Synergistic Effects of Neratinib in Combination With Palbociclib or Miransertib in Brain Cancer Cells.

Background: Aberrant expression and activation of epidermal growth factor receptor (EGFR) resulted in approval of several forms of EGFR inhibitors in the treatment of patients with a wide range of epithelial cancers. However, no EGFR inhibitor has yet been approved for the treatment of patients with brain cancer, indicating that targeting EGFR alone may not be sufficient in some patients. Methods: In this study, we investigated the role of all members of the EGFR family, other growth factor receptors, cell-cycle proteins, and downstream cell signaling pathways (e.g., mitogen-activated protein kinase (MAPK), serine/threonine protein kinase (AKT), signal transducer and activator of transcription (STAT3), Src, Abelson murine leukemia viral oncogene homolog (Abl)) on the growth of a panel of human brain cancer cell lines (HBCCLs). We examined the growth response of HBCCLs to treatment with 17 targeted agents compared to two cytotoxic drugs. Results: Of the targeted agents, the irreversible pan-human epidermal growth factor receptor (HER) inhibitors neratinib and afatinib were more effective than erlotinib and lapatinib at inhibiting the growth of all HBCCLs, and the cyclin-dependent kinase (CDK)1/2/5/9 inhibitor dinaciclib was the most potent targeted agent. We found that treatment with Src/Abl/c-kit inhibitor dasatinib, signal transducer and activator of transcription (STAT3) inhibitor stattic, Abl/platelet-derived growth factor receptor (PDGFR)α/vascular endothelial growth factor (VEGFR)2/fibroblast growth factor receptor (FGFR)1 inhibitor ponatinib, and the tropomyosin receptor kinase (TRK)/ROS proto-oncogene 1 receptor tyrosine kinase (ROS)/anaplastic lymphoma kinase (ALK) inhibitor entrectinib, also inhibited the growth of all HBCCLs. Interestingly, these agents were more effective in inhibiting growth of HBCCLs when proliferating at a slower rate. In addition to inhibiting the proliferation of HBCCLs, treatment with neratinib, dinaciclib, dasatinib, stattic and trametinib inhibited the migration of brain tumor cell line A172. Conclusions: Notably, we found that treatment with neratinib in combination with palbociclib (CDK4/6 inhibitor), or miransertib (AKT1/2/3 inhibitor) resulted in synergistic growth inhibition of all HBCCLs. Our results support that repurposing drugs like neratinib in combination with the palbociclib or miransertib may be of therapeutic potential in brain cancer and warrants further investigations.

Cash Transfers and After-School Programs: A Randomized Controlled Trial for Young Men at Risk of Violence Exposure in Wilmington, Delaware.

We conducted a randomized controlled trial to determine whether an after-school program paired with a cash transfer (a conditional cash transfer) or a cash transfer alone (an unconditional cash transfer) can help improve health and economic outcomes for young men between the ages of 14 and 17 whose parents have low incomes and who live in neighborhoods with high crime rates. We find that receiving the cash transfer alone was associated with an increase in healthy behaviors (one of our primary outcome composite measures) and that the cash transfer paired with after-school programming was associated with an improvement in the financial health of participants (one of our secondary outcome composite measures). We find no differences in spending on alcohol, marijuana, cigarettes, or other drugs between either the treatment group and the control group. Neither the cash transfer alone nor the programming plus cash transfer had statistically significant effects on our other primary composite measures (physical and mental health or school attendance and disciplinary actions), or our other secondary composite measures (criminal justice engagement or social supports) but in most cases, confidence intervals were too large to rule out meaningful effects. Results suggest that cash transfers hold promise to improve the health of youth without any indication of any adverse effects.

Automated Text Message-Based Program and Use of Acute Health Care Resources After Hospital Discharge: A Randomized Clinical Trial.

Importance: Postdischarge outreach from the primary care practice is an important component of transitional care support. The most common method of contact is via telephone call, but calls are labor intensive and therefore limited in scope. Objective: To test whether a 30-day automated texting program to support primary care patients after hospital discharge reduces acute care revisits. Design, Setting, and Participants: A 2-arm randomized clinical trial was conducted from March 29, 2022, through January 5, 2023, at 30 primary care practices within a single academic health system in Philadelphia, Pennsylvania. Patients were followed up for 60 days after discharge. Investigators were blinded to assignment, but patients and practice staff were not. Participants included established patients of the study practices who were aged 18 years or older, discharged from an acute care hospitalization, and considered medium to high risk for adverse health events by a health system risk score. All analyses were conducted using an intention-to-treat approach. Intervention: Patients in the intervention group received automated check-in text messages from their primary care practice on a tapering schedule for 30 days following discharge. Any needs identified by the automated messaging platform were escalated to practice staff for follow-up via an electronic medical record inbox. Patients in the control group received a standard transitional care management telephone call from their practice within 2 business days of discharge. Main Outcomes and Measures: The primary study outcome was any acute care revisit (readmission or emergency department visit) within 30 days of discharge. Results: Of the 4736 participants, 2824 (59.6%) were female; the mean (SD) age was 65.4 (16.5) years. The mean (SD) length of index hospital stay was 5.5 (7.9) days. A total of 2352 patients were randomized to the intervention arm and 2384 were randomized to the control arm. There were 557 (23.4%) acute care revisits in the control group and 561 (23.9%) in the intervention group within 30 days of discharge (risk ratio, 1.02; 95% CI, 0.92-1.13). Among the patients in the intervention arm, 79.5% answered at least 1 message and 41.9% had at least 1 need identified. Conclusions and Relevance: In this randomized clinical trial of a 30-day postdischarge automated texting program, there was no significant reduction in acute care revisits. Trial Registration: ClinicalTrials.gov Identifier: NCT05245773.

Health Care Use Among Patients Retroactively Insured via a Hospital-Based Insurance Linkage Program.

OBJECTIVE: Over 25% of the 27 million uninsured individuals in the United States are eligible for Medicaid. Many hospitals have insurance linkage programs that assist eligible patients with enrollment, but little is known about the impact of these programs on care utilization. This research assessed health care utilization and health outcomes among patients enrolled in Medicaid via a hospital-based insurance linkage program. METHODS: This retrospective cohort study included adults aged 18-64 admitted to the hospital from 2016 to 2021. Those who obtained insurance retroactively via insurance linkage (RI) were compared with those who presented with Medicaid (MI) or remained uninsured (UI). The primary outcome was the presence of at least one visit with a primary care provider (PCP) in the 12 months following index admission. Secondary outcomes included having an assigned PCP, ED revisits, and hospital readmissions. For patients with diabetes and hypertension, 12-month hemoglobin A1c (HbA1c) and blood pressure (BP) readings were tracked. RESULTS: Of 3882 patients admitted with no insurance, 2905 (74.8%) were enrolled in insurance (RI). In multivariable analysis, RI patients were 14% more likely (OR 1.14, p = 0.020) to have completed at least one PCP visit by 12 months after index admission compared to those with preexisting Medicaid (MI), and uninsured patients were 29% less likely (OR 0.71, p = 0.003). MI and RI patients also had more ED revisits (p < 0.001) and greater 12-month reductions in blood pressure (p < 0.001) compared with uninsured patients. CONCLUSION: Hospital-based insurance linkage reached three-quarters of uninsured patients and was associated with increased utilization of acute and outpatient health care services. An acute care encounter represents an opportunity to connect patients to insurance, a key step toward improving their health outcomes.

Which Came First? When Usher Syndrome Type 1 Couples with Neuropsychiatric Disorders.

Usher syndrome (USH) is an autosomal recessive disorder characterized by sensorineural hearing loss (HL), retinopathy, and vestibular areflexia, with variable severity. Although a high prevalence of behavioural and mental disorders in USH patients has been reported, few studies on these psychiatric and psychological issues have been conducted. This work describes the case of a 16-year-old boy affected by congenital bilateral sensorineural HL, presenting a suddenly altered behaviour concomitant with a decrease in visual acuity. To establish a molecular diagnosis, Whole-Exome Sequencing analysis was performed, detecting a pathogenetic homozygous variant (c. 5985C>A, p.(Tyr1995*)) within the CDH23 gene. CDH23 is a known USH type 1 causative gene, recently associated with schizophrenia-like symptoms and bipolar disorders. To date, no studies have provided evidence of a direct genotype-phenotype correlation between USH patients carrying CDH23 variants and mental/behavioural issues; however, considering the multiple biological functions of CDH23, it can be hypothesised that it could have a pleiotropic effect. Overall, this study highlights the relevance of a continuous clinical evaluation of USH patients, to monitor not only the disease progression, but to early detect any psychological or behavioural alterations, thus allowing a rapid implementation of therapeutic strategies aimed at improving their quality of life and well-being.

Puzzling Out the Genetic Architecture of Endometriosis: Whole-Exome Sequencing and Novel Candidate Gene Identification in a Deeply Clinically Characterised Cohort.

Endometriosis (EM) is a common multifactorial gynaecological disorder. Although Genome-Wide Association Studies have largely been employed, the current knowledge of the genetic mechanisms underlying EM is far from complete, and other approaches are needed. To this purpose, whole-exome sequencing (WES) was performed on a deeply characterised cohort of 80 EM patients aimed at the identification of rare and damaging variants within 46 EM-associated genes and novel candidates. WES analysis detected 63 rare, predicted, and damaging heterozygous variants within 24 genes in 63% of the EM patients. In particular, (1) a total of 43% of patients carried variants within 13 recurrent genes (FCRL3, LAMA5, SYNE1, SYNE2, GREB1, MAP3K4, C3, MMP3, MMP9, TYK2, VEGFA, VEZT, RHOJ); (2) a total of 8.8% carried private variants within eight genes (KAZN, IL18, WT1, CYP19A1, IL1A, IL2RB, LILRB2, ZNF366); (3) a total of 24% carried variants within three novel candidates (ABCA13, NEB, CSMD1). Finally, to deepen the polygenic architecture of EM, a comprehensive evaluation of the analysed genes was performed, revealing a higher burden (p < 0.05) of genes harbouring rare and damaging variants in the EM patients than in the controls. These results highlight new insights into EM genetics, allowing for the definition of novel genotype-phenotype correlations, thereby contributing, in a long-term perspective, to the development of personalised care for EM patients.

The Impact of the Dobbs Decision on Diagnostic Radiology Applicants, Residents, and Program Directors.

In the Dobbs decision the United States Supreme Court overturned Roe v. Wade, returning the issue of abortion to the states. To date, there is little published data on the impact this might have on where future residents choose to pursue graduate medical education. We investigated the potential effects of the resultant varied political landscape of abortion care access laws with respect to influence on the selection of prospective diagnostic radiology training programs by medical students, comparing application rates for the 2022 recruitment cycle to the prior 4 years across a geographically diverse group of 22 academic and community sites across the United States. We provide strategies for program directors to consider in dealing with topics related to this continually evolving issue as it pertains to resident recruitment and retention.

Patient and clinician perspectives of a remote monitoring program for COVID-19 and lessons for future programs.

COVID Watch is a remote patient monitoring program implemented during the pandemic to support home dwelling patients with COVID-19. The program conferred a large survival advantage. We conducted semi-structured interviews of 85 patients and clinicians using COVID Watch to understand how to design such programs even better. Patients and clinicians found COVID Watch to be comforting and beneficial, but both groups desired more clarity about the purpose and timing of enrollment and alternatives to text-messages to adapt to patients' preferences as these may have limited engagement and enrollment among marginalized patient populations. Because inclusiveness and equity are important elements of programmatic success, future programs will need flexible and multi-channel human-to-human communication pathways for complex clinical interactions or for patients who do not desire tech-first approaches.

Insights Into Patients' Perceptions of Health-Related Social Needs and the Role of the Adult Primary Care Clinic.

INTRODUCTION/OBJECTIVES: While it is well established that unmet healthrelated social needs (HRSN) adversely affect health outcomes, there has been limited evaluation in adult primary care of patients' perceptions of how these needs impact their health and the role of the primary care provider (PCP). The objective of this study is to identify patients' perceptions of HRSN and how PCPs could help address them. Secondary objectives include exploring the impact of goal setting and a 1-time cash transfer (CT). METHODS: This qualitative study used semi-structured baseline and follow-up interviews with patients in internal medicine clinics. Adult primary care patients were included if they screened positive as having 1 of 3 HRSN: financial resource strain, transportation needs, or food insecurity. All participants completed an initial interview about their HRSN and health, and were asked to set a 6-month health goal. At enrollment, participants were randomized to receive a $500 CT or a $50 participation reward. At 6-months, patients were interviewed again to investigate progress toward meeting their health goals, [when applicable] how the CT helped, and their beliefs about the role of PCPs in addressing HRSN. RESULTS: We completed 30 initial and 25 follow-up interviews. Participants identified their HRSN, however most did not readily connect identified needs to health. Although participants were receptive to HRSN screening, they did not feel it was their PCP's responsibility to address these needs. Verbal goal-setting appeared to be a useful tool, and while the CTs were appreciated, patients often found them inadequate to address HRSN. CONCLUSIONS: Given the importance of identifying the social conditions that shape patients' health, providers, and health systems have an opportunity to re-evaluate their role in helping patients address these barriers. Future studies could examine the effect of more frequent disbursement of CTs over time.

Identifying missing pieces in color vision defects: a genome-wide association study in Silk Road populations.

Introduction: Color vision defects (CVDs) are conditions characterized by the alteration of normal trichromatic vision. CVDs can arise as the result of alterations in three genes (OPN1LW, OPN1MW, OPN1SW) or as a combination of genetic predisposition and environmental factors. To date, apart from Mendelian CVDs forms, nothing is known about multifactorial CVDs forms. Materials and Methods: Five hundred and twenty individuals from Silk Road isolated communities were genotyped and phenotypically characterized for CVDs using the Farnsworth D-15 color test. The CVDs traits Deutan-Protan (DP) and Tritan (TR) were analysed. Genome Wide Association Study for both traits was performed, and results were corrected with a False Discovery Rate linkage-based approach (FDR-p). Gene expression of final candidates was investigated using a published human eye dataset, and pathway analysis was performed. Results: Concerning DP, three genes: PIWIL4 (FDR-p: 9.01*10-9), MBD2 (FDR-p: 4.97*10-8) and NTN1 (FDR-p: 4.98*10-8), stood out as promising candidates. PIWIL4 is involved in the preservation of Retinal Pigmented Epithelium (RPE) homeostasis while MBD2 and NTN1 are both involved in visual signal transmission. With regards to TR, four genes: VPS54 (FDR-p: 4.09*10-9), IQGAP (FDR-p: 6,52*10-10), NMB (FDR-p: 8.34*10-11), and MC5R (FDR-p: 2.10*10-8), were considered promising candidates. VPS54 is reported to be associated with Retinitis pigmentosa; IQGAP1 is reported to regulate choroidal vascularization in Age-Related Macular Degeneration; NMB is involved in RPE homeostasis regulation; MC5R is reported to regulate lacrimal gland function. Discussion: Overall, these results provide novel insights regarding a complex phenotype (i.e., CVDs) in an underrepresented population such as Silk Road isolated communities.

Increase of Severe Pulmonary Infections in Adults Caused by M1UK Streptococcus pyogenes, Central Scotland, UK.

We characterized the epidemiology, host-pathogen characteristics, and outcomes of severe adult pulmonary Streptococcus pyogenes infections that coincided with a high community caseload in central Scotland, UK. The pulmonary infections had high illness and death rates and were associated with socioeconomic deprivation, influenza A co-infection, and the M1UK lineage of S. pyogenes.

The Enigmatic Genetic Landscape of Hereditary Hearing Loss: A Multistep Diagnostic Strategy in the Italian Population.

Hearing loss is the most frequent sensorineural disorder, affecting approximately 1:1000 newborns. Hereditary forms (HHL) represent 50-60% of cases, highlighting the relevance of genetic testing in deaf patients. HHL is classified as non-syndromic (NSHL-70% of cases) or syndromic (SHL-30% of cases). In this study, a multistep and integrative approach aimed at identifying the molecular cause of HHL in 102 patients, whose GJB2 analysis already showed a negative result, is described. In NSHL patients, multiplex ligation probe amplification and long-range PCR analyses of the STRC gene solved 13 cases, while whole exome sequencing (WES) identified the genetic diagnosis in 26 additional ones, with a total detection rate of 47.6%. Concerning SHL, WES detected the molecular cause in 55% of cases. Peculiar findings are represented by the identification of four subjects displaying a dual molecular diagnosis and eight affected by non-syndromic mimics, five of them presenting Usher syndrome type 2. Overall, this study provides a detailed characterisation of the genetic causes of HHL in the Italian population. Furthermore, we highlighted the frequency of Usher syndrome type 2 carriers in the Italian population to pave the way for a more effective implementation of diagnostic and follow-up strategies for this disease.

Haploinsufficiency as a Foreground Pathomechanism of Poirer-Bienvenu Syndrome and Novel Insights Underlying the Phenotypic Continuum of CSNK2B-Associated Disorders.

CSNK2B encodes for the regulatory subunit of the casein kinase II, a serine/threonine kinase that is highly expressed in the brain and implicated in development, neuritogenesis, synaptic transmission and plasticity. De novo variants in this gene have been identified as the cause of the Poirier-Bienvenu Neurodevelopmental Syndrome (POBINDS) characterized by seizures and variably impaired intellectual development. More than sixty mutations have been described so far. However, data clarifying their functional impact and the possible pathomechanism are still scarce. Recently, a subset of CSNK2B missense variants affecting the Asp32 in the KEN box-like domain were proposed as the cause of a new intellectual disability-craniodigital syndrome (IDCS). In this study, we combined predictive functional and structural analysis and in vitro experiments to investigate the effect of two CSNK2B mutations, p.Leu39Arg and p.Met132LeufsTer110, identified by WES in two children with POBINDS. Our data prove that loss of the CK2beta protein, due to the instability of mutant CSNK2B mRNA and protein, resulting in a reduced amount of CK2 complex and affecting its kinase activity, may underlie the POBINDS phenotype. In addition, the deep reverse phenotyping of the patient carrying p.Leu39Arg, with an analysis of the available literature for individuals with either POBINDS or IDCS and a mutation in the KEN box-like motif, might suggest the existence of a continuous spectrum of CSNK2B-associated phenotypes rather than a sharp distinction between them.

Whole genome sequencing for USH2A-associated disease reveals several pathogenic deep-intronic variants that are amenable to splice correction.

A significant number of individuals with a rare disorder such as Usher syndrome (USH) and (non-)syndromic autosomal recessive retinitis pigmentosa (arRP) remain genetically unexplained. Therefore, we assessed subjects suspected of USH2A-associated disease and no or mono-allelic USH2A variants using whole genome sequencing (WGS) followed by an improved pipeline for variant interpretation to provide a conclusive diagnosis. One hundred subjects were screened using WGS to identify causative variants in USH2A or other USH/arRP-associated genes. In addition to the existing variant interpretation pipeline, a particular focus was put on assessing splice-affecting properties of variants, both in silico and in vitro. Also structural variants were extensively addressed. For variants resulting in pseudoexon inclusion, we designed and evaluated antisense oligonucleotides (AONs) using minigene splice assays and patient-derived photoreceptor precursor cells. Biallelic variants were identified in 49 of 100 subjects, including novel splice-affecting variants and structural variants, in USH2A or arRP/USH-associated genes. Thirteen variants were shown to affect USH2A pre-mRNA splicing, including four deep-intronic USH2A variants resulting in pseudoexon inclusion, which could be corrected upon AON treatment. We have shown that WGS, combined with a thorough variant interpretation pipeline focused on assessing pre-mRNA splicing defects and structural variants, is a powerful method to provide subjects with a rare genetic condition, a (likely) conclusive genetic diagnosis. This is essential for the development of future personalized treatments and for patients to be eligible for such treatments.

Patient perspectives on technology-based approaches to social needs screening.

OBJECTIVES: Social determinants have an outsized impact on health outcomes. Given the increasing awareness of this impact and the adoption of alternative payment models that incentivize addressing social needs, expectations are growing that health systems will appropriately screen for patients' social needs. However, there is limited evidence on how patients would like their health systems to engage with them around these needs. Our objective was to understand patient perspectives on completing social needs screening through technology-based modalities. STUDY DESIGN: We performed a qualitative study with semistructured patient interviews from November 2021 to April 2022. METHODS: Patients were eligible for our health system's standardized social needs screening survey if they had not completed it in the past year and were scheduled for a nonacute primary care visit. Patients were selected for interview if they completed the survey via portal or tablet or if they were eligible for but did not complete the survey. Interviews were analyzed using an integrated approach. Domains, subdomains, and themes were identified. RESULTS: We completed interviews with 54 participants. Participants were broadly accepting of screening, and most were comfortable with portal or tablet-based screening. They were motivated to complete the screening and recognized the connection between social needs and health. Having a trusting relationship with their clinician and feeling that their information was private were noted by patients as important factors for process endorsement. CONCLUSIONS: This qualitative study provides insight into patient-centered approaches for identifying patients' social needs.

Feasibility of combining biosensor and ecological momentary assessment to measure stress experiences among economically disadvantaged adolescents.

Adolescent stress is complex and impairing. Novel measures are needed to understand stress variability within individuals over time from a physiological as well as a subjective perspective. To test the feasibility of combining ecological momentary assessment (EMA) and wearable biosensors to assess adolescent stress, using an idiographic approach with experience sampling methods. A small sample (n = 23) of predominantly African American, economically disadvantaged adolescents were asked to complete EMA surveys four times per day and wear an armband measuring Heart rate (HR) and skin response for a 2-week period. Descriptive analyses examined number of hours of armband wear, percentage of viable data, and percentage of surveys completed by gender and race. Associations between biosensor data and EMA reports within and across individuals were also examined using hierarchical linear regression. EMA survey completion was good (81%) as was adherence to biosensor protocols, although technological difficulties interfered with collection of HR variability for youth with darker skin tones. Youth reported stressful events in 12.79% of EMA surveys, although 43% reported no negative mood experiences. Convergent validity was supported for detecting between-person (EMA) and within-person (EMA and biosensors) variability in stress across time, although associations across youth were highly variable. Results suggest value for biobehavioral methods in understanding day-to-day stress in adolescents but highlight variability in stress experiences as well as technological limitations, especially for youth of colour.

Patient and clinician perspectives of a remote monitoring program for COVID-19 and lessons for future programs.

COVID Watch is a remote patient monitoring program implemented during the pandemic to support home dwelling patients with COVID-19. The program conferred a large survival advantage. We conducted semi-structured interviews of 85 patients and clinicians using COVID Watch to understand how to design such programs even better. Patients and clinicians found COVID Watch to be comforting and beneficial, but both groups desired more clarity about the purpose and timing of enrollment and alternatives to text-messages to adapt to patients’ preferences as these may have limited engagement and enrollment among marginalized patient populations. Because inclusiveness and equity are important elements of programmatic success, future programs will need flexible and multi-channel human-to-human communication pathways for complex clinical interactions or patients who do not desire tech-first approaches.