DNA Methylation signatures underpinning blood neutrophil to lymphocyte ratio during first week of human life.

Understanding of newborn immune ontogeny in the first week of life will enable age-appropriate strategies for safeguarding vulnerable newborns against infectious diseases. Here we conducted an observational study exploring the immunological profile of infants longitudinally throughout their first week of life. Our Expanded Program on Immunization - Human Immunology Project Consortium (EPIC-HIPC) studies the epigenetic regulation of systemic immunity using small volumes of peripheral blood samples collected from West African neonates on days of life (DOL) 0, 1, 3, and 7. Genome-wide DNA methylation and single nucleotide polymorphism markers are examined alongside matched transcriptomic and flow cytometric data. Integrative analysis reveals that a core network of transcription factors mediates dynamic shifts in neutrophil-to-lymphocyte ratios (NLR), which are underpinned by cell-type specific methylation patterns in the two cell types. Genetic variants are associated with lower NLRs at birth, and healthy newborns with lower NLRs at birth are more likely to subsequently develop sepsis. These findings provide valuable insights into the early-life determinants of immune system development.

Control of Hepatitis B Virus with Imdusiran, a Small Interfering RNA Therapeutic.

Chronic hepatitis B is a global health concern with a high risk of end-stage liver disease. Current standard-of-care agents have low cure rates, and new therapies are needed. Small interfering RNAs (siRNAs) that target viral RNAs fulfill a gap not addressed by standard-of-care agents and may contribute to a functional cure. Here, we describe the preclinical characterization of imdusiran (AB-729), a novel, pan-genotypic siRNA therapeutic that effectively reduces HBsAg, viral antigens, and viral replication in chronic hepatitis B patients and is currently in Phase 2 clinical studies. In hepatitis B virus (HBV) cell-based systems, imdusiran possessed pan-genotypic nanomolar potency and retained activity against HBV target site polymorphisms. Imdusiran was active against nucleos(t)ide analogue- and capsid assembly modulator-resistant HBV isolates, and combination with standard-of-care agents was additive. In an HBV adeno-associated virus mouse model, HBsAg was reduced up to 3.7 log10 after a single imdusiran dose, with sustained suppression for 10 weeks. Imdusiran did not intrinsically stimulate cytokine release in healthy donor human whole blood, supportive of its mechanism of action as a direct acting RNA interference antiviral. Taken together, these data support imdusiran in combination treatment approaches toward chronic hepatitis B functional cure.

Rational Design, Synthesis, and Structure-Activity Relationship of a Novel Isoquinolinone-Based Series of HBV Capsid Assembly Modulators Leading to the Identification of Clinical Candidate AB-836.

Inhibition of Hepatitis B Virus (HBV) replication by small molecules that modulate capsid assembly and the encapsidation of pgRNA and viral polymerase by HBV core protein is a clinically validated approach toward the development of new antivirals. Through definition of a minimal pharmacophore, a series of isoquinolinone-based capsid assembly modulators (CAMs) was identified. Structural biology analysis revealed that lead molecules possess a unique binding mode, exploiting electrostatic interactions with accessible phenylalanine and tyrosine residues. Key analogs demonstrated excellent primary potency, absorption, distribution, metabolism, and excretion (ADME) and pharmacokinetic properties, and efficacy in a mouse model of HBV. The optimized lead also displayed potent inhibition of capsid uncoating in HBV-infected HepG2 cells expressing the sodium-taurocholate cotransporting polypeptide (NTCP) receptor, affecting the generation of HBsAg and cccDNA establishment. Based on these results, isoquinolinone derivative AB-836 was advanced into clinical development. In Phase 1b trials, AB-836 demonstrated >3 log10 reduction in serum HBV DNA, however, further development was discontinued due to the observation of incidental alanine aminotransferase (ALT) elevations.

Cerebrospinal fluid liquid biopsy by low-pass whole genome sequencing for clinical disease monitoring in pediatric embryonal tumors.

Background: Liquid biopsy assays that detect cell-free DNA (cfDNA) in cerebrospinal fluid (CSF) are a promising tool for disease monitoring in pediatric patients with primary central nervous system (CNS) tumors. As a compliment to tissue-derived molecular analyses, CSF liquid biopsy has the potential to transform risk stratification, prognostication, and precision medicine approaches. Methods: In this pilot study, we evaluated a clinical pipeline to determine feasibility and sensitivity of low-pass whole genome sequencing (LP-WGS) of CSF-derived cfDNA from patients with CNS embryonal tumors. Thirty-two longitudinal CSF samples collected from 17 patients with molecularly characterized medulloblastoma (12), embryonal tumor with multilayered rosettes (2), CNS embryonal tumor, not elsewhere classified (NEC) (2), and atypical teratoid/rhabdoid tumor (1) were analyzed. Results: Adequate CSF-derived cfDNA for LP-WGS analysis was obtained in 94% of samples (30/32). Copy number variants compatible with neoplasia were detected in 90% (27/30) and included key alterations, such as isodicentric ch17, monosomy 6, and MYCN amplification, among others. Compared to tissue specimens, LP-WGS detected additional aberrations in CSF not previously identified in corresponding primary tumor specimens, suggesting a more comprehensive profile of tumor heterogeneity or evolution of cfDNA profiles over time. Among the 12 CSF samples obtained at initial staging, only 2 (17%) were cytologically positive, compared to 11 (92%) that were copy number positive by LP-WGS. Conclusions: LP-WGS of CSF-derived cfDNA is feasible using a clinical platform, with greater sensitivity for tumor detection compared to conventional CSF cytologic analysis at initial staging. Large prospective studies are needed to further evaluate LP-WGS as a predictive biomarker.

Targeting stress induction of GRP78 by cardiac glycoside oleandrin dually suppresses cancer and COVID-19.

BACKGROUND: Despite recent therapeutic advances, combating cancer resistance remains a formidable challenge. The 78-kilodalton glucose-regulated protein (GRP78), a key stress-inducible endoplasmic reticulum (ER) chaperone, plays a crucial role in both cancer cell survival and stress adaptation. GRP78 is also upregulated during SARS-CoV-2 infection and acts as a critical host factor. Recently, we discovered cardiac glycosides (CGs) as novel suppressors of GRP78 stress induction through a high-throughput screen of clinically relevant compound libraries. This study aims to test the possibility that agents capable of blocking stress induction of GRP78 could dually suppress cancer and COVID-19. RESULTS: Here we report that oleandrin (OLN), is the most potent among the CGs in inhibiting acute stress induction of total GRP78, which also results in reduced cell surface and nuclear forms of GRP78 in stressed cells. The inhibition of stress induction of GRP78 is at the post-transcriptional level, independent of protein degradation and autophagy and may involve translational control as OLN blocks stress-induced loading of ribosomes onto GRP78 mRNAs. Moreover, the human Na+/K+-ATPase α3 isoform is critical for OLN suppression of GRP78 stress induction. OLN, in nanomolar range, enhances apoptosis, sensitizes colorectal cancer cells to chemotherapeutic agents, and reduces the viability of patient-derived colon cancer organoids. Likewise, OLN, suppresses GRP78 expression and impedes tumor growth in an orthotopic breast cancer xenograft model. Furthermore, OLN blocks infection by SARS-CoV-2 and its variants and enhances existing anti-viral therapies. Notably, GRP78 overexpression mitigates OLN-mediated cancer cell apoptotic onset and suppression of virus release. CONCLUSION: Our findings validate GRP78 as a target of OLN anti-cancer and anti-viral activities. These proof-of-principle studies support further investigation of OLN as a readily accessible compound to dually combat cancer and COVID-19.

Neurological Surgery Resident ABNS Written Exam Scores Before and After Introduction of a Weekly Didactic Educational Intervention: A 12-Year Single-Institution Retrospective Study.

United States neurological surgery residency education has undergone substantive changes over the past 2 decades. Neurosurgical professional bodies have developed numerous initiatives providing standardized assessments and training opportunities for residency programs. However, there have been few studies using standardized measures to assess core components of educational programming in individual programs. We conducted a 12-year retrospective review of resident American Board of Neurological Surgery (ABNS) board scores using our institutional data from 2010 to 2021 to determine the effect of introducing a weekly didactic resident education hour (REH) on resident scores in the ABNS written in-training examination. ABNS scaled scores were analyzed before (2010-2016) and after (2017-2021) REH introduction. To account for a practice effect, we used a 2-factor linear regression model with an interaction term. We obtained ABNS scores from 43 residents representing 132 test attempts. The average ABNS scaled score significantly improved after the introduction of REH (319 vs 410, t = -3.44, P = .0008). Accounting for the practice effect revealed a significant interaction effect between the number of attempts taking the ABNS examination and whether formal didactics were taught, accounting for 46.2 points on the examination (t = 2.309, P = .023); however, REH alone did not have a significant effect on the scaled scores (t = -1.649, P = .102). ABNS written board scores represent a standardized metric by which educational initiatives within training programs may be assessed for efficacy. Further research is needed to identify educational approaches that are effective to meet the goal of demonstrated mastery of fundamental knowledge in neurosurgery across a diversity of neurological surgery residency programs.

GRP78 inhibitor YUM70 upregulates 4E-BP1 and suppresses c-MYC expression and viability of oncogenic c-MYC tumors.

The 78-kDa glucose regulated protein (GRP78) commonly upregulated in a wide variety of tumors is an important prognostic marker and a promising target for suppressing tumorigenesis and treatment resistance. While GRP78 is well established as a major endoplasmic reticulum (ER) chaperone with anti-apoptotic properties and a master regulator of the unfolded protein response, its new role as a regulator of oncoprotein expression is just emerging. MYC is dysregulated in about 70 % of human cancers and is the most commonly activated oncoprotein. However, despite recent advances, therapeutic targeting of MYC remains challenging. Here we identify GRP78 as a new target for suppression of MYC expression. Using multiple MYC-dependent cancer models including head and neck squamous cell carcinoma and their cisplatin-resistant clones, breast and pancreatic adenocarcinoma, our studies revealed that GRP78 knockdown by siRNA or inhibition of its activity by small molecule inhibitors (YUM70 or HA15) reduced c-MYC expression, leading to onset of apoptosis and loss of cell viability. This was observed in 2D cell culture, 3D spheroid and in xenograft models. Mechanistically, we determined that the suppression of c-MYC is at the post-transcriptional level and that YUM70 and HA15 treatment potently upregulated the eukaryotic translation inhibitor 4E-BP1, which targets eIF4E critical for c-MYC translation initiation. Furthermore, knock-down of 4E-BP1 via siRNA rescued YUM70-mediated c-MYC suppression. As YUM70 is also capable of suppressing N-MYC expression, this study offers a new approach to suppress MYC protein expression through knockdown or inhibition of GRP78.

Equivalence of Alcohol Use Disorder Symptom Assessments in Routine Clinical Care When Completed Remotely via Online Patient Portals Versus In Clinic via Paper Questionnaires: Psychometric Evaluation.

BACKGROUND: The National Institute on Alcohol Abuse and Alcoholism (NIAAA) recommends the paper-based or computerized Alcohol Symptom Checklist to assess alcohol use disorder (AUD) symptoms in routine care when patients report high-risk drinking. However, it is unknown whether Alcohol Symptom Checklist response characteristics differ when it is administered online (eg, remotely via an online electronic health record [EHR] patient portal before an appointment) versus in clinic (eg, on paper after appointment check-in). OBJECTIVE: This study evaluated the psychometric performance of the Alcohol Symptom Checklist when completed online versus in clinic during routine clinical care. METHODS: This cross-sectional, psychometric study obtained EHR data from the Alcohol Symptom Checklist completed by adult patients from an integrated health system in Washington state. The sample included patients who had a primary care visit in 2021 at 1 of 32 primary care practices, were due for annual behavioral health screening, and reported high-risk drinking on the behavioral health screen (Alcohol Use Disorder Identification Test-Consumption score ≥7). After screening, patients with high-risk drinking were typically asked to complete the Alcohol Symptom Checklist-an 11-item questionnaire on which patients self-report whether they had experienced each of the 11 AUD criteria listed in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) over a past-year timeframe. Patients could complete the Alcohol Symptom Checklist online (eg, on a computer, smartphone, or tablet from any location) or in clinic (eg, on paper as part of the rooming process at clinical appointments). We examined sample and measurement characteristics and conducted differential item functioning analyses using item response theory to examine measurement consistency across these 2 assessment modalities. RESULTS: Among 3243 patients meeting eligibility criteria for this secondary analysis (2313/3243, 71% male; 2271/3243, 70% White; and 2014/3243, 62% non-Hispanic), 1640 (51%) completed the Alcohol Symptom Checklist online while 1603 (49%) completed it in clinic. Approximately 46% (752/1640) and 48% (764/1603) reported ≥2 AUD criteria (the threshold for AUD diagnosis) online and in clinic (P=.37), respectively. A small degree of differential item functioning was observed for 4 of 11 items. This differential item functioning produced only minimal impact on total scores used clinically to assess AUD severity, affecting total criteria count by a maximum of 0.13 criteria (on a scale ranging from 0 to 11). CONCLUSIONS: Completing the Alcohol Symptom Checklist online, typically prior to patient check-in, performed similarly to an in-clinic modality typically administered on paper by a medical assistant at the time of the appointment. Findings have implications for using online AUD symptom assessments to streamline workflows, reduce staff burden, reduce stigma, and potentially assess patients who do not receive in-person care. Whether modality of DSM-5 assessment of AUD differentially impacts treatment is unknown.

Pseudomonas aeruginosa in chronic lung disease: untangling the dysregulated host immune response.

Pseudomonas aeruginosa is a highly adaptable opportunistic pathogen capable of exploiting barriers and immune defects to cause chronic lung infections in conditions such as cystic fibrosis. In these contexts, host immune responses are ineffective at clearing persistent bacterial infection, instead driving a cycle of inflammatory lung damage. This review outlines key components of the host immune response to chronic P. aeruginosa infection within the lung, beginning with initial pathogen recognition, followed by a robust yet maladaptive innate immune response, and an ineffective adaptive immune response that propagates lung damage while permitting bacterial persistence. Untangling the interplay between host immunity and chronic P. aeruginosa infection will allow for the development and refinement of strategies to modulate immune-associated lung damage and potentiate the immune system to combat chronic infection more effectively.

Molecular analysis of human tick-bitten skin yields signatures associated with distinct spatial and temporal trajectories - A proof-of-concept study.

Tick-associated diseases present challenges due to tridirectional interactions among host-specific responses, tick toxins and salivary proteins as well as microbes. We aimed to uncover molecular mechanisms in tick-bitten skin samples (cases) and contralateral skin samples (controls) collected simultaneously from the same participants, using spatial transcriptomics. Cases and controls analysed using NanoString GeoMx Digital Spatial Profiler identified 274 upregulated and 840 downregulated differentially expressed genes (DEGs), revealing perturbations in keratinization and immune system regulation. Samples of skin biopsies taken within 72 h post tick-bite DEGs had changes in protein metabolism and viral infection pathways as compared to samples taken 3 months post tick-bite, which instead displayed significant perturbations in several epigenetic regulatory pathways, highlighting the temporal nature of the host response following tick bites. Within-individual signatures distinguished tick-bitten samples from controls and identified between-individual signatures, offering promise for future biomarker discovery to guide prognosis and therapy.

Breastfeeding and Neonatal Age Influence Neutrophil-Driven Ontogeny of Blood Cell Populations in the First Week of Human Life.

The first few days of life are characterized by rapid external and internal changes that require substantial immune system adaptations. Despite growing evidence of the impact of this period on lifelong immune health, this period remains largely uncharted. To identify factors that may impact the trajectory of immune development, we conducted stringently standardized, high-throughput phenotyping of peripheral white blood cell (WBC) populations from 796 newborns across two distinct cohorts (The Gambia, West Africa; Papua New Guinea, Melanesia) in the framework of a Human Immunology Project Consortium (HIPC) study. Samples were collected twice from each newborn during the first week of life, first at Day of Life 0 (at birth) and then subsequently at Day of Life 1, 3, or 7 depending on the randomization group the newborn belongs to. The subsequent analysis was conducted at an unprecedented level of detail using flow cytometry and an unbiased automated gating algorithm. The results showed that WBC composition in peripheral blood changes along patterns highly conserved across populations and environments. Changes across days of life were most pronounced in the innate myeloid compartment. Breastfeeding, and at a smaller scale neonatal vaccination, were associated with changes in peripheral blood neutrophil and monocyte cell counts. Our results suggest a common trajectory of immune development in newborns and possible association with timing of breastfeeding initiation, which may contribute to immune-mediated protection from infection in early life. These data begin to outline a specific window of opportunity for interventions that could deliberately direct WBC composition, and with that, immune trajectory and thus ontogeny in early life. This trial is registered with NCT03246230.

Creation of a novel CRISPR-generated allele to express HA epitope-tagged C1QL1 and improved methods for its detection at synapses.

C1QL1 is expressed in a subset of cells in the brain and likely has pleiotropic functions, including the regulation of neuron-to-neuron synapses. Research progress on C1QL proteins has been slowed by a dearth of available antibodies. Therefore, we created a novel knock-in mouse line in which an HA-tag is inserted into the endogenous C1ql1 locus. We examined the entire brain, identifying previously unappreciated nuclei expressing C1QL1, presumably in neurons. By total numbers, however, the large majority of C1QL1-expressing cells are of the oligodendrocyte lineage. Subcellular immunolocalization of synaptic cleft proteins is challenging, so we developed a new protocol to improve signal at synapses. Lastly, we compared various anti-HA antibodies to assist future investigations using this and likely other HA epitope-tagged alleles.

Offering nurse care management for opioid use disorder in primary care: Impact on emergency and hospital utilization in a cluster-randomized implementation trial.

BACKGROUND: Patients with opioid use disorder (OUD) have increased emergency and hospital utilization. The PROUD trial showed that implementation of office-based addiction treatment (OBAT) increased OUD medication treatment compared to usual care, but did not decrease acute care utilization in patients with OUD documented pre-randomization (clinicaltrials.gov/study/NCT03407638). This paper reports secondary emergency and hospital utilization outcomes in patients with documented OUD in the PROUD trial. METHODS: This cluster-randomized implementation trial was conducted in 12 clinics from 6 diverse health systems (March 2015-February 2020). Patients who visited trial clinics and had an OUD diagnosis within 3 years pre-randomization were included in primary analyses; secondary analyses added patients with OUD who were new to the clinic or with newly-documented OUD post-randomization. Outcomes included days of emergency care and hospital utilization over 2 years post-randomization. Explanatory outcomes included measures of OUD treatment. Patient-level analyses used mixed-effect regression with clinic-specific random intercepts. RESULTS: Among 1988 patients with documented OUD seen pre-randomization (mean age 49, 53 % female), days of emergency care or hospitalization did not differ between intervention and usual care; OUD treatment also did not differ. In secondary analyses among 1347 patients with OUD post-randomization, there remained no difference in emergency or hospital utilization despite intervention patients receiving 32.2 (95 % CI 4.7, 59.7) more days of OUD treatment relative to usual care. CONCLUSIONS: Implementation of OBAT did not reduce emergency or hospital utilization among patients with OUD, even in the sample with OUD first documented post-randomization in whom the intervention increased treatment.

A large-scale type I CBASS antiphage screen identifies the phage prohead protease as a key determinant of immune activation and evasion.

Cyclic oligonucleotide-based signaling system (CBASS) is an antiviral system that protects bacteria from phage infection and is evolutionarily related to human cGAS-STING immunity. cGAS-STING signaling is initiated by the recognition of viral DNA, but the molecular cues activating CBASS are incompletely understood. Using a screen of 975 type I CBASS operon-phage challenges, we show that operons with distinct cGAS/DncV-like nucleotidyltransferases (CD-NTases) and CD-NTase-associated protein (Cap) effectors exhibit marked patterns of phage restriction. We find that some type I CD-NTase enzymes require a C-terminal AGS-C immunoglobulin (Ig)-like fold domain for defense against select phages. Escaper phages evade CBASS via protein-coding mutations in virion assembly proteins, and acquired resistance is largely operon specific. We demonstrate that the phage Bas13 prohead protease interacts with the CD-NTase EcCdnD12 and can induce CBASS-dependent growth arrest in cells. Our results define phage virion assembly as a determinant of type I CBASS immune evasion and support viral protein recognition as a putative mechanism of cGAS-like enzyme activation.

Detection of tumor-derived cell-free DNA in cerebrospinal fluid using a clinically validated targeted sequencing panel for pediatric brain tumors.

PURPOSE: Clinical sequencing of tumor DNA is necessary to render an integrated diagnosis and select therapy for children with primary central nervous system (CNS) tumors, but neurosurgical biopsy is not without risk. In this study, we describe cell-free DNA (cfDNA) in blood and cerebrospinal fluid (CSF) as sources for "liquid biopsy" in pediatric brain tumors. METHODS: CSF samples were collected by lumbar puncture, ventriculostomy, or surgery from pediatric patients with CNS tumors. Following extraction, CSF-derived cfDNA was sequenced using UW-OncoPlex™, a clinically validated next-generation sequencing platform. CSF-derived cfDNA results and paired plasma and tumor samples concordance was also evaluated. RESULTS: Seventeen CSF samples were obtained from 15 pediatric patients with primary CNS tumors. Tumor types included medulloblastoma (n = 7), atypical teratoid/rhabdoid tumor (n = 2), diffuse midline glioma with H3 K27 alteration (n = 4), pilocytic astrocytoma (n = 1), and pleomorphic xanthoastrocytoma (n = 1). CSF-derived cfDNA was detected in 9/17 (53%) of samples, and sufficient for sequencing in 8/10 (80%) of extracted samples. All somatic mutations and copy-number variants were also detected in matched tumor tissue, and tumor-derived cfDNA was absent in plasma samples and controls. Tumor-derived cfDNA alterations were detected in the absence of cytological evidence of malignant cells in as little as 200 µl of CSF. Several clinically relevant alterations, including a KIAA1549::BRAF fusion were detected. CONCLUSIONS: Clinically relevant genomic alterations are detectable using CSF-derived cfDNA across a range of pediatric brain tumors. Next-generation sequencing platforms are capable of producing a high yield of DNA alterations with 100% concordance rate with tissue analysis.

Angiogenesis-associated pathways play critical roles in neonatal sepsis outcomes.

Neonatal sepsis is a major cause of childhood mortality. Limited diagnostic tools and mechanistic insights have hampered our abilities to develop prophylactic or therapeutic interventions. Biomarkers in human neonatal sepsis have been repeatedly identified as associated with dysregulation of angiopoietin signaling and altered arachidonic acid metabolism. We here provide the mechanistic evidence in support of the relevance for these observations. Angiopoetin-1 (Ang-1), which promotes vascular integrity, was decreased in blood plasma of human and murine septic newborns. In preclinical models, administration of Ang-1 provided prophylactic protection from septic death. Arachidonic acid metabolism appears to be functionally connected to Ang-1 via reactive oxygen species (ROS) with a direct role of nitric oxide (NO). Strengthening this intersection via oral administration of arachidonic acid and/or the NO donor L-arginine provided prophylactic as well as therapeutic protection from septic death while also increasing plasma Ang-1 levels among septic newborns. Our data highlight that targeting angiogenesis-associated pathways with interventions that increase Ang-1 activity directly or indirectly through ROS/eNOS provide promising avenues to prevent and/or treat severe neonatal sepsis.

What to do with an incidental finding of a fused sagittal suture: a modified Delphi study.

OBJECTIVE: As many as 5% of normocephalic children may have a prematurely fused sagittal suture, yet the clinical significance and best course of management of this finding remain unclear. Providers in the Synostosis Research Group were surveyed to create a multicenter consensus on an optimal treatment and monitoring algorithm for this condition. METHODS: A four-round modified Delphi method was utilized. The first two rounds consisted of anonymous surveys distributed to 10 neurosurgeons and 9 plastic surgeons with expertise in craniosynostosis across 9 institutions, and presented 3 patients (aged 3 years, 2 years, and 2 months) with incidentally discovered fused sagittal sutures, normal cephalic indices, and no parietal dysmorphology. Surgeons were queried about their preferred term for this entity and how best to manage these patients. Results were synthesized to create a treatment algorithm. The third and fourth feedback rounds consisted of open discussion of the algorithm until no further concerns arose. RESULTS: Most surgeons preferred the term "premature fusion of the sagittal suture" (93%). At the conclusion of the final round, all surgeons agreed to not operate on the 3- and 2-year-old patients unless symptoms of intracranial hypertension or papilledema were present. In contrast, 50% preferred to operate on the 2-month-old. However, all agreed to utilize shared decision-making, taking into account any concerns about future head shape and neurodevelopment. Panelists agreed that patients over 18 months of age without signs or symptoms suggesting elevated intracranial pressure (ICP) should not undergo surgical treatment. CONCLUSIONS: Through the Delphi method, a consensus regarding management of premature fusion of the sagittal suture was obtained from a panel of North American craniofacial surgeons. Without signs or symptoms of ICP elevation, surgery is not recommended in patients over 18 months of age. However, for children younger than 18 months, surgery should be discussed with caregivers using a shared decision-making process.

Adherence to adjuvant endocrine therapy for breast cancer: a qualitative exploration of attribution of symptoms among post-menopausal women.

PURPOSE: Oral adjuvant endocrine therapy (AET) is an effective treatment for hormone receptor positive breast cancer to decrease recurrence and mortality, but adherence is poor. This study explored post-menopausal women's experiences with AET, with a particular focus on adherence to AET as well as distress and symptoms experienced prior to and during AET treatment. METHODS: Participants were recruited from a hospital registry, stratified by adherence to/discontinuation of AET. Telephone interviews followed a semi-structured interview guide and were recorded and transcribed verbatim. Transcripts were systematically coded using team-based coding, with analysis of themes using a grounded theory approach. RESULTS: Thirty-three participants were interviewed; ages ranged from 57 to 86 years. Participants included 10 discontinued patients and 23 patients who completed their AET course or were adherent to AET at the time of interviewing. Both adherent and discontinued patients reported symptoms throughout their AET treatment course, and both attributed symptoms to factors other than AET (e.g., older age and pre-existing comorbidities). However, discontinued patients were more likely to attribute symptoms to AET and to describe difficulty managing their symptoms, with some directly citing symptoms as the reason for discontinuing AET therapy. Conversely, adherent patients were more likely to describe the necessity of taking AET, despite symptoms. CONCLUSIONS: AET adherence was associated with beliefs about AET, symptom attribution, and symptom management. Routine symptom monitoring during AET and addressing both symptoms and patients' understanding of their symptoms may promote adherence to AET.

Storylines of family medicine IV: perspectives on practice-lenses of appreciation.

Storylines of Family Medicine is a 12-part series of thematically linked mini-essays with accompanying illustrations that explore the many dimensions of family medicine, as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world. In 'IV: perspectives on practice-lenses of appreciation', authors address the following themes: 'Relational connections in the doctor-patient partnership', 'Feminism and family medicine', 'Positive family medicine', 'Mindful practice', 'The new, old ethics of family medicine', 'Public health, prevention and populations', 'Information mastery in family medicine' and 'Clinical courage.' May readers nurture their curiosity through these essays.

The Potential Economic Impact of the Updated COVID-19 mRNA Fall 2023 Vaccines in Japan.

This analysis estimates the economic and clinical impact of a Moderna updated COVID-19 mRNA Fall 2023 vaccine for adults ≥18 years in Japan. A previously developed Susceptible-Exposed-Infected-Recovered (SEIR) model with a one-year analytic time horizon (September 2023-August 2024) and consequences decision tree were used to estimate symptomatic infections, COVID-19 related hospitalizations, deaths, quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratio (ICER) for a Moderna updated Fall 2023 vaccine versus no additional vaccination, and versus a Pfizer-BioNTech updated mRNA Fall 2023 vaccine. The Moderna vaccine is predicted to prevent 7.2 million symptomatic infections, 272,100 hospitalizations and 25,600 COVID-19 related deaths versus no vaccine. In the base case (healthcare perspective), the ICER was ¥1,300,000/QALY gained ($9400 USD/QALY gained). Sensitivity analyses suggest results are most affected by COVID-19 incidence, initial vaccine effectiveness (VE), and VE waning against infection. Assuming the relative VE between both bivalent vaccines apply to updated Fall 2023 vaccines, the base case suggests the Moderna version will prevent an additional 1,100,000 symptomatic infections, 27,100 hospitalizations, and 2600 deaths compared to the Pfizer-BioNTech vaccine. The updated Moderna vaccine is expected to be highly cost-effective at a ¥5 million willingness-to-pay threshold across a wide range of scenarios.