateral pain as standard diagnostic criteria in the future. We found no relation to periods of rapid growth and suggest that the term is a misnomer. Etiology and long-term courses of pain need to be explored in future studies.

Lying is sometimes ethical, but honesty is the best policy: The desire to avoid harmful lies leads to moral preferences for unconditional honesty.

People believe that some lies are ethical, while also claiming that "honesty is the best policy." In this article, we introduce a theory to explain this apparent inconsistency. Even though people view prosocial lies as ethical, they believe it is more important-and more moral-to avoid harmful lies than to allow prosocial lies. Unconditional honesty (simply telling the truth, without finding out how honesty will affect others) is therefore seen as ethical because it prevents the most unethical actions (i.e., harmful lies) from occurring, even though it does not optimize every moral decision. We test this theory across five focal experiments and 10 supplemental studies. Consistent with our account, we find that communicators who tell the truth without finding out how honesty will affect others are viewed as more ethical, and are trusted more, than communicators who look for information about the social consequences of honesty before communicating. However, the moral preference for unconditional honesty attenuates when it is certain that looking for more information will not lead to harmful lies. Overall, this research provides a holistic understanding of how people think about honesty and suggests that moral rules are not valued because people believe all rule violations are wrong, but rather, because they believe some violations must be avoided entirely. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Health-related quality of life in people with different diabetes-related foot ulcer health states: A cross-sectional study of healed, non-infected, infected, hospitalised and amputated ulcer states.

AIMS: Diabetes-related foot ulcers (DFU) are a leading cause of infection, hospitalisation and amputation. However, to our knowledge no studies have compared the health-related quality of life (HRQoL) of people with DFU that were infected, hospitalised or amputated. This study aimed to investigate and compare the HRQoL of different groups of people with healed, non-infected, infected, hospitalised, or amputated DFU. METHODS: This was a multi-centre cross-sectional study measuring the HRQoL of patients, attending one of 18 Diabetic Foot Services across Queensland, Australia, with one of five DFU health states: healed, non-infected, infected, hospitalised, amputated. HRQoL was measured using the EQ-5D-5L to estimate age-sex adjusted utility values. RESULTS: Of 376 included patients (mean age 63 (12) years, 75% male), age-sex adjusted HRQoL utility estimates (95% CIs) were: healed DFU 0.57 (0.51-0.64), non-infected DFU 0.55 (0.49-0.62), infected DFU 0.45 (0.36-0.55), hospitalised DFU 0.53 (0.42-0.64), and amputated DFU 0.55 (0.46-0.63). CONCLUSION: People in any DFU health state have considerably reduced HRQoL, with greatest reductions in those with infected DFU. These findings provide valuable HRQoL estimates and comparisons for several different important DFU health states, adding to our understanding of the impact of DFU on HRQoL and facilitating future economic evaluations.

Measuring the cost-effectiveness of a home-visiting intervention to promote early child development among rural families linked to the Rwandan social protection system.

Early childhood development (ECD) programmes are heralded as a way to improve children's health and educational outcomes. However, few studies in developing countries calculate the effectiveness of quality early childhood interventions. This study estimates the cost and cost-effectiveness of the Sugira Muryango (SM) trial, a home-visiting intervention to improve ECD outcomes through positive parent-child relationships. Cost-effectiveness analysis of ECD interventions is challenging given their potential to have multiple benefits. We propose a cost-effectiveness method using a single outcome, in this case the improvement in cognitive development per home-visit session, as an indication of efficiency comparable across similar interventions. The trial intervention cost US$456 per family. This cost will likely fall below US$200 if the intervention is scaled through government systems. The cost-effectiveness analysis suggests that while SM generated a relatively small impact on markers of early development, it did so efficiently. The observed improvements in cognitive development per home-visit are similar to other home-visiting interventions of longer duration. SM by focusing on the family had benefits beyond ECD, including reductions in violence against children and intermate partner violence, further analysis is needed to include these returns in the economic evaluation.

Low- versus standard- pneumoperitoneum in patients undergoing robot-assisted radical prostatectomy: a randomised, triple-blinded study.

OBJECTIVE: To investigate the effectiveness and impact of low-pressure pneumoperitoneum (Pnp) on postoperative quality of recovery (QoR) and surgical workspace (SWS) in patients with prostate cancer undergoing robot-assisted radical prostatectomy (RARP). PATIENTS AND METHODS: A randomised, triple-blinded trial was conducted in a single centre in Denmark from March 2021 to January 2022. A total of 98 patients with prostate cancer undergoing RARP were randomly assigned to either low-pressure Pnp (7 mmHg) or standard-pressure Pnp (12 mmHg). Co-primary outcomes were postoperative QoR measured via the QoR-15 questionnaire on postoperative Day 1 (POD1), POD3, POD14, and POD30, and SWS assessed intraoperatively by a blinded assessor (surgeon) via a validated SWS scale. Data analysis was performed according to the intention-to-treat principle. RESULTS: Patients who underwent RARP at low Pnp pressure demonstrated better postoperative QoR on POD1 (mean difference = 10, 95% confidence interval [CI] 4.4-15.5), but no significant differences were observed in the SWS (mean difference = 0.25, 95% CI -0.02 to 0.54). Patients allocated to low-pressure Pnp experienced statistically higher blood loss than those in the standard-pressure Pnp group (mean difference = 67 mL, P = 0.01). Domain analysis revealed significant improvements in pain (P = 0.001), physical comfort (P = 0.007), and emotional state (P = 0.006) for patients with low-pressure Pnp. This trial was registered at ClinicalTrials.gov, NCT04755452, on 16/02/2021. CONCLUSION: Performing RARP at low Pnp pressure is feasible without compromising the SWS and improves postoperative QoR, including pain, physical comfort, and emotional state, compared to the standard pressure.

Systemic Cytokine Expression in Diabetes Is Associated with Prolonged Gastrointestinal Transit Times and Cardinal Gastroparesis Symptoms.

Gastroenteropathy is a common complication in diabetes associated with damages to the enteric nervous system. Systemic low-grade inflammation facilitates neurotoxicity, and associations with peripheral and autonomic neuropathy have been reported. However, less is known of associations with gastroenteropathy. To explore the area cross-sectionally, we included individuals with diabetes (type 1: 56, type 2: 100) and 21 healthy controls. Serum levels of interleukin (IL)-6, IL-8, IL-10, tumour necrosis factor (TNF)-α, and interferon (IFN)-γ were measured by multiplex technology. Segmental gastrointestinal transit times were assessed by wireless motility capsule investigations. Symptoms of gastroparesis were rated on Gastroparesis Cardinal Symptom Index questionnaires. Compared to healthy, levels of TNF-α were decreased in type 1 diabetes and increased in type 2 diabetes, while colonic transit time was increased (all p < 0.05). In diabetes, associations between IL-8 and prolonged gastric emptying (odds ratio (OR) 1.07, p = 0.027) and between IL-10 and prolonged colonic transit (OR 29.99, p = 0.013) were seen. Inverse correlations between IL-6 and nausea/vomiting (rho = -0.19, p = 0.026) and bloating (rho = -0.29; p < 0.001) were found. These findings indicate a plausible interaction between inflammation and the enteric nervous system in diabetes, which raises the question of whether anti-inflammatory strategies could be applied in management of diabetic gastroenteropathy.

Family Violence Reduction Within a Parenting Intervention in Rwanda: A Mixed-Methods Study.

BACKGROUND AND OBJECTIVES: A mixed-methods study of mechanisms of change through which a home-visiting-based early childhood development intervention, Sugira Muryango ("strong family"), reduced violent discipline and intimate partner violence in Rwanda. METHODS: The cluster-randomized trial of Sugira Muryango enrolled socioeconomically vulnerable families with children aged 6 to 36 months in rural Rwanda. We interviewed 18 female caregivers early in the intervention, and 21 female caregivers and 11 male intimate partners were interviewed after the intervention. Coded interviews identify risk factors for violence and mechanisms of intervention-related change in violence. Quantitative analyses included 931 caregivers (52.6% female) who lived with an intimate partner to examine risk factors for violence, intervention effects, and mechanisms of violence reduction. RESULTS: The qualitative data identified daily hardships and alcohol problems as risk factors for violent discipline and intimate partner violence. Through Sugira Muryango, caregivers learned that strong relationships between partners and engagement of male caregivers in child care has positive impacts on children's development. Techniques taught by community lay workers improved communication, promoted positive parent-child interactions, and reduced intimate partner violence and violent discipline. Quantitative analyses also found that daily hardships predict violent discipline and intimate partner violence. Sugira Muryango reduced violent discipline, increased father engagement, and increased female caregiving warmth. Moreover, pre- to postintervention change in caregiving warmth was associated with reduced use of violent discipline among female caregivers and marginally associated with reduced female victimization. CONCLUSIONS: Violence reduction can be integrated into early child development programs to reduce violent discipline and intimate partner violence.

EHBP1L1 Frameshift Deletion in English Springer Spaniel Dogs with Dyserythropoietic Anemia and Myopathy Syndrome (DAMS) or Neonatal Losses.

Hereditary myopathies are well documented in dogs, whereas hereditary dyserythropoietic anemias are rarely seen. The aim of this study was to further characterize the clinical and clinicopathological features of and to identify the causative genetic variant for a dyserythropoietic anemia and myopathy syndrome (DAMS) in English springer spaniel dogs (ESSPs). Twenty-six ESSPs, including five dogs with DAMS and two puppies that died perinatally, were studied. Progressive weakness, muscle atrophy-particularly of the temporal and pelvic muscles-trismus, dysphagia, and regurgitation due to megaesophagus were observed at all ages. Affected dogs had a non-regenerative, microcytic hypochromic anemia with metarubricytosis, target cells, and acanthocytes. Marked erythroid hyperplasia and dyserythropoiesis with non-orderly maturation of erythrocytes and inappropriate microcytic metarubricytosis were present. Muscle biopsies showed centralized nuclei, central pallor, lipocyte infiltrates, and fibrosis, which was consistent with centronuclear myopathy. The genome sequencing of two affected dogs was compared to 782 genomes of different canine breeds. A homozygous frameshift single-base deletion in EHBP1L1 was identified; this gene was not previously associated with DAMS. Pedigree analysis confirmed that the affected ESSPs were related. Variant genotyping showed appropriate complete segregation in the family, which was consistent with an autosomal recessive mode of inheritance. This study expands the known genotype-phenotype correlation of EHBP1L1 and the list of potential causative genes in dyserythropoietic anemias and myopathies in humans. EHBP1L1 deficiency was previously reported as perinatally lethal in humans and knockout mice. Our findings enable the genetic testing of ESSP dogs for early diagnosis and disease prevention through targeted breeding strategies.

Validation of a dry-slide immunoassay for progesterone analysis in canine plasma in a clinical setting.

BACKGROUND: The identification of canine ovulation is critical for successful breeding. Progesterone measurements are useful for identifying ovulation. Progesterone assays are also quantitative and easily accessed, making them valuable in veterinary practice. OBJECTIVES: We aimed to validate a dry-slide immunoassay (DSI) for use in dogs, including a method comparison with the chemiluminescence assay (CLIA) and mass spectrometry. METHODS: Twenty-nine bitches were prospectively recruited. Accuracy, precision, interference, and stability were evaluated. Method comparison between DSI and CLIA and mass spectrometry was conducted, and bias was calculated. RESULTS: Repeatability was 8.0%-10.8%, and within-laboratory imprecision was 8.8%-11.1% for four concentration levels. Recovery under dilution was 61%-100%, and the method was linear to a concentration of ~50 nmol/L. Recovery after the addition of a high progesterone sample was 76%-83%. Minor changes were seen in one hemolytic and two lipemic samples. Storage at room temperature for 12-24 hours resulted in concentrations that were 57%-96% of the initial concentrations. For samples frozen at -80°C, the concentrations were reduced 17%-27%. There was a significant difference between results from the DSI and CLIA, and a proportional bias was seen when DSI was compared with mass spectrometry, where CLIA correlated better than DSI. CONCLUSIONS: Precision and accuracy were acceptable. A proportional bias was seen between DSI and CLIA. A small amount of interference was seen with hemolysis and lipemia. Progesterone concentrations were decreased in samples stored at room temperature and -80°C. The results support the use of the DSI for ovulation timing but not for artificial insemination with frozen semen since progesterone concentrations might exceed the assay's linearity and precision limits.

An adaptive teosinte mexicana introgression modulates phosphatidylcholine levels and is associated with maize flowering time.

Native Americans domesticated maize (Zea mays ssp. mays) from lowland teosinte parviglumis (Zea mays ssp. parviglumis) in the warm Mexican southwest and brought it to the highlands of Mexico and South America where it was exposed to lower temperatures that imposed strong selection on flowering time. Phospholipids are important metabolites in plant responses to low-temperature and phosphorus availability and have been suggested to influence flowering time. Here, we combined linkage mapping with genome scans to identify High PhosphatidylCholine 1 (HPC1), a gene that encodes a phospholipase A1 enzyme, as a major driver of phospholipid variation in highland maize. Common garden experiments demonstrated strong genotype-by-environment interactions associated with variation at HPC1, with the highland HPC1 allele leading to higher fitness in highlands, possibly by hastening flowering. The highland maize HPC1 variant resulted in impaired function of the encoded protein due to a polymorphism in a highly conserved sequence. A meta-analysis across HPC1 orthologs indicated a strong association between the identity of the amino acid at this position and optimal growth in prokaryotes. Mutagenesis of HPC1 via genome editing validated its role in regulating phospholipid metabolism. Finally, we showed that the highland HPC1 allele entered cultivated maize by introgression from the wild highland teosinte Zea mays ssp. mexicana and has been maintained in maize breeding lines from the Northern United States, Canada, and Europe. Thus, HPC1 introgressed from teosinte mexicana underlies a large metabolic QTL that modulates phosphatidylcholine levels and has an adaptive effect at least in part via induction of early flowering time.

Prenatal Considerations and Outcomes for Girls Aged 14 and Under: Development of a Multidisciplinary Team in a Large Tertiary Care Facility.

INTRODUCTION: Adolescent girls account for 11% of all births that occur globally every year. Among developing countries, the United States continues to have one of the highest adolescent birth rates, despite a decreasing trend between 1990 and 2010. Pregnant adolescents are a vulnerable population who are at increased risk for maternal morbidity and mortality. Additional risks are noted within the early adolescent population, usually defined as age 10 to 14. PROCESS: At Parkland hospital, a large tertiary care facility in Dallas, Texas, a multidisciplinary team was created in 2017 to care for this vulnerable population. The team consisted of a certified nurse-midwife (CNM), a Certified Child Life Specialist, a maternal fetal medicine physician, a social worker, and a Spanish interpreter, with additional services consulted as needed. Between 2017 and 2020, this team grew to include 8 CNMs and provided care to 76 young adolescents ages 14 and younger. OUTCOMES: Of the young adolescents who attended prenatal visits with the Adolescent Prenatal Care Team at Parkland, 87% presented to Parkland for birth. Eighteen percent had pregnancy-induced hypertension or eclampsia. Only 7% of adolescents in the program gave birth prior to 37 weeks. Seventy-four percent had vaginal births. Sixty percent of the adolescents attended known postpartum visits. DISCUSSION: In contrast to most studies, this Adolescent Care Team did not find a high rate of premature birth in early adolescents. Further work by this team is needed to compare the data obtained during this period with data on similar adolescents who have given birth at Parkland in prior years. In addition, comparing outcomes of early adolescents with those aged 15 to 19, who were not included in the Adolescent Care Team, will help to understand the impact that such a team or similar intervention might have on this vulnerable population.

Systemic inflammation during the first year of life is associated with brain functional connectivity and future cognitive outcomes.

The first years of life are a sensitive period of rapid neural and immune system development vulnerable to the impact of adverse experiences. Several studies support inflammation as a consequence of various adversities and an exposure negatively associated with developmental outcomes. The mechanism by which systemic inflammation may affect brain development and later cognitive outcomes remains unclear. In this longitudinal cohort study, we examine the associations between recurrent systemic inflammation, defined as C-reactive protein elevation on ≥ 2 of 4 measurements across the first year of life, electroencephalography (EEG) functional connectivity (FC) at 36 months, and composite cognitive outcomes at 3, 4, and 5 years among 122 children living in a limited-resource setting in Dhaka, Bangladesh. Recurrent systemic inflammation during the first year of life is significantly negatively associated with cognitive outcomes at 3, 4, and 5 years, after accounting for stunting and family care indicators (a measure of stimulation in the home environment). Recurrent systemic inflammation is significantly positively associated with parietal-occipital FC in the Beta band at 36 months, which in turn is significantly negatively associated with composite cognitive scores at 3 and 4 years. However, FC does not mediate the relationship between recurrent systemic inflammation and cognitive outcomes.

Detection and characterization of lung cancer using cell-free DNA fragmentomes.

Non-invasive approaches for cell-free DNA (cfDNA) assessment provide an opportunity for cancer detection and intervention. Here, we use a machine learning model for detecting tumor-derived cfDNA through genome-wide analyses of cfDNA fragmentation in a prospective study of 365 individuals at risk for lung cancer. We validate the cancer detection model using an independent cohort of 385 non-cancer individuals and 46 lung cancer patients. Combining fragmentation features, clinical risk factors, and CEA levels, followed by CT imaging, detected 94% of patients with cancer across stages and subtypes, including 91% of stage I/II and 96% of stage III/IV, at 80% specificity. Genome-wide fragmentation profiles across ~13,000 ASCL1 transcription factor binding sites distinguished individuals with small cell lung cancer from those with non-small cell lung cancer with high accuracy (AUC = 0.98). A higher fragmentation score represented an independent prognostic indicator of survival. This approach provides a facile avenue for non-invasive detection of lung cancer.

Coparenting and Mental Health in Families with Jailed Parents.

The number of families affected by parental incarceration in the United States has increased dramatically in the past three decades, with primarily negative implications for adult mental health and child and family well-being. Despite research documenting increased strain on coparenting relationships, less is known regarding the relation between adult mental health and coparenting quality. This study investigated coparenting in families with young children currently experiencing parental incarceration. In a diverse sample of 86 jailed parent-caregiver dyads (n = 172), this analysis of a short-term longitudinal study examined the links among jailed parents' and children's at-home caregivers' externalizing mental health symptoms and perceived coparenting alliance quality using the Actor-Partner Interdependence Model. Analyses using structural equation modeling revealed a medium sized negative partner effect for externalizing behaviors on coparenting alliance for jailed parents, wherein caregivers increased externalizing symptoms related to jailed parents' lower reported coparenting quality. Caregiver-partner effects and both actor effects resulted in small effects. These findings highlight the roles of mental health and coparenting relationship quality when a parent is incarcerated and contribute to the existing literature on incarcerated coparenting, with implications for theory and practice.

Associations of socioeconomic and other environmental factors with early brain development in Bangladeshi infants and children.

Studies of infants growing up in high-income countries reveal developmental changes in electroencephalography (EEG) power whereby socioeconomic factors - specifically, low SES and low income - are associated with lower EEG power in infants aged newborn to nine months. In the current paper we explore relationships of spectral EEG power across three regions (frontal, central, and parietal) and four frequency bands (theta, alpha, beta, and gamma) with socioeconomic and psychosocial factors in a cohort of n = 160 6-month-old infants and n = 187 36-month-old children living in Dhaka, Bangladesh. Household wealth is assessed as a multi-dimensional composite score encompassing income, assets, and housing materials. Psychosocial factors include maternal perceived stress and family caregiving activities. Among the 6-month-old infants we do not observe any association of household wealth or psychosocial factors with EEG power. Among the 36-month-old children, we find that household wealth is negatively associated absolute power in the beta and gamma bands across frontal, central, and parietal electrodes. We also find that higher reports of maternal perceived stress are associated with more absolute theta power in frontal and central regions in the 36-month-old children. The finding of a negative relationship of household wealth with beta and gamma power in 36-month-old children differs from findings previously observed in infants in high-income countries. Overall, findings suggest that children's environment continues to influence the development of EEG oscillations and provide support for the utility of EEG to quantify developmental effects of early life experiences on neural functional outcomes in low income countries.

COVID-19 Inspired Relational Telemental Health Services for Incarcerated Individuals and Their Families.

The novel coronavirus pandemic has caused marriage and family therapists (MFTs) to alter how they provide clinical services. MFTs must determine how to deliver relationship-oriented services to underserved populations that are often forgotten during crises, including incarcerated individuals and their families. The primary purpose of this paper is to showcase how relational telemental health (TMH) services for incarcerated individuals and their families can increase access to services and improve relational health. Information is presented about corrections in the U.S., effects of incarceration on partners, children, and other family members, the behavioral health and relationship needs of incarcerated individuals, and current approaches to relational mental health and telehealth in corrections. Finally, suggestions are offered on how relational TMH could be used in corrections during the COVID-19 pandemic, including advocacy for collaborative healthcare, recommended implementation practices, and ethical considerations.