Nacc1 Mutation in Mice Models Rare Neurodevelopmental Disorder with Underlying Synaptic Dysfunction.

A missense mutation in the transcription repressor Nucleus accumbens-associated 1 (NACC1) gene at c.892C>T (p.Arg298Trp) on chromosome 19 causes severe neurodevelopmental delay ( Schoch et al., 2017). To model this disorder, we engineered the first mouse model with the homologous mutation (Nacc1+/R284W ) and examined mice from E17.5 to 8 months. Both genders had delayed weight gain, epileptiform discharges and altered power spectral distribution in cortical electroencephalogram, behavioral seizures, and marked hindlimb clasping; females displayed thigmotaxis in an open field. In the cortex, NACC1 long isoform, which harbors the mutation, increased from 3 to 6 months, whereas the short isoform, which is not present in humans and lacks aaR284 in mice, rose steadily from postnatal day (P) 7. Nuclear NACC1 immunoreactivity increased in cortical pyramidal neurons and parvalbumin containing interneurons but not in nuclei of astrocytes or oligodendroglia. Glial fibrillary acidic protein staining in astrocytic processes was diminished. RNA-seq of P14 mutant mice cortex revealed over 1,000 differentially expressed genes (DEGs). Glial transcripts were downregulated and synaptic genes upregulated. Top gene ontology terms from upregulated DEGs relate to postsynapse and ion channel function, while downregulated DEGs enriched for terms relating to metabolic function, mitochondria, and ribosomes. Levels of synaptic proteins were changed, but number and length of synaptic contacts were unaltered at 3 months. Homozygosity worsened some phenotypes including postnatal survival, weight gain delay, and increase in nuclear NACC1. This mouse model simulates a rare form of autism and will be indispensable for assessing pathophysiology and targets for therapeutic intervention.

Patterns of initial distant metastases in 151 patients undergoing surveillance for treated Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is associated with high rates of recurrence and distant metastatic progression. Current guidelines for surveillance imaging are not evidence based. Better characterization of the pattern of distant metastatic spread will better inform surveillance and facilitate earlier detection of metastases. OBJECTIVES: This retrospective study aimed to assess potential relationships between primary tumour site and site of initial distant metastasis, time to distant metastasis, overall survival (OS) and MCC-specific death (MSD). METHODS: Patients with local or regional (Stage I-III) disease who were treated with curative intent and progressed to Stage IV were included in this study (n = 151). Fisher's exact test was used to assess differences in patterns of initial distant metastases based on primary tumour site. Time to initial distant metastasis was calculated from date of MCC diagnosis. OS and MSD were calculated from date of initial distant metastasis to date of death from any or MCC-related causes, respectively. RESULTS: Of 151 patients included in analysis, 89 (58.9%) had a single initial distant metastatic site, and 62 (41.1%) had multiple sites. Patients with upper limb primary tumours were significantly less likely to develop distant lymph node or liver metastases (p = 0.02 and 0.04, respectively). Median time to distant metastasis was 11 months (IQR 6.7-17.9 months). Median OS was 15.3 months, and was shorter for patients with liver (7.0 months, p = 0.0004) or bone metastases (8.9 months, p < 0.0001). Using skin/soft tissue metastasis as a reference group, patients with multiple metastatic sites had significantly higher hazards of MSD (HR = 3.46 univariate, 3.77 multivariate analysis). Time to distant metastasis, OS and MSD did not differ by viral status. CONCLUSION: Sites of initial distant metastasis are related to primary tumour sites and survival outcomes. Because patients often have multiple initial metastases, full-body cross-sectional rather than region-specific imaging may facilitate earlier detection of metastatic disease.

Genetic Testing Resources and Practice Patterns Among Pediatric Cardiomyopathy Programs.

The use of genetic testing has enhanced the diagnostic accuracy of heritable genetic cardiomyopathies. However, it remains unclear how genetic information is interpreted and incorporated into clinical practice for children with cardiomyopathy. The primary aim of this study was to understand how clinical practice differs regarding sequence variant classifications amongst pediatric cardiologists who treat children with cardiomyopathy. A secondary aim was to understand the availability of genetic testing and counseling resources across participating pediatric cardiomyopathy programs. An electronic survey was distributed to pediatric heart failure, cardiomyopathy, or heart transplantation physicians between August and September 2022. A total of 106 individual providers from 68 unique centers responded to the survey. Resources for genetic testing and genetic counseling vary among large pediatric cardiomyopathy programs. A minority of centers reported having a geneticist (N = 16, 23.5%) or a genetic counselor (N = 21, 31%) on faculty within the division of pediatric cardiology. A total of 9 centers reported having both (13%). Few centers (N = 13, 19%) have a formal process in place to re-engage patients who were previously discharged from cardiology follow-up if variant reclassification would alter clinical management. Clinical practice patterns were uniform in response to pathogenic or likely pathogenic variants but were more variable for variants of uncertain significance. Efforts to better incorporate genetic expertise and resources into the clinical practice of pediatric cardiomyopathy may help to standardize the interpretation of genetic information and better inform clinical decision-making surrounding heritable cardiomyopathies.

Pain Control Associated With Gabapentinoid Prescription After Elective Total Knee Arthroplasty.

BACKGROUND: Gabapentinoid (GABA) prescribing has substantially increased as a nonopioid analgesics for surgical conditions. We examined the effectiveness of GABA use for postoperative pain control among patients receiving total knee arthroplasty (TKA). METHODS: This retrospective cohort study using 2016 to 2019 data from a 20% national sample of Medicare enrollees included patients aged 66 and over years who received an elective TKA, were discharged to home, received home health care, and had both admission and discharge assessments of pain (n = 35,186). Study outcomes were pain score difference between admission and discharge and less-than-daily pain interfering with activity at discharge. Opioid and GABA prescriptions after surgery and receipt of nerve block within 3 days of surgery were also assessed. RESULTS: There were 30% of patients who had a pain score decrease of 3 to 4 levels and 55.8% had pain score decreases of 1 to 2 levels. In multivariable analyses, receiving a nerve block was significantly associated with pain score reduction. A GABA prescription increased the magnitude of pain score reduction among those receiving a nerve block. Results from inverse probability weighted analysis with propensity score showed that coprescribing of GABA and low-dose opioid was associated with significantly lower pain scores. CONCLUSIONS: Post-TKA opioid use was not associated with pain score reduction. Receiving a nerve block was associated with a modest pain score reduction. Co-prescribing GABA with low-dose opioid or receiving a nerve block was associated with increasing magnitudes of pain reduction. Further research should identify alternatives to opioid use for managing postoperative TKA pain.

Scope of practice of oculofacial plastic and reconstructive surgeons: a public perception survey.

PURPOSE: The purpose of this study is to determine the public's perception of the scope of practice for oculofacial plastic and reconstructive surgeons (OFPRS). METHODS: A 49-question survey was distributed by QualtricsⓇ to a panel similar to the US demographic composition. Responses collected underwent bivariate statistical analysis. RESULT: A total of 530 responses were obtained, with most respondents being white, female, over the age of 35, from the Midwest, and with at least a college education or above. Most respondents did not think ophthalmologists or optometrists were surgeons, and only 158 people (29.8%) knew the primary specialty of OFPRS was ophthalmology. Board certification was preferred by 98.87% of respondents, and 95.28% preferred ASOPRS-trained OFPRS. CONCLUSIONS: Our study highlights the gap in knowledge about OFPRS as a field, the qualifications and training required, and the scope of practice. Notably, even for OFPRS-specific procedures, PRS remained the leading subspecialist chosen for interventions such as orbital decompression (58.5% vs. 71.5%), orbital reconstruction (57.9% vs. 74.2%), enucleation/evisceration (48.1% vs. 53.4%), optic nerve-related surgery (39.8% vs. 43.4%), orbital cancer resection (42.8% vs. 46.8%), and tear duct surgery (41.9% vs. 52.5%). Additionally, most respondents did not feel that facial fillers, laser skin resurfacing, eyelid cancer removal, or cataract surgery were within the OFPRS scope of practice.

Loss of Oxidation Resistance 1, OXR1, Is Associated with an Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction.

We report an early-onset autosomal-recessive neurological disease with cerebellar atrophy and lysosomal dysfunction. We identified bi-allelic loss-of-function (LoF) variants in Oxidative Resistance 1 (OXR1) in five individuals from three families; these individuals presented with a history of severe global developmental delay, current intellectual disability, language delay, cerebellar atrophy, and seizures. While OXR1 is known to play a role in oxidative stress resistance, its molecular functions are not well established. OXR1 contains three conserved domains: LysM, GRAM, and TLDc. The gene encodes at least six transcripts, including some that only consist of the C-terminal TLDc domain. We utilized Drosophila to assess the phenotypes associated with loss of mustard (mtd), the fly homolog of OXR1. Strong LoF mutants exhibit late pupal lethality or pupal eclosion defects. Interestingly, although mtd encodes 26 transcripts, severe LoF and null mutations can be rescued by a single short human OXR1 cDNA that only contains the TLDc domain. Similar rescue is observed with the TLDc domain of NCOA7, another human homolog of mtd. Loss of mtd in neurons leads to massive cell loss, early death, and an accumulation of aberrant lysosomal structures, similar to what we observe in fibroblasts of affected individuals. Our data indicate that mtd and OXR1 are required for proper lysosomal function; this is consistent with observations that NCOA7 is required for lysosomal acidification.

Adaptation of an Evidence-Based Intervention for Disability Prevention, Implemented by Community Health Workers Serving Ethnic Minority Elders.

INTRODUCTION: Changing demographics have created substantial unmet needs for mental health and physical disability services for immigrant and racial/ethnic minority elders. Workforce shortages can be reduced by task-shifting to community health workers (CHWs) who speak the same language and share the culture of these elders. Yet, implementation of interventions offered by CHWs requires adaptations of content and delivery, ideally under clinical supervision. OBJECTIVE: To culturally adapt two evidence-based interventions, offered in community settings, to address mental health and physical disability prevention for diverse minority elders. METHODS: We followed the Castro-Barrera stepped model for cultural adaptation of two evidence-based interventions into one combined program of disability management and prevention delivered by CHWs. We used feedback from key stakeholders, including four clinical supervisors, 16 CHWs, 17 exercise trainers, and 153 participants, collected at three time points to further adapt the intervention to a diverse population of elders. RESULTS: Adaptations for administration by CHWs/exercise trainers included: systematization of supervision process, increased flexibility in sessions offered per participants' needs, inclusion of self-care content, modification of materials to better reflect elders' daily life experiences, and greater focus on patient engagement in care. Areas for additional adaptation included enhancing examples with culturally relevant metaphors, incorporating visual aids, and training CHWs in the importance of building trust. CONCLUSION: This study identifies key aspects of the cultural adaptation process that facilitates broader cultural sensitivity of service delivery by CHWs to diverse elders in community settings.

Predictors of Enrollment of Older Smokers in Six Smoking Cessation Trials in the Lung Cancer Screening Setting: The Smoking Cessation at Lung Examination (SCALE) Collaboration.

SIGNIFICANCE: Increased rates of smoking cessation will be essential to maximize the population benefit of low-dose CT screening for lung cancer. The NCI's Smoking Cessation at Lung Examination (SCALE) Collaboration includes eight randomized trials, each assessing evidence-based interventions among smokers undergoing lung cancer screening (LCS). We examined predictors of trial enrollment to improve future outreach efforts for cessation interventions offered to older smokers in this and other clinical settings. METHODS: We included the six SCALE trials that randomized individual participants. We assessed demographics, intervention modalities, LCS site and trial administration characteristics, and reasons for declining. RESULTS: Of 6285 trial- and LCS-eligible individuals, 3897 (62%) declined and 2388 (38%) enrolled. In multivariable logistic regression analyses, Blacks had higher enrollment rates (OR 1.5, 95% CI 1.2,1.8) compared to Whites. Compared to "NRT Only" trials, those approached for "NRT + prescription medication" trials had higher odds of enrollment (OR 6.1, 95% CI 4.7,7.9). Regarding enrollment methods, trials using "Phone + In Person" methods had higher odds of enrollment (OR 1.6, 95% CI 1.2,1.9) compared to trials using "Phone Only" methods. Some of the reasons for declining enrollment included "too busy" (36.6%), "not ready to quit" (8.2%), "not interested in research" (7.7%), and "not interested in the intervention offered" (6.2%). CONCLUSION: Enrolling smokers in cessation interventions in the LCS setting is a major priority that requires multiple enrollment and intervention modalities. Barriers to enrollment provide insights that can be addressed and applied to future cessation interventions to improve implementation in LCS and other clinical settings with older smokers. IMPLICATIONS: We explored enrollment rates and reasons for declining across six smoking cessation trials in the lung cancer screening setting. Offering multiple accrual methods and pharmacotherapy options predicted increased enrollment across trials. Enrollment rates were also greater among Blacks compared to Whites. The findings offer practical information for the implementation of cessation trials and interventions in the lung cancer screening context and other clinical settings, regarding intervention modalities that may be most appealing to older, long-term smokers.

Path analysis of survivorship care needs, symptom experience, and quality of life among multiethnic cancer survivors.

PURPOSE: Cancer survivors continue to experience issues that persist across the survivorship trajectory. This study aims to explore the relationship among survivorship care need, symptom experience, and quality of life (QoL) of multiethnic cancer survivors by using path analytic methods. METHODS: Participants were recruited from an academic medical center in Singapore that provides inpatient and outpatient oncology and hematology service. The Cancer Survivor Unmet Needs measure, physical effects subscale of the Cancer Survivors' Survey of Needs tool, and a Global QoL 10-point Likert scale were used to identify survivorship care needs, symptom experience, and QoL. Descriptive statistics were used to compute sociodemographic information, total survivorship needs, symptom experienced, and quality of life scores. The symptom experience model was used as the hypothetical model. The Analysis of Moment Structure was used to conduct the path analysis to evaluate the relationship between survivorship care needs, symptom experience, and quality of life. RESULTS: Older cancer survivors were more likely to have spent a longer duration having cancer. Males were unlikely to suffer from solid tumor malignancies. Survivors with solid tumor malignancies were less likely to require supportive care. Survivors who require more supportive care were more likely to have a greater symptom burden. Cancer survivors with more symptoms have poorer QoL. The findings from this study partially supported the symptom experience model. CONCLUSIONS: Our findings reveal that cancer survivors continue to experience symptoms across the survivorship trajectory. The results provide information for nurses during the planning and execution of survivorship care.

Treatment with an immature dendritic cell-targeting vaccine supplemented with IFN-α and an inhibitor of DNA methylation markedly enhances survival in a murine melanoma model.

BACKGROUND: The chemokine MIP-3α (CCL20) binds to CCR6 on immature dendritic cells. DNA vaccines fusing MIP-3α to melanoma-associated antigens have shown improved efficacy and immunogenicity in the B16F10 mouse melanoma model. Here, we report that the combination of type-I interferon therapy (IFNα) with 5-Aza-2'-deoxycitidine (5Aza) profoundly enhanced the therapeutic efficacy of a MIP-3α-Gp100-Trp2 DNA vaccine. METHODS: Beginning on day 5 post-transplantation of B16F10 melanoma, vaccine was administered intramuscularly (i.m.) by electroporation. CpG adjuvant was given 2 days later. 5Aza was given intraperitoneally at 1 mg/kg and IFNα therapy either intratumorally or i.m. as noted. Tumor sizes, tumor growth, and mouse survival were assessed. Tumor lysate gene expression levels and tumor-infiltrating lymphocytes (TILs) were assessed by qRT-PCR and flow cytometry, respectively. RESULTS: Adding IFNα and 5Aza treatments to mice vaccinated with MIP-3α-Gp100-Trp2 leads to reduced tumor burden and increased median survival (39% over vaccine and 95% over controls). Tumor lysate expression of CCL19 and CCR7 were upregulated ten and fivefold over vaccine, respectively. Vaccine-specific and overall CD8+ TILs were increased over vaccine (sevenfold and fourfold, respectively), as well as the proportion of TILs that were CD8+ (twofold). CONCLUSIONS: Efficient targeting of antigen to immature dendritic cells with a chemokine-fusion vaccine offers an alternative to classic and dendritic cell vaccines. Combining this approach with IFNα and 5Aza treatment significantly improved vaccine efficacy. This improved efficacy correlated with changes in chemokine gene expression and CD8+ TIL infiltration and was dependent on the presence of all therapeutic components.

A Clinical Teaching Blended Learning Program to Enhance Registered Nurse Preceptors' Teaching Competencies: Pretest and Posttest Study.

BACKGROUND: Clinical nursing education provides opportunities for students to learn in multiple patient care settings, receive appropriate guidance, and foster the development of clinical competence and professionalism. Nurse preceptors guide students to integrate theory into practice, teach clinical skills, assess clinical competencies, and enhance problem-solving and critical thinking skills. Previous research has indicated that the teaching competencies of nurse preceptors can be transferred to students' clinical learning to enhance their clinical competencies. OBJECTIVE: This study aimed to develop a clinical teaching blended learning (CTBL) program with the aid of web-based clinical pedagogy (WCP) and case-based learning for nurse preceptors and to examine the effectiveness of the CTBL program on nurse preceptors' clinical teaching competencies, self-efficacies, attitudes toward web-based learning, and blended learning outcomes. METHODS: A quasi-experimental single-group pretest and posttest design was adopted. A total of 150 nurse preceptors participated in the CTBL program, which was conducted from September 2019 to December 2019. A set of questionnaires, including the clinical teaching competence inventory, preceptor self-efficacy questionnaire, attitudes toward web-based continuing learning survey, and e-learning experience questionnaire, was used to assess the outcomes before and after the CTBL program. RESULTS: Compared with the baseline, the participants had significantly higher total mean scores and subdomain scores for clinical teaching competence (mean 129.95, SD 16.38; P<.001), self-efficacy (mean 70.40, SD 9.35; P<.001), attitudes toward web-based continuing learning (mean 84.68, SD 14.76; P<.001), and blended learning outcomes (mean 122.13, SD 14.86; P<.001) after the CTBL program. CONCLUSIONS: The CTBL program provides a comprehensive coverage of clinical teaching pedagogy and assessment strategies. The combination of the WCP and case-based approach provides a variety of learning modes to fit into the diverse learning needs of the preceptors. The CTBL program allows the preceptors to receive direct feedback from the facilitators during face-to-face sessions. Preceptors also gave feedback that the web-based workload is manageable. This study provides evidence that the CTBL program increases the clinical teaching competencies and self-efficacies of the preceptors and promotes positive attitudes toward web-based learning and better blended learning outcomes. The health care organization can consider the integration of flexible learning and intellect platforms for preceptorship education.

The importance of using multiple outcome measures in infant research.

Collecting data with infants is notoriously difficult. As a result, many of our studies consist of small samples, with only a single measure, in a single age group, at a single time point. With renewed calls for greater academic rigor in data collection practices, using multiple outcome measures in infant research is one way to increase rigor, and, at the same time, enable us to more accurately interpret our data. Here, we illustrate the importance of using multiple measures in psychological research with examples from our own work on rapid threat detection and from the broader infancy literature. First, we describe our initial studies using a single outcome measure, and how this strategy caused us to nearly miss a rich and complex story about attention biases for threat and their development. We demonstrate how using converging measures can help researchers make inferences about infant behavior, and how using additional measures allows us to more deeply examine the mechanisms that drive developmental change. Finally, we provide practical and statistical recommendations for how researchers can use multiple measures in future work.

Implementing advance care planning: A qualitative exploration of nurses' perceived benefits and challenges.

AIM: To explore nurses' perspectives on implementing advance care planning (ACP) in an acute setting. BACKGROUND: Advance care planning can assist patients to achieve peace of mind and a sense of control in decision-making. Nurses are well-positioned to integrate ACP into practice. METHODS: A descriptive, qualitative study using face-to-face semi-structured interviews was conducted among 16 nurses. A theoretical sampling strategy was used to inform data collection. Data were analysed using a thematic approach. RESULTS: Three major themes were found from nurses' narratives of implementing ACP: value of ACP, communicating ACP and barriers to advocating ACP. IMPLICATIONS FOR NURSING MANAGEMENT: Implementing ACP will require a multi-pronged approach, which includes specific training and changes in hospital policies. Findings from this study will enable hospital administrators to make informed decisions in preparing training programmes for ACP from nurses' perspectives. CONCLUSION: Advance care planning provides a clear direction for health care professionals in meeting patients' desired outcomes. However, a lack of understanding and acceptance among the public, as well as systematic clinical routine supporting nurses' roles and responsibilities in ACP, was recognized.

Clinical and molecular spectrum of thymidine kinase 2-related mtDNA maintenance defect.

Mitochondrial DNA maintenance (mtDNA) defects have a wide range of causes, each with a set of phenotypes that overlap with many other neurological or muscular diseases. Clinicians face the challenge of narrowing down a long list of differential diagnosis when encountered with non-specific neuromuscular symptoms. Biallelic pathogenic variants in the Thymidine Kinase 2 (TK2) gene cause a myopathic form of mitochondrial DNA maintenance defect. Since the first description in 2001, there have been 71 patients reported with 42 unique pathogenic variants. Here we are reporting 11 new cases with 5 novel pathogenic variants. We describe and analyze a total of 82 cases with 47 unique TK2 pathogenic variants in effort to formulate a comprehensive molecular and clinical spectrum of TK2-related mtDNA maintenance disorders.

Mortality from an aspiration of dental crown during extraction.

An aspiration of a dental crown during a dental extraction requires appropriate and timely diagnosis and management. While foreign body aspiration in dental procedures is relatively uncommon, it constitutes a true medical emergency and is associated with significant morbidity and mortality. We report a case of mortality from a foreign body aspiration and discuss the epidemiology, risk factors, signs and symptoms, management, and prevention of foreign body ingestion and aspiration events.

Evaluation of Bacteriuria Treatment and Follow-up Initiated in the Emergency Department at a Veterans Affairs Hospital.

Background: This study aims to evaluate the treatment and follow-up of bacteriuria in the emergency department (ED). Objective: The primary objective was to determine the frequency of patients discharged from the ED with antibiotics for symptomatic and asymptomatic bacteriuria, and the secondary objectives were to determine the frequency of patients receiving postdischarge antibiotic interventions and antibiotic-related adverse drug reactions (ADRs). Methods: This retrospective study evaluated patients with ED urine cultures sent between October 1, 2015, and November 24, 2015. Patients with indwelling catheters, concurrent antibiotics, and admission for inpatient care were excluded. T tests and contingency tables were applied in SAS; P < .05 was considered significant. Results: Of 429 unique patients with urine cultures drawn in the ED, 13.1% (n = 56) received treatment for a bacteriuria. The majority of patients discharged from the ED with antibiotics had urinary tract infection (UTI) symptoms documented in the medical record (76.8%; n = 43). Of those patients who required postdischarge interventions, 4 out of 13 had appropriate antibiotic adjustments based on culture and sensitivity results at follow-up. In a subset of patients with inappropriately ordered urine cultures (no UTI symptoms documented or antibiotic prescribed), a higher percentage of patients had normal urinalyses (UA) compared to abnormal UAs (83.3% vs 10.4%, P = .0008). No significant ADRs were identified. Conclusions: The majority of patients treated for bacteriuria in the ED had documented symptoms consistent with UTIs and appropriate empiric antibiotics. However, incorporating antimicrobial stewardship activities in the ED targeting unnecessary urine cultures and assuring postdischarge follow-up if treatment modification is needed based on culture results can improve antibiotic prescribing.