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While methadone treatment (MT) is effective in treating opioid use disorder (OUD), retention remains an issue nationwide, especially among low-income, minoritized populations. Peer recovery specialists (PRSs), individuals with lived substance use experience, are particularly well suited to support vulnerable populations, though often are not trained in delivering evidence-based interventions. Thus, our team developed a Type 1 hybrid effectiveness-implementation open-label pilot trial to evaluate the effectiveness of PRS-delivered BA (Peer Activate) in improving MT retention and establish feasibility, acceptability and PRS fidelity of the intervention. In this case series, we provide a more in-depth depiction of the adaption of Peer Activate and present three cases to illustrate how Peer Activate can be implemented among patients in routine MT care and adapted to meet the needs of varying clinical presentations. We include descriptive data on participant substance use and MT outcomes to supplement the narrative discussion. While varying participant presentations and needs presented challenges to the PRS interventionist, the PRS utilized his shared, lived substance use and recovery experiences and met participants where they were at, as well as successfully used BA techniques, ultimately leading to intervention success.

Introduction: Clinical notes, biomarkers, and neuroimaging have proven valuable in dementia prediction models. Whether commonly available structured clinical data can predict dementia is an emerging area of research. We aimed to predict gold-standard, research-based diagnoses of dementia including Alzheimer's disease (AD) and/or Alzheimer's disease related dementias (ADRD), in addition to ICD-based AD and/or ADRD diagnoses, in a well-phenotyped, population-based cohort using a machine learning approach., Methods: Administrative healthcare data (k = 163 diagnostic features), in addition to census/vital record sociodemographic data (k = 6 features), were linked to the Cache County Study (CCS, 1995-2008)., Results: Among successfully linked UPDB-CCS participants (n = 4206), 522 (12.4%) had incident dementia (AD alone, AD comorbid with ADRD, or ADRD alone) as per the CCS "gold standard" assessments. Random Forest models, with a 1-year prediction window, achieved the best performance with an Area Under the Curve (AUC) of 0.67. Accuracy declined for dementia subtypes: AD/ADRD (AUC = 0.65); ADRD (AUC = 0.49). Accuracy improved when using ICD-based dementia diagnoses (AUC = 0.77)., Discussion: Commonly available structured clinical data (without labs, notes, or prescription information) demonstrate modest ability to predict "gold-standard" research-based AD/ADRD diagnoses, corroborated by prior research. Using ICD diagnostic codes to identify dementia as done in the majority of machine learning dementia prediction models, as compared to "gold-standard" dementia diagnoses, can result in higher accuracy, but whether these models are predicting true dementia warrants further research., (© 2024. The Author(s).)

Introduction: The C9orf72 mutation can manifest in diverse clinical ways, including rapid cognitive decline, parkinsonism, or late-life neuropsychiatric symptoms, sometimes mimicking autoimmune encephalitis., Case Report: A 64-year-old female presented to the autoimmune neurology clinic with rapidly progressive dementia (RPD) associated with episodes of headache, confusion, auditory hallucinations, and abnormal electroencephalogram. She was treated empirically at an outside hospital for possible autoimmune encephalitis with intravenous methylprednisolone, but there was no improvement, and rapid cognitive decline continued. Family history was notable for RPD with akinetic mutism in her sister, sudden severe depression followed by parkinsonism with progressive dementia in her father in his 60s, and late-life gradually progressive dementia in her mother. Additional testing revealed a low titer positive contactin-associated protein-like 2 (CASPR2) immunoglobulin G (IgG) in the serum and elevated CSF 14-3-3 protein. CSF CASPR2 IgG and real-time quaking-induced conversion for Creutzfeldt-Jakob disease were negative. Brain MRI showed normal parenchymal volume. Genetic testing was conducted, which identified a heterozygous pathogenic hexanucleotide tandem repeat expansion in the C9orf72 gene., Conclusion: This case underscores the phenotypic variability of C9orf72 mutation and the importance of a detailed family history exploring young or atypical deaths and neuropsychiatric symptoms or behavioral changes. Genetic etiologies are crucial to consider in those with a family history concerning autosomal dominant inheritance patterns of early-onset dementia, parkinsonism, or late-onset psychiatric disease. Emphasis is placed on considering alternative etiologies early, particularly when there is no response to first-line immunomodulation for suspected autoimmune dementia., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The objective of this study was to compare the anastomotic leak rates between powered and manual circular staplers in elective left-sided colorectal resections., Methods: A retrospective cohort study of elective left-sided colorectal resections before and after implementation of a powered circular stapler at a tertiary care center was conducted. The manual stapler group consisted of consecutive resections performed between January 2016 to December 2016 and the powered stapler group, between September 2021 and December 2022. Primary outcome was 30-day anastomotic leak rate. A chi-squared analysis was performed to compare anastomotic leak rates. Factors associated with anastomotic leak were examined., Results: Two-hundred forty-seven patients were included: 154 in the manual stapler group and 93 in the powered stapler group. Mean (SD) age was 60 (15) years old, 37.7% were female and 72.9% of resections were performed for malignancy. Both groups had similar patient characteristics and surgical technique. Overall leak rate was 2.0% in the manual stapler group and 10.8% in the powered stapler group. The powered staplers were found to have 6.06 times the odds of leak compared to manual staplers (95% CI, 1.62-22.65; p = 0.01). None of the other factors were found to be associated with anastomotic leak., Conclusions: Patients who had left-sided colorectal anastomosis had higher anastomotic leak rates with powered compared to manual circular staplers. This finding is contrary to previous retrospective studies that found lower leak rates with powered staplers., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Social networks undergo changes in later life, reflecting proactive decreases as well as increases in size, but relatively little is known about the factors that motivate older adults to expand their social ties. Loneliness might be expected to motivate older adults to expand their social ties. Paradoxically, however, studies of younger age groups have linked loneliness to a self-protective reluctance to initiate social contact. The current study investigated whether loneliness fosters or inhibits older adults' efforts to expand their social ties and whether successful efforts are related to gains in emotional health., Methods: Loneliness, motivation to expand social ties, and emotional health were assessed in a subset of older participants (N = 375) from the Later Life Study of Social Exchanges., Results: Greater loneliness was associated with less interest, less investment of effort, and less success in making new ties and rekindling dormant ties. Nonetheless, lonelier older adults who expanded their social ties, particularly by rekindling dormant ties, exhibited some gains in emotional health over a 1-year period., Discussion: Greater attention to the role of loneliness in older adults' motivations for making new ties or rekindling dormant ties will broaden our understanding of social network changes in later life., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Kono-S anastomosis has gained increasing interest although evaluation of its impact on reducing Crohn's recurrence shows conflicting results. This study aimed to evaluate the short- and long-term outcomes for patients with Crohn's disease requiring surgery with Kono-S compared to conventional anastomosis., Methods: A systematic review and meta-analysis included patients with Crohn's disease treated with bowel resection and Kono-S anastomosis reconstruction versus a comparator arm of conventional anastomosis technique. Recurrence outcomes examined were endoscopic recurrence rates, mean postoperative Rutgeerts score, surgical recurrence, clinical recurrence, and postoperative biologics use. Short-term postoperative outcomes include anastomotic leaks, surgical site infection, postoperative ileus, and mean operative time., Results: A total of 873 studies were identified with 15 remaining after abstract review encompassing 1501 patients, 765 with Kono-S and 736 with conventional anastomosis. Recurrence was significantly lower in the Kono-S arm, with endoscopic recurrence rates of 41% vs 48% (RR 0.86, 95% CI 0.73-1.00, p = 0.05) and surgical recurrence rates of 2.7% vs 21.0% (RR 0.13, 95% CI 0.06-0.30, p < 0.001). There was a significantly lower anastomotic leak rate in the Kono-S arm when compared to conventional anastomosis, 1.7% vs 4.9% (RR 0.37, 95% CI 0.19-0.74, p = 0.005). Mean operative time was similar between both groups., Conclusions: Kono-S is a safe and feasible anastomotic technique with lower rates of endoscopic and surgical postoperative recurrence. While we await further trials to substantiate this benefit, Kono-S anastomosis should be considered as an important tool in the armamentarium of a surgeon in anastomotic construction to reduce recurrence., (© 2024. Springer Nature Switzerland AG.)

Untargeted tandem mass spectrometry (MS/MS) is an essential technique in modern analytical chemistry, providing a comprehensive snapshot of chemical entities in complex samples and identifying unknowns through their fragmentation patterns. This high-throughput approach generates large data sets that can be challenging to interpret. Molecular Networks (MNs) have been developed as a computational tool to aid in the organization and visualization of complex chemical space in untargeted mass spectrometry data, thereby supporting comprehensive data analysis and interpretation. MNs group related compounds with potentially similar structures from MS/MS data by calculating all pairwise MS/MS similarities and filtering these connections to produce a MN. Such networks are instrumental in metabolomics for identifying novel metabolites, elucidating metabolic pathways, and even discovering biomarkers for disease. While MS/MS similarity metrics have been explored in the literature, the influence of network topology approaches on MN construction remains unexplored. This manuscript introduces metrics for evaluating MN construction, benchmarks state-of-the-art approaches, and proposes the Transitive Alignments approach to improve MN construction. The Transitive Alignment technique leverages the MN topology to realign MS/MS spectra of related compounds that differ by multiple structural modifications. Combining this Transitive Alignments approach with pseudoclique finding, a method for identifying highly connected groups of nodes in a network, resulted in more complete and higher-quality molecular families. Finally, we also introduce a targeted network construction technique called induced transitive alignments where we demonstrate effectiveness on a real world natural product discovery application. We release this transitive alignment technique as a high-throughput workflow that can be used by the wider research community.

Objective: This investigation examines burden of comorbidity measured by the Charlson Comorbidity Index (CCI) and Elixhauser Comorbidity Index (ECI) among inpatients based on age, sex, and race., Methods: Cross-sectional analysis of 2012-2018 US NIS datasets. Participants were inpatients 55y+. ICD-9/10 codes for admitting diagnoses were used to calculate disease burden using the CCI and ECI. Unweighted mean CCI and ECI scores were compared across demographic variables., Results: An increase in mean CCI and ECI scores across age, sex, and races (p<.001) was identified. Compared to the youngest age group (55-59y), all age groups had higher mean CCI and ECI adjusting for time (p<.001). Increases were greatest in older age groups until age 80-84 for CCI and 85-89 for ECI. The female group had lower CCI adjusting for time (p<.001) compared to males. There was no difference between sex groups in mean ECI (p=.409). Compared with the White group, all other race groups had higher mean CCI adjusting for time (p<.001). Black inpatients had the highest CCI followed by Native American inpatients. Findings were similar for ECI, but with no difference between Hispanic and White groups (p=.434)., Conclusions: Growing multimorbidity burden among adult inpatients across age, sex, and race supports the continued need for programs for preventing and reducing multimorbidity, especially among communities that experience health inequity including older, Black, and Native American patients., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Background: Identifying priority challenges of older adults with chronic obstructive pulmonary disease (COPD) is critical to designing interventions aimed at improving their well-being and independence., Objective: To prioritize challenges of older adults with COPD and those who care for them to guide refinement of a telephonic nurse coach intervention for patients with COPD and their family caregivers (EPIC: Empowering People to Independence in COPD)., Design: Multiphase study guided by Baltes Theory of Successful Aging and the 5Ms Framework: Phase 1: Nominal group technique (NGT), a structured process of prioritizing responses to a question through group consensus. Phase 2: Rapid qualitative analysis. Phase 3: Intervention mapping and refinement., Setting: Ambulatory, virtual., Participants: Older adults with COPD, family caregivers, clinic staff (nurses, respiratory therapists), clinicians (physicians, nurse practitioners), and health system leaders., Results: NGT sessions were conducted by constituency group with 37 participants (n = 7 patients, n = 6 family caregivers, n = 8 clinic staff, n = 9 clinicians, n = 7 health system leaders) (Phase 1). Participants generated 92 statements across five themes (Phase 2): (1) "Barriers to care", (2) "Family caregiver needs", (3) "Functional status and mobility issues", (4) "Illness understanding", and (5) "COPD care complexities". Supplemental oxygen challenges emerged as a critical problem, and prioritized challenges differed by group. Patients and clinic staff prioritized "Functional status and mobility issues", family caregivers prioritized "Family caregiver needs", and clinicians and health system leaders prioritized "COPD care complexities". Intervention mapping (Phase 3) guided EPIC refinement focused on meeting patient priorities of independence and mobility but accounting for all priorities., Conclusions: Diverse constituency groups identified priority challenges for older adults with COPD. Functional status and mobility issues, particularly related to supplemental oxygen, emerged as patient prioritized challenges., Implications: Patient-centered interventions for older adults with COPD must account for their prioritized functional and supplemental oxygen needs and explore diverse constituent perspectives to facilitate intervention enrichment., (© 2024 The American Geriatrics Society.)

Effective fisheries management requires accurate estimates of stock biomass and trends; yet, assumptions in stock assessment models generate high levels of uncertainty and error. For 230 fisheries worldwide, we contrasted stock biomass estimates at the time of assessment with updated hindcast estimates modeled for the same year in later assessments to evaluate systematic over- or underestimation. For stocks that were overfished, low value, or located in regions with rising temperatures, historical biomass estimates were generally overstated compared with updated assessments. Moreover, rising trends reported for overfished stocks were often inaccurate. With consideration of bias identified retrospectively, 85% more stocks than currently recognized have likely collapsed below 10% of maximum historical biomass. The high uncertainty and bias in modeled stock estimates warrants much greater precaution by managers.

Plans for habitat restoration will benefit from predictions of timescales for recovery. Theoretical models have been a powerful tool for informing practical guidelines in planning marine protected areas, suggesting restoration planning could also benefit from a theoretical framework. We developed a model that can predict recovery times following restoration action, under dispersal, recruitment and connectivity constraints. We apply the model to a case study of seagrass restoration and find recovery times following restoration action can vary greatly, from <1 to >20 years. The model also shows how recovery can be accelerated when restoration actions are matched to the constraints on recovery. For example, spreading of propagules can be used when connectivity is the critical restriction. The recovery constraints we articulated mathematically also apply to the restoration of coral reefs, mangroves, saltmarsh, shellfish reefs and macroalgal forests, so our model provides a general framework for choosing restoration actions that accelerate coastal habitat recovery.

Driven by the United Nations Decade on Restoration and international funding initiatives, such as the Mangrove Breakthrough, investment in mangrove restoration is expected to increase. Yet, mangrove restoration efforts frequently fail, usually because of ad hoc site-selection processes that do not consider mangrove ecology and the socioeconomic context. Using decision analysis, we developed an approach that accounts for socioeconomic and ecological data to identify sites with the highest likelihood of mangrove restoration success. We applied our approach in the Biosphere Reserve Marismas Nacionales Nayarit, Mexico, an area that recently received funding for implementing mangrove restoration actions. We identified 468 potential restoration sites, assessed their restorability potential based on socioeconomic and ecological metrics, and ranked sites for implementation with spatial optimization. The metrics we used included favorable conditions for propagules to establish and survive under sea-level rise, provision of ecosystem services, and community dynamics. Sites that were selected based on socioeconomic or ecological metrics alone had lower likelihood of mangrove restoration success than sites that were selected based on integrated socioeconomic and ecological metrics. For example, selecting sites based on only socioeconomic metrics captured 16% of the maximum attainable value of functioning mangroves able to provide propagules to potential restoration sites, whereas selecting sites based on ecological and socioeconomic metrics captured 46% of functioning mangroves. Our approach was developed as part of a collaboration between nongovernmental organizations, local government, and academics under rapid delivery time lines given preexisting mangrove restoration implementation commitments. The systematic decision process we used integrated socioeconomic and ecological considerations even under short delivery deadlines, and our approach can be adapted to help mangrove restoration site-selection decisions elsewhere., (© 2024 The Authors. Conservation Biology published by Wiley Periodicals LLC on behalf of Society for Conservation Biology.)

Objectives: To describe the effects of two types of auditory training on both behavioral and physiological measures of auditory function in cochlear implant (CI) users, and to examine whether a relationship exists between the behavioral and objective outcome measures., Design: This study involved two experiments, both of which used a within-subject design. Outcome measures included behavioral and cortical electrophysiological measures of auditory processing. In Experiment I, 8 CI users participated in a music-based auditory training. The training program included both short training sessions completed in the laboratory as well as a set of 12 training sessions that participants completed at home over the course of a month. As part of the training program, study participants listened to a range of different musical stimuli and were asked to discriminate stimuli that differed in pitch or timbre and to identify melodic changes. Performance was assessed before training and at three intervals during and after training was completed. In Experiment II, 20 CI users participated in a more focused auditory training task: the detection of spectral ripple modulation depth. Training consisted of a single 40-minute session that took place in the laboratory under the supervision of the investigators. Behavioral and physiologic measures of spectral ripple modulation depth detection were obtained immediately pre- and post-training. Data from both experiments were analyzed using mixed linear regressions, paired t tests, correlations, and descriptive statistics., Results: In Experiment I, there was a significant improvement in behavioral measures of pitch discrimination after the study participants completed the laboratory and home-based training sessions. There was no significant effect of training on electrophysiologic measures of the auditory N1-P2 onset response and acoustic change complex (ACC). There were no significant relationships between electrophysiologic measures and behavioral outcomes after the month-long training. In Experiment II, there was no significant effect of training on the ACC, although there was a small but significant improvement in behavioral spectral ripple modulation depth thresholds after the short-term training., Conclusions: This study demonstrates that auditory training improves spectral cue perception in CI users, with significant perceptual gains observed despite cortical electrophysiological responses like the ACC not reliably predicting training benefits across short- and long-term interventions. Future research should further explore individual factors that may lead to greater benefit from auditory training, in addition to optimization of training protocols and outcome measures, as well as demonstrate the generalizability of these findings., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Despite heightened interest, measurement of hospital mobility remains challenging. Available assessment tools lack patient input regarding level and frequency of hospital mobility. The purpose of this study was to validate a brief self-reported mobility assessment to measure out-of-bed activity during hospitalization., Methods: We recruited cognitively intact hospitalized adults (age ≥ 65 years) who walked prior to admission, to wear an accelerometer for 24 hours, and to complete the Acute Care Mobility Assessment (ACMA), a self-report of mobility that ranges from bed rest to walking off the hospital unit in the prior 24 hours. For each mobility level from sitting in a chair to walking off the unit, patients reported the frequency of the activity and the need for help from another person or equipment. Spearman correlation coefficients were calculated using several scoring algorithms to compare ACMA to accelerometer data., Results: Fifty-one patients (mean age 74.3 [standard deviation 6.2] years, 63% female, 39% Black) had complete data. Steps taken in 24 hours ranged from 10 to 2 831. Correlation analyses identified strong associations between ACMA scores and total steps, and moderate correlations with total time walking using all algorithms. However, the unweighted frequency count using the 3 ambulation levels only (walking in room, in hall, and off ward) had the highest correlation with total steps (r = 0.84; p < .001) and total time walking (r = 0.66; p < .001)., Conclusions: ACMA is a valid measure of mobility among cognitively intact hospitalized older adults. The ACMA may add value to our current armamentarium of tools by adding patient reports of hospital mobility., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Adult-born granule cells (abGCs) project to the CA2 region of the hippocampus, but it remains unknown how this circuit affects behavioral function. Here, we show that abGC input to the CA2 of adult mice is involved in the retrieval of remote developmental memories of the mother. Ablation of abGCs impaired the ability to discriminate between a caregiving mother and a novel mother, and this ability returned after abGCs were regenerated. Chemogenetic inhibition of projections from abGCs to the CA2 also temporarily prevented the retrieval of remote mother memories. These findings were observed when abGCs were inhibited at 4-6 weeks old, but not when they were inhibited at 10-12 weeks old. We also found that abGCs are necessary for differentiating features of CA2 network activity, including theta-gamma coupling and sharp wave ripples, in response to novel versus familiar social stimuli. Taken together, these findings suggest that abGCs are necessary for neuronal oscillations associated with discriminating between social stimuli, thus enabling retrieval of remote developmental memories of the mother by their adult offspring., Competing Interests: BL, IG, CB, EG No competing interests declared, (© 2023, Laham et al.)

Background: Transanal total mesorectal excision is a novel surgical treatment for mid to low rectal cancers. Norwegian population data have raised concerns about local recurrence in patients treated with transanal total mesorectal excision., Objective: This study aimed to analyze local recurrence and disease-free survival in patients treated by transanal total mesorectal excision for rectal cancer at a high-volume tertiary center., Design: This retrospective study used a prospectively maintained institutional transanal total mesorectal excision database. Patient demographics, treatment, and outcomes data were analyzed. Local recurrence, disease-free survival, and overall survival were analyzed using Kaplan-Meier analysis., Settings: The study was conducted at a single academic institution in Vancouver, Canada., Patients: All patients treated by transanal total mesorectal excision for rectal adenocarcinoma between 2014 and 2022 were included., Main Outcome Measures: The primary outcome was local recurrence-free survival., Results: Between 2014 and 2022, 306 patients were treated by transanal total mesorectal excision at St. Paul's Hospital. Of these, 279 patients met the inclusion criteria. The mean age was 62 years (SD ± 12.3), and 66.7% of patients were men. Restorative resection was achieved in 97.5% of patients, with a conversion rate from laparoscopic to open surgery of 6.8%. The composite optimal pathological outcome was 93.9%. The median follow-up was 26 months (interquartile range, 12-47), and 82.8% of patients achieved reestablishment of GI continuity to date. The overall local recurrence rate was 4.7% (n = 13). The estimated 2-year local recurrence-free survival rate was 95.0% (95% CI, 92-98) and the estimated 5-year local recurrence-free survival rate was 94.5% (95% CI, 91-98)., Limitations: Limitations include the retrospective nature of the study and the generalizability of a Canadian population., Conclusions: Recent European data have challenged the presumed oncologic safety of transanal total mesorectal excision. Although the learning curve for this procedure is challenging and poor outcomes are associated with low volume, this high-volume single-center study confirms acceptable oncologic outcomes consistent with the current standard. See Video Abstract ., Sobrevida Sin Recidiva Despus De Tatme Experiencia Institucional Canadiense: ANTECEDENTES:La excisión total del mesorecto por vía transanal es un tratamiento quirúrgico novedoso para los cánceres de recto medio a bajo. Estudios sobre la población noruega han generado preocupación debido a la recidiva local en pacientes tratados con excisión total del mesorecto por vía transanal.OBJETIVO:Nuestra finalidad fué de analizar la recidiva local y la sobrevida libre de enfermedad en pacientes tratados mediante la excisión total del mesorecto por vía transanal, debido a un cáncer de recto en un centro terciario de alto volúmen.DISEÑO:El presente estudio retrospectivo, utiliza una base de datos institucional sobre la excisión total del mesorecto por vía transanal mantenida prospectivamente. Se analizaron los datos demográficos, de tratamiento y los resultados de los pacientes sometidos a la técnica mencionada. La recidiva local, la sobrevida libre de enfermedad y la sobrevida global se analizaron mediante el modelo de Kaplan-Meier.AJUSTES:El estudio se llevó a cabo en una sola institución académica en Vancouver, Canadá.PARTICIPANTES:Se incluyeron todos los pacientes tratados mediante excisión total del mesorecto por vía transanal causado por adenocarcinomas de recto entre 2014 y 2022.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue la sobrevida libre de recidiva local.RESULTADOS:Entre 2014 y 2022, 306 pacientes fueron tratados mediante la excisión total del mesorecto por vía transanal en el Hospital St. Paul. De estos, 279 pacientes cumplieron los criterios de inclusión. La edad media fue de 62 años (DE ± 12,3) y el 66,7% de los pacientes eran varones. La resección restauradora se logró en el 97,5% de los pacientes con una tasa de conversión de cirugía laparoscópica en laparotomía del 6,8%. El resultado patológico óptimo combinado fué del 93,9%. La mediana de seguimiento fue de 26 meses (rango intercuartil 12-47) y el 82,8% logró el restablecimiento de la continuidad gastrointestinal hasta la fecha. La tasa global de recidiva local fué del 4,7% (n = 13). La sobrevida libre de recidiva local estimada a los 2 años fué del 95,0% (IC del 95%: 92-98) y del 94,5% a los 5 años (IC del 95%: 91-98).LIMITACIONES:Las limitaciones incluyen la naturaleza retrospectiva del estudio y la generalización de una población canadiense.CONCLUSIONES:Datos europeos recientes han cuestionado la supuesta seguridad oncológica de la excisión total del mesorecto por vía transanal. Si bien la curva de aprendizaje de este procedimiento es muy desafiante y los malos resultados se asocian con un volumen bajo, el presente estudio, unicéntrico de gran volumen confirma los resultados oncológicos aceptables consistentes con el estándar actual. (Traducción-Dr. Xavier Delgadillo )., (Copyright © The ASCRS 2024.)

Background: EPIC (Empowering People to Independence in COPD) is a geriatric-palliative care telephonic, nurse coach intervention informed by Baltes' Theory of Successful Aging and adapted from the ENABLE (Educate, Nurture, Advise, Before Life Ends) intervention. EPIC, focused on improving independence, mobility, well-being, and COPD symptoms, has undergone formative and summative evaluation for adults with COPD., Methods: The primary study aim is to assess the refined EPIC intervention's feasibility and acceptability via a pilot hybrid effectiveness-implementation randomized control trial in community-dwelling older adults with moderate to severe COPD and their family caregivers. The secondary aim is to explore the impact of EPIC on patient and caregiver outcomes. Older adults with COPD and their family caregivers (target N = 60 dyads) will be randomized to EPIC (intervention) or usual COPD care (control). EPIC includes six patient and four family caregiver weekly, telephone-based nurse coach sessions using a manualized curriculum (Charting Your Course), plus three monthly follow-up calls. Feasibility will be measured as completion of EPIC intervention and trial components (e.g., recruitment, retention, data collection). Acceptability will be evaluated using satisfaction surveys and post-study feedback interviews. A blinded data collector will assess exploratory outcomes (e.g., Life-Space mobility, quality of life, caregiver burden, emotional symptoms, loneliness, cognitive impairment, functional status, healthcare utilization) at baseline, 12, and 24 weeks., Discussion: This intervention fills a gap in addressing the geriatrics and palliative care needs and equity for adults with COPD and their family caregivers., Trial Registration: ClinicalTrials.gov Identifier: NCT05040386., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Background: Rectal neuroendocrine tumors (RNETs) are often discovered on screening colonoscopy. Indications for staging and definitive resection are inconsistent in current guidelines. We evaluated the role of grade in guiding staging and procedural decision-making., Methods: Patients with biopsy confirmed RNETs between 2004 and 2015 were reviewed. Baseline characteristics, staging investigations (biochemical and imaging), and endoscopic/surgical treatment were recorded. Associations between grade, preoperative staging, interventions, and survival were determined using Fisher-Freeman-Halton Exact, log-rank, and Kaplan-Meier analysis., Results: Amongst 139 patients with RNETs, 9% were aged ≥ 75 years and 44% female. Tumor grade was: 73% grade 1 (G1), 18%, grade 2 (G2) and 9% grade 3 (G3). Staging investigations were performed in 52% of patients. All serum chromogranin A and 97% of 24-hour urine 5-hydroxyindoleacetic acid tests were normal. The large majority of staging computed tomography (CT) scans were negative (76%) with subgroup analysis showing no G1 patients with CT identified distant disease compared with 38% of G2 and 50% of G3 patients (p < 0.001). G1 patients were more likely to achieve R0/R1 resections compared to G2 (95% vs. 50%, p < 0.001) and G1 patients had significantly better 5-year overall survival (G1: 98%, G2: 67%, G3: 10%, p < 0.001)., Conclusion: Tumor grade is important in preoperative workup and surgical decision-making. Biochemical staging may be omitted but staging CT should be considered for patients with grade ≥ 2 lesions. Anatomic resections should be considered for patients with grade 2 disease., (© 2024. The Author(s).)

Background : The incidence of colorectal cancer (CRC) is decreasing in individuals >50 years due to organised screening but has increased for younger individuals. We characterized symptoms and their timing before diagnosis in young individuals. Methods : We identified all patients diagnosed with CRC between 1990-2017 in British Columbia, Canada. Individuals <50 years ( n = 2544, EoCRC) and a matched cohort >50 ( n = 2570, LoCRC) underwent chart review to identify CRC related symptoms at diagnosis and determine time from symptom onset to diagnosis. Results: Across all stages of CRC, EoCRC presented with significantly more symptoms than LoCRC (Stage 1 mean ± SD: 1.3 ± 0.9 vs. 0.7 ± 0.9, p = 0.0008; Stage 4: 3.3 ± 1.5 vs. 2.3 ± 1.7, p < 0.0001). Greater symptom burden at diagnosis was associated with worse survival in both EoCRC ( p < 0.0001) and LoCRC ( p < 0.0001). When controlling for cancer stage, both age (HR 0.87, 95% CI 0.8-1.0, p = 0.008) and increasing symptom number were independently associated with worse survival in multivariate models. Conclusions : Patients with EoCRC present with a greater number of symptoms of longer duration than LoCRC; however, time from patient reported symptom onset was not associated with worse outcomes.

The coastal environment is not managed in a way that considers the impact of cumulative threats, despite being subject to threats from all realms (marine, land, and atmosphere). Relationships between threats and species are often nonlinear; thus, current (linear) approaches to estimating the impact of threats may be misleading. We developed a data-driven approach to assessing cumulative impacts on ecosystems and applied it to explore nonlinear relationships between threats and a temperate reef fish community. We used data on water quality, commercial fishing, climate change, and indicators of recreational fishing and urbanization to build a cumulative threat map of the northern region in New South Wales, Australia. We used statistical models of fish abundance to quantify associations among threats and biophysical covariates and predicted where cumulative impacts are likely to have the greatest impact on fish. We also assessed the performance of no-take zones (NTZs), to protect fish from cumulative threats across 2 marine protected area networks (marine parks). Fishing had a greater impact on fish than water quality threats (i.e., percent increase above the mean for invertivores was 337% when fishing was removed and was 11% above the mean when water quality was removed inside NTZs), and fishing outside NTZs affected fish abundances inside NTZs. Quantifying the spatial influence of multiple threats enables managers to understand the multitude of management actions required to address threats., (© 2023 The Authors. Conservation Biology published by Wiley Periodicals LLC on behalf of Society for Conservation Biology.)

Objective: This systematic review and meta-analysis seeks to evaluate the impact of total neoadjuvant therapy (TNT) for rectal cancers on surgical complications and surgical pathology when compared with standard long-course chemoradiotherapy (LCRT)., Background: The oncological benefits of TNT are well published in previous meta-analyses, but there is little synthesized information on how it affects surgical outcomes. A recent study has suggested an increase in local recurrence and higher rates of breached total mesorectal excision (TME) plane in TNT patients., Methods: This study conformed to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A search was performed in Medline (via PubMed), Cochrane databases, EMBASE and CINAHL to identify relevant randomized controlled trials (RCTs) comparing outcomes between TNT and LCRT. Meta-analyses of pooled proportions between TNT and LCRT were performed, comparing primary outcomes of surgical mortality, morbidity and all reported complications; surgical-pathology differences, namely mesorectal quality, R0 resection rates, circumferential resection margin positive rates, and sphincter preservation rates. Death and progression of disease during neoadjuvant treatment period was also compared. Risk of bias of RCTs was performed using the Cochrane risk-of-bias tool by 2 independent reviewers., Results: A total of 3185 patients with rectal cancer from 11 RCTs were included in the analysis: 1607 received TNT and 1578 received LCRT, of which 1422 (TNT arm) and 1391 (LCRT arm) underwent surgical resection with curative intent. There was no significant difference in mortality [risk ratio (RR)=0.86, 95% CI: 0.13-5.52, P =0.88, I2 =52%] or major complications (RR=1.04, 95% CI: 0.86-1.26, P =0.70, I2 =0%) between TNT and LCRT. There was a significantly higher risk of breached TME in TNT group on pooled analysis (RR=1.49, 95% CI: 1.03-12.16, P =0.03, I2 =0%), and on subgroup analysis there is higher risk of breached TME in those receiving extended duration of neoadjuvant treatment (>17 weeks from start of treatment to surgery) when compared with LCRT (RR=1.61, 95% CI: 1.06-2.44, P =0.03). No difference in R0 resection rates (RR=0.85, 95% CI: 0.66-1.10, P =0.21, I2 =15%), circumferential resection margin positive rates (RR=0.87, 95% CI: 0.65-1.16, P =0.35, I2 =10%) or sphincter preservation rates (RR=1.02, 95% CI: 0.83-1.25, P =0.88, I2 =57%) were observed. There was a significantly lower risk of progression of disease to an unresectable stage during the neoadjuvant treatment period in TNT patients (RR=0.60, 95% CI: 0.39-0.92, P =0.03, I2 =18%). On subgroup analysis, it appears to favor those receiving extended duration of neoadjuvant treatment (RR=0.44, 95% CI: 0.26-0.80, P =0.002), and those receiving induction-type chemotherapy in TNT (RR=0.25, 95% CI: 0.07-0.88, P =0.03)., Conclusions: TNT increases rates of breached TME which can contribute to higher local recurrence rates. TNT, however, improves systemic control by reducing early progression of disease during neoadjuvant treatment period. Further research is warranted to identify patients that will benefit from this strategy., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objectives: Increasing age brings a greater risk of death of friends and family (hereafter referred to as loss) potentially impacting individuals' life-space mobility (LSM) trajectory., Research Design and Methods: Using the UAB study of aging, we examined differences in LSM trajectories of 1,000 community-dwelling older Alabamians (65 + years) with and without loss over 8.5 years. We measured LSM using UAB's Life-Space Assessment (LSA), a validated instrument assessing movement through zones ranging from their bedroom to out of town. We assessed loss every 6 months using a standard bereavement questionnaire capturing spousal, other relative, or friend loss. We used piecewise linear mixed-effects models to compare LSA trajectories., Results: At baseline, those who later experienced loss, compared with those who did not were younger, more likely to be female, and overall in better health. Those without loss had a baseline mean LSA score of 49.5 and a decline of 0.08 points per year (p < .001). Those with loss had a baseline LSA score of 60 and declined by 1.0 point per year before loss (p < .001), accelerating to 1.8 points per year after loss (p < .001)., Discussion and Implications: Those with loss do not experience acute decline postloss but do have an acceleration of the preexisting decline. Although additional research may explain the impact of loss on LSM; this finding suggests that more interventions such as social, mental, or health care services, may be needed for those who experience loss. Specifically, bereaved individuals may benefit from it., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Collagen XVII is most typically associated with human disease when biallelic COL17A1 variants (>230) cause junctional epidermolysis bullosa (JEB), a rare, genetically heterogeneous, mucocutaneous blistering disease with amelogenesis imperfecta (AI), a developmental enamel defect. Despite recognition that heterozygous carriers in JEB families can have AI, and that heterozygous COL17A1 variants also cause dominant corneal epithelial recurrent erosion dystrophy (ERED), the importance of heterozygous COL17A1 variants causing dominant non-syndromic AI is not widely recognised., Methods: Probands from an AI cohort were screened by single molecule molecular inversion probes or targeted hybridisation capture (both a custom panel and whole exome sequencing) for COL17A1 variants. Patient phenotypes were assessed by clinical examination and analyses of affected teeth., Results: Nineteen unrelated probands with isolated AI (no co-segregating features) had 17 heterozygous, potentially pathogenic COL17A1 variants, including missense, premature termination codons, frameshift and splice site variants in both the endo-domains and the ecto-domains of the protein. The AI phenotype was consistent with enamel of near normal thickness and variable focal hypoplasia with surface irregularities including pitting., Conclusion: These results indicate that COL17A1 variants are a frequent cause of dominantly inherited non-syndromic AI. Comparison of variants implicated in AI and JEB identifies similarities in type and distribution, with five identified in both conditions, one of which may also cause ERED. Increased availability of genetic testing means that more individuals will receive reports of heterozygous COL17A1 variants. We propose that patients with isolated AI or ERED, due to COL17A1 variants, should be considered as potential carriers for JEB and counselled accordingly, reflecting the importance of multidisciplinary care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

A digital design tool that can transfer material property information between unit operations to predict the product attributes in integrated purification processes has been developed to facilitate end-to-end integrated pharmaceutical manufacturing. This work aims to combine filtration and washing operations frequently using active pharmaceutical ingredient (API) isolation. This is achieved by coupling predicted and experimental data produced during the upstream crystallization process. To reduce impurities in the isolated cake, a mechanistic model-based workflow was used to optimize an integrated filtration and washing process model. The Carman-Kozeny filtration model has been combined with a custom washing model that incorporates diffusion and axial dispersion mechanisms. The developed model and approach were applied to two systems, namely, mefenamic acid and paracetamol, which are representative compounds, and various crystallization and wash solvents and related impurities were used. The custom washing model provides a detailed evolution of species concentration during washing, simulating the washing curve with the three stages of the wash curve: constant rate, intermediate stage, and diffusion stage. A model validation approach was used to estimate cake properties (e.g., specific cake resistance, cake volume, cake composition after washing, and washing curve). A global systems analysis was conducted by using the calibrated model to explore the design space and aid in the setup of the optimization decision variables. Qualitative optimization was performed in order to reduce the concentration of impurities in the final cake after washing. The findings of this work were translated into a final model to simulate the optimal isolation conditions., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Aim: Prehabilitation for colorectal cancer has focused on exercise-based interventions that are typically designed by clinicians; however, no research has yet been patient-oriented. The aim of this feasibility study was to test a web-based multimodal prehabilitation intervention (known as PREP prehab) consisting of four components (physical activity, diet, smoking cessation, psychological support) co-designed with five patient partners., Method: A longitudinal, two-armed (website without or with coaching support) feasibility study of 33 patients scheduled for colorectal surgery 2 weeks or more from consent (January-September 2021) in the province of British Columbia, Canada. Descriptive statistics analysed a health-related quality of life questionnaire (EQ5D-5L) at baseline (n = 25) and 3 months postsurgery (n = 21), and a follow-up patient satisfaction survey to determine the acceptability, practicality, demand for and potential efficacy in improving overall health., Results: Patients had a mean age of 52 years (SD 14 years), 52% were female and they had a mean body mass index of 25 kg m -2 (SD 3.8 kg m -2 ). Only six patients received a Subjective Global Assessment for being at risk for malnutrition, with three classified as 'severely/moderately' malnourished. The majority (86%) of patients intended to use the prehabilitation website, and nearly three-quarters (71%) visited the website while waiting for surgery. The majority (76%) reported that information, tools and resources provided appropriate support, and 76% indicated they would recommend the PREP prehab programme. About three-quarters (76%) reported setting goals for lifestyle modification: 86% set healthy eating goals, 81% aimed to stay active and 57% sought to reduce stress once a week or more. No patients contacted the team to obtain health coaching, despite broad interest (71%) in receiving active support and 14% reporting they received 'active support'., Conclusion: This web-based multimodal prehabilitation programme was acceptable, practical and well-received by all colorectal surgery patients who viewed the patient-oriented multimodal website. The feasibility of providing active health coaching support requires further investigation., (© 2024 The Authors. Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

Aim: The aim was to estimate the 10-year cost-utility of haemorrhoidectomy surgery with preference-based measures of health using Canadian health utility measures and costs., Methods: Patients undergoing elective haemorrhoidectomies by general and colorectal surgeons in British Columbia, Vancouver, between September 2015 and November 2022, completed preoperatively and postoperatively the EuroQol five-dimension five-level health-related quality of life questionnaire (EQ-5D-5L). Quality-adjusted life years (QALYs) attributable to surgery were calculated by discounting preoperative and postoperative health utility values derived from the EQ-5D-5L. Costs were measured from a health system perspective which incorporated costs of hospital stay and specialists' fees. Results are presented in 2021 Canadian dollars., Results: Of 94 (47%) patients who completed both the preoperative and postoperative questionnaires, the mean gain in QALYs 10 years after surgery was 1.0609, assuming a 3.5% annual discounting rate. The average cost of the surgery was $3166. The average cost per QALY was $2985 when benefits of the surgery were assumed to accrue for 10 years. The cost per QALY was higher for women ($3821) compared with men ($2485). Participants over the age of 70 had the highest cost per QALY ($8079/QALY)., Conclusions: Haemorrhoidectomies have been associated with significant gains in health status and are inexpensive relative to the associated gains in quality of life based on patients' perspectives of their improvement in health and well-being., (© 2024 The Authors. Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

Background: Delirium is a common complication during acute care hospitalizations in older adults. A substantial percentage of admissions are for ambulatory care-sensitive conditions (ACSCs) or potentially avoidable hospitalizations-conditions that might be treated early in the outpatient setting to prevent hospitalization and hospital complications., Methods: This retrospective cross-sectional study examined rates of delirium among older adults hospitalized for ACSCs. Participants were 39 933 older adults ≥65 years of age admitted from January 1, 2015 to December 31, 2019 to general inpatient units and ICUs of a large Southeastern academic medical center. Delirium was defined as a score ≥ 2 on the Nursing Delirium Screening Scale or positive on the Confusion Assessment Method for the Intensive Care Unit during admission, and ACSCs were identified from the primary admission diagnosis using standardized definitions. Generalized linear mixed models were used to examine the association between ACSCs and delirium, compared with admissions for non-ACSC diagnoses, adjusting for covariates and repeated observations for individuals with multiple admissions., Results: Delirium occurred in 15.6% of admissions for older adults. Rates were lower for ACSC admissions versus admissions for other conditions (13.9% vs 15.8%, p < .001). Older age and higher comorbidity were significant predictors of the development of delirium., Conclusions: Rates of delirium among older adults hospitalized for ACSCs were lower than rates for non-ACSC hospitalization but still substantial. Optimizing the treatment of ACSCs in the outpatient setting is an important goal not only for reducing hospitalizations but also for reducing risks for hospital-associated complications such as delirium., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Water availability for human and ecological uses depends on both water quantity and water quality. The U.S. Geological Survey (USGS) is developing strategies for prioritizing regional-scale and watershed basin-scale studies of water availability across the nation. Previous USGS ranking processes for basin-scale studies incorporated primarily water quantity factors but are now considering additional water quality factors. This study presents a ranking based on the potential impacts of geogenic constituents on water quality and consideration of societal factors related to water quality. High-concentration geogenic constituents, including trace elements and radionuclides, are among the most prevalent contaminants limiting water availability in the USA and globally. Geogenic constituents commonly occur in groundwater because of subsurface water-rock interactions, and their distributions are controlled by complex geochemical processes. Geogenic constituent mobility can also be affected by human activities (e.g., mining, energy production, irrigation, and pumping). Societal factors and relations to drinking water sources and water quality information are often overlooked when evaluating research priorities. Sociodemographic characteristics, data gaps resulting from historical data-collection disparities, and infrastructure condition/age are examples of factors to consider regarding environmental justice. This paper presents approaches for ranking and prioritizing potential basin-scale study areas across the contiguous USA by considering a suite of conventional physical and geochemical variables related to geogenic constituents, with and without considering variables related to societal factors. Simultaneous consideration of societal and conventional factors could provide decision makers with more diverse, interdisciplinary tools to increase equity and reduce bias in prioritizing focused research areas and future water availability studies., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Life-space mobility, which measures the distance, frequency, and independence achieved as individuals move through their community, is one of the most important contributors to healthy aging. The University of Alabama at Birmingham Life-Space Assessment (LSA) is the most commonly used measure of life-space mobility in older adults, yet U.S. national norms for LSA have not previously been reported. This study reports such norms based on age and sex among community-dwelling older adults., Methods: A cross-sectional analysis using data from the national REasons for Geographic and Racial Disparities in Stroke cohort study. LSA data were available for 10 118 Black and White participants over age 50, which were grouped by age (in 5-year increments) and sex, weighted for the U.S. national population. Correlations were calculated between LSA and measures of functional and cognitive impairment and physical performance., Results: The weighted mean LSA ranged from 102.9 for 50-54-year-old males to 69.5 for males aged 85 and older, and from 102.1 for 50-54-year-old females to 60.1 for females aged 85 and older. LSA was strongly correlated with measures of timed walking, activities of daily living, cognition, depressive symptoms, and quality of life (all p < .001)., Conclusions: We report U.S. national norms for LSA among community-dwelling Black and White older adults. These norms can serve as a reference tool for determining if clinical and research samples have greater or lesser life-space mobility than typical older adults in the United States for their age and sex., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Crystallization kinetic parameter estimation is important for the classification, design, and scale-up of pharmaceutical manufacturing processes. This study investigates the impact of supersaturation and temperature on the induction time, nucleation rate, and growth rate for the compounds lamivudine (slow kinetics) and aspirin (fast kinetics). Adaptive Bayesian optimization (AdBO) has been used to predict experimental conditions that achieve target crystallization kinetic values for each of these parameters of interest. The use of AdBO to guide the choice of the experimental conditions reduced material usage up to 5-fold when compared to a more traditional statistical design of experiments (DoE) approach. The reduction in material usage demonstrates the potential of AdBO to accelerate process development as well as contribute to Net-Zero and green chemistry strategies. Implementation of AdBO can lead to reduced experimental effort and increase efficiency in pharmaceutical crystallization process development. The integration of AdBO into the experimental development workflows for crystallization development and kinetic experiments offers a promising avenue for advancing the field of autonomous data collection exploiting digital technologies and the development of sustainable chemical processes., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Peptides are promising drug modalities that can modulate protein-protein interactions, but their application is hampered by their limited ability to reach intracellular targets. Here, we improved the cytosolic delivery of a peptide blocking p53:MDM2/X interactions using a cyclotide as a stabilizing scaffold. We applied several design strategies to improve intracellular delivery and found that the conjugation of the lead cyclotide to the cyclic cell-penetrating peptide cR10 was the most effective. Conjugation allowed cell internalization at micromolar concentration and led to elevated intracellular p53 levels in A549, MCF7, and MCF10A cells, as well as inducing apoptosis in A549 cells without causing membrane disruption. The lead peptide had >35-fold improvement in inhibitory activity and increased cellular uptake compared to a previously reported cyclotide p53 activator. In summary, we demonstrated the delivery of a large polar cyclic peptide in the cytosol and confirmed its ability to modulate intracellular protein-protein interactions involved in cancer.

Lithium (Li) concentrations in drinking-water supplies are not regulated in the United States; however, Li is included in the 2022 U.S. Environmental Protection Agency list of unregulated contaminants for monitoring by public water systems. Li is used pharmaceutically to treat bipolar disorder, and studies have linked its occurrence in drinking water to human-health outcomes. An extreme gradient boosting model was developed to estimate geogenic Li in drinking-water supply wells throughout the conterminous United States. The model was trained using Li measurements from ∼13,500 wells and predictor variables related to its natural occurrence in groundwater. The model predicts the probability of Li in four concentration classifications, ≤4 μg/L, >4 to ≤10 μg/L, >10 to ≤30 μg/L, and >30 μg/L. Model predictions were evaluated using wells held out from model training and with new data and have an accuracy of 47-65%. Important predictor variables include average annual precipitation, well depth, and soil geochemistry. Model predictions were mapped at a spatial resolution of 1 km 2 and represent well depths associated with public- and private-supply wells. This model was developed by hydrologists and public-health researchers to estimate Li exposure from drinking water and compare to national-scale human-health data for a better understanding of dose-response to low (<30 μg/L) concentrations of Li.

Although stapled α-helical peptides can address challenging targets, their advancement is impeded by poor understandings for making them cell permeable while avoiding off-target toxicities. By synthesizing >350 molecules, we present workflows for identifying stapled peptides against Mdm2(X) with in vivo activity and no off-target effects. Key insights include a clear correlation between lipophilicity and permeability, removal of positive charge to avoid off-target toxicities, judicious anionic residue placement to enhance solubility/behavior, optimization of C-terminal length/helicity to enhance potency, and optimization of staple type/number to avoid polypharmacology. Workflow application gives peptides with >292x improved cell proliferation potencies and no off-target cell proliferation effects ( > 3800x on-target index). Application of these 'design rules' to a distinct Mdm2(X) peptide series improves ( > 150x) cellular potencies and removes off-target toxicities. The outlined workflow should facilitate therapeutic impacts, especially for those targets such as Mdm2(X) that have hydrophobic interfaces and are targetable with a helical motif., (© 2024. Merck & Co., Inc., Rahway, NJ, USA and its affiliates and Tsz Ying Yuen, Diana Spiegelberg, Pietro G. Aronica, Yee Hwee Lim, Marika Nestor, Chandra S. Verma, David P. Lane, Srinivasaraghavan Kannan, Christopher J. Brown, Charles W. Johannes.)

Background: Despite a better understanding of the increasing incidence of young-onset colorectal cancer (yCRC; age at diagnosis <50 years), little is known about its economic burden. Therefore, we estimated direct medical spending on yCRC before and after diagnosis., Methods: We used linked administrative health databases in British Columbia, Canada, to create a study population of yCRC and average-age onset colorectal cancer (aCRC; age at diagnosis ≥50 years) cases, along with cancer-free controls. Over the 1-year period preceding a colorectal cancer diagnosis, we estimated direct medical spending on hospital visits, healthcare practitioners, and prescription medications. After diagnosis, we calculated cost attributable to yCRC and aCRC, which additionally included the cost of cancer treatments (e.g., chemotherapy and radiotherapy) across phases of care., Results: We included 1,058 yCRC (45.4% females; age at diagnosis 42.4 ± 6.2 years) and 12,619 aCRC (44.8% females; age at diagnosis of 68.1 ± 9.2 years) cases. Direct medical spending on the average yCRC and aCRC case during the year before diagnosis was $6,711 and $8,056, respectively. After diagnosis, the overall average annualized cost attributable to yCRC significantly differed in comparison with aCRC for the initial ($50,216 vs. $37,842; P < 0.001), continuing ($8,361 vs. $5,014; P < 0.001), and end-of-life cancer phase ($86,125 vs. $61,512; P < 0.001) but not end-of-life non-cancer phase ($77,273 vs. $23,316; P = 0.372)., Conclusions: Reported cost estimates may be used as inputs for future economic evaluations pertaining to yCRC., Impact: We provided comprehensive cost estimates for healthcare spending on young-onset colorectal cancer., (©2023 The Authors; Published by the American Association for Cancer Research.)

Modern deep learning training procedures rely on model regularization techniques such as data augmentation methods, which generate training samples that increase the diversity of data and richness of label information. A popular recent method, mixup , uses convex combinations of pairs of original samples to generate new samples. However, as we show in our experiments, mixup  can produce undesirable synthetic samples, where the data is sampled off the manifold and can contain incorrect labels. We propose ζ - mixup , a generalization of mixup  with provably and demonstrably desirable properties that allows convex combinations of T ≥ 2 samples, leading to more realistic and diverse outputs that incorporate information from T original samples by using a p -series interpolant. We show that, compared to mixup , ζ - mixup  better preserves the intrinsic dimensionality of the original datasets, which is a desirable property for training generalizable models. Furthermore, we show that our implementation of ζ - mixup  is faster than mixup , and extensive evaluation on controlled synthetic and 26 diverse real-world natural and medical image classification datasets shows that ζ - mixup  outperforms mixup , CutMix, and traditional data augmentation techniques. The code will be released at https://github.com/kakumarabhishek/zeta-mixup., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2024.)

Amelogenesis imperfecta (AI) comprises a group of rare, inherited disorders with abnormal enamel formation. Ameloblastin (AMBN), the second most abundant enamel matrix protein (EMP), plays a critical role in amelogenesis. Pathogenic biallelic loss-of-function AMBN variants are known to cause recessive hypoplastic AI. A report of a family with dominant hypoplastic AI attributed to AMBN missense change p.Pro357Ser, together with data from animal models, suggests that the consequences of AMBN variants in human AI remain incompletely characterized. Here we describe 5 new pathogenic AMBN variants in 11 individuals with AI. These fall within 3 groups by phenotype. Group 1, consisting of 6 families biallelic for combinations of 4 different variants, have yellow hypoplastic AI with poor-quality enamel, consistent with previous reports. Group 2, with 2 families, appears monoallelic for a variant shared with group 1 and has hypomaturation AI of near-normal enamel volume with pitting. Group 3 includes 3 families, all monoallelic for a fifth variant, which are affected by white hypoplastic AI with a thin intact enamel layer. Three variants, c.209C>G; p.(Ser70*) (groups 1 and 2), c.295T>C; p.(Tyr99His) (group 1), and c.76G>A; p.(Ala26Thr) (group 3) were identified in multiple families. Long-read AMBN locus sequencing revealed these variants are on the same conserved haplotype, implying they originate from a common ancestor. Data presented therefore provide further support for possible dominant as well as recessive inheritance for AMBN -related AI and for multiple contrasting phenotypes. In conclusion, our findings suggest pathogenic AMBN variants have a more complex impact on human AI than previously reported., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: As coronavirus disease 2019 (COVID-19) spread, efforts were made to preserve resources for the anticipated surge of COVID-19 patients in British Columbia, Canada. However, the relationship between COVID-19 hospitalizations and access to cancer surgery is unclear. In this project, we analyze the impact of COVID-19 patient volumes on wait time for cancer surgery., Methods: We conducted a retrospective study using population-based datasets of regional surgical wait times and COVID-19 patient volumes. Weekly median wait times for urgent, nonurgent, cancer, and noncancer surgeries, and maximum volumes of hospitalized patients with COVID-19 were studied. The results were qualitatively analyzed., Results: A sustained association between weekly median wait time for priority and other cancer surgeries and increase hospital COVID-19 patient volumes was not qualitatively discernable. In response to the first phase of COVID-19 patient volumes, relative to pre-COVID-19 pandemic levels, wait time were shortened for urgent cancer surgery but increased for nonurgent surgeries. During the second phase, for all diagnostic groups, wait times returned to pre-COVID-19 pandemic levels. During the third phase, wait times for all surgeries increased., Conclusion: Cancer surgery access may have been influenced by other factors, such as policy directives and local resource issues, independent of hospitalized COVID-19 patient volumes. The initial access limitations gradually improved with provincial and institutional resilience, and vaccine rollout.

Mangrove forests support unique biodiversity and provide a suite of ecosystem services (ES) that benefit people. Decades of continual mangrove loss and degradation have necessitated global efforts to protect and restore this important ecosystem. Generating and evaluating asset maps of biodiversity and ES is an important precursor to identifying locations that can deliver conservation outcomes across varying scales, such as maximising the co-occurrence of specific ES. We bring together global datasets on mangrove-affiliated biodiversity, carbon stocks, fish and invertebrate production, and coastal protection to provide insight into potential trade-offs, synergies and opportunities from mangrove conservation. We map opportunities where high ES provision co-occurs with these areas that could be leveraged in conservation planning, and identify potential high-value opportunities for single ES that might otherwise be missed with a biodiversity focus. Hotspots of single ES, co-occurrence of multiple ES, and opportunities to simultaneously leverage biodiversity and ES occurred throughout the world. For example, efforts that focus on conserving or restoring mangroves to store carbon can be targed to deliver multiple ES benefits. Some nations, such as Vietnam, Oman, Ecuador and China, showed consistent (although not necessarily strong) correlations between ES pairs. A lack of clear or consistent spatial trends elsewhere suggests that some nations will likely benefit more from complementarity-based approaches that focus on multiple sites with high provision of different services. Individual sites within these nations, however, such as Laguna de Terminos in Mexico still provide valuable opportunities to leverage co-benefits. Ensuring that an ES focused approach is complemented by strategic spatial planning is a priority, and our analyses provide a precursor towards decisions about where and how to invest., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The silencing of all but one X chromosome in mammalian cells is a remarkable epigenetic process leading to near dosage equivalence in X-linked gene products between the sexes. However, equally remarkable is the ability of a subset of genes to continue to be expressed from the otherwise inactive X chromosome-in some cases constitutively, while other genes are variable between individuals, tissues or cells. In this review we discuss the advantages and disadvantages of the approaches that have been used to identify escapees. The identity of escapees provides important clues to mechanisms underlying escape from XCI, an arena of study now moving from correlation to functional studies. As most escapees show greater expression in females, the not-so-inactive X chromosome is a substantial contributor to sex differences in humans, and we highlight some examples of such impact.

Ecosystems are increasingly affected by multiple anthropogenic stressors that contribute to habitat degradation and loss. Natural ecosystems are highly dynamic, yet multiple stressor experiments often ignore variability in stressor intensity and do not consider how effects could be mediated across trophic levels, with implications for models that underpin stressor management. Here, we investigated the in situ effects of changes in stressor intensity (i.e., fluctuations) and synchronicity (i.e., timing of fluctuations) on a seagrass community, applying the stressors reduced light and physical disturbance to the sediment. We used structural equation models (SEMs) to identify causal effects of dynamic multiple stressors on seagrass shoot density and leaf surface area, and abundance of associated crustaceans. Responses depended on whether stressor intensities fluctuated or remained static. Relative to static stressor exposure at the end of the experiment, shoot density, leaf surface area, and crustacean abundance all declined under in-phase (synchronous; 17, 33, and 30 % less, respectively) and out-of-phase (asynchronous; 11, 28, and 39 % less, respectively) fluctuating treatments. Static treatment increased seagrass leaf surface area and crustacean abundance relative to the control group. We hypothesised that crustacean responses are mediated by changes in seagrass; however, causal analysis found only weak evidence for a mediation effect via leaf surface area. Changes in crustacean abundance, therefore, were primarily a direct response to stressors. Our results suggest that the mechanisms underpinning stress responses change when stressors fluctuate. For instance, increased leaf surface area under static stress could be caused by seagrass acclimating to low light, whereas no response under fluctuating stressors suggests an acclimation response was not triggered. The SEMs also revealed that community responses to the stressors can be independent of one another. Therefore, models based on static experiments may be representing ecological mechanisms not observed in natural ecosystems, and underestimating the impacts of stressors on ecosystems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Acoustic backscatter has been used as a tool to map the seafloor in greater detail and plays an increasingly important role in seafloor mapping to meet multiple ocean management needs. An outstanding challenge to the use of backscatter for seafloor mapping is the distinction between acoustically similar substrates, such as mixed sediments from rhodoliths. Rhodolith beds are a biogenic substrate that provides important ecological services, and are typically classified as a single categorical substrate type-though nodules coverage may be spatially variable. Recently, multispectral acoustic backscatter has demonstrated great potential to improve thematic seafloor mapping compared to single-frequency systems. This work employs multispectral multibeam backscatter and underwater imagery to characterize and map rhodolith beds in the Costa das Algas Marine Protected Area (Brazil). A support vector machine classifier was used to classify multifrequency backscatter mosaics according to rhodolith classes identified from underwater imagery. Results suggest that multispectral backscatter is effective both in providing information for mapping different proportions of rhodolith coverage and in predicting the presence or absence of these nodules. The backscatter of the lowest frequency was the most useful for distinguishing variable proportions of rhodolith coverage, and the two higher frequencies were better predictors of presence and absence., (© 2023. The Author(s).)

This is a case of a neonate with suspected duodenal atresia on prenatal imaging. However, distal bowel gas was identified postnatally on regular X-rays with a possible pyloric obstructing mass visualised on ultasound. No contrast was visualised passing through the stomach on fluoroscopic studies. Operative evaluation revealed an atypical asymmetric hypertrophic pylorus with exophytic lesions of ectopic glandular tissue. Longitudinal open pyloromyotomy was performed which relieved the gastric obstruction resulting in symptomatic relief without any anatomy altering procedure required., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

DAXX (Death Domain Associated Protein 6) is frequently upregulated in various common cancers, and its suppression has been linked to reduced tumor progression. Consequently, DAXX has gained significant interest as a therapeutic target in such cancers. DAXX is known to function in several critical biological pathways including chromatin remodelling, transcription regulation, and DNA repair. Leveraging structural information, we have designed and developed a novel set of stapled/stitched peptides that specifically target a surface on the N-terminal helical bundle domain of DAXX. This surface serves as the anchor point for binding to multiple interaction partners, such as Rassf1C, p53, Mdm2, and ATRX, as well as for the auto-regulation of the DAXX N-terminal SUMO interaction motif (SIM). Our experiments demonstrate that these peptides effectively bind to and inhibit DAXX with a higher affinity than the known interaction partners. Furthermore, these peptides release the auto-inhibited SIM, enabling it to interact with SUMO-1. Importantly, we have developed stitched peptides that can enter cells, maintaining their intracellular concentrations at nanomolar levels even after 24 hours, without causing any membrane perturbation. Collectively, our findings suggest that these stitched peptides not only serve as valuable tools for probing the molecular interactions of DAXX but also hold potential as precursors to the development of therapeutic interventions., Competing Interests: The authors declare no conflicts of interest., (This journal is © The Royal Society of Chemistry.)