Associations of cognitive appraisal and patient activation on disability and mental health outcomes: a prospective cohort study of patients undergoing spine surgery.

BACKGROUND: With the increased use of patient-reported outcomes measures (PROMs) to assess spine surgery outcomes, it is important to understand how patients interpret their health changes over time. The measurement of cognitive-appraisal processes enables the quantification of how individuals think about quality of life (QOL). This study examined how appraisal processes were associated with patients' views of their role in managing their health-patient activation. METHODS: This longitudinal cohort study from August 2019 to January 2022 included 222 adults undergoing spine surgery for cervical (n = 107) and/or lumbar (n = 148) pathology at an academic medical center. PROMs assessed disability (Neck Disability Index for cervical or Oswestry Disability Index for lumbar) and mental health (PROMIS-29 v2.0), cognitive-appraisal processes (QOLAPv2-SF), and patient activation (Patient Activation Measure). ANOVA models were used to examine the relationships between QOL and cognitive appraisal processes before and after surgery, overall and stratified by patient-activation stage. Effect sizes facilitated interpretation. RESULTS: There were significant improvements in pain-related disability and mental health following surgery. Cognitive appraisal processes explained substantial amounts of variance, particularly with changes in mental health (45% before surgery, 75% at three months, and 63%, at 12-months after surgery). With respect to physical disability, less disability was associated with a lesser focus on negative aspects of QOL. Appraisal explained the most variance before surgery for high-activation patients. At 12-months post-surgery, however, appraisal explained the most variance for the low-activation patients. Appraisal explained similar amounts of variance in mental health at baseline and three-months post-surgery for all activation groups, but substantially more variance in the low-activation group at 12-months post-surgery. There were differences in the direction of appraisal-outcome associations by activation group in selected appraisal items/domains. CONCLUSIONS: Cognitive-appraisal processes demonstrate a significant relationship with QOL among spine surgery patients. These processes explain substantial variance in pain-related disability and mental health, especially among those high in activation before surgery and those low in activation at 12-months post-surgery. Our findings suggest that patients' ways of thinking about their health may be effective targets of motivational coaching, to help them become more engaged over the recovery trajectory.

Psychosocial Risks and Adolescent Mental Health: The Moderating Role of Objective Neighborhood Characteristics.

PURPOSE: Although previous studies have examined the association between youth psychosocial risks and their perceptions of their neighborhood, it is unclear how objective neighborhood characteristics are associated with psychosocial risks and mental health symptoms among adolescents. We investigated how neighborhood characteristics moderate the relationship between youth psychosocial characteristics and mental health symptoms. METHODS: This cross-sectional study examined 13,837 emergency department visits by 14-18-year-olds who completed a standardized Behavioral Health Screening in a tertiary pediatric hospital in Philadelphia from 2013 to 2020. Psychosocial risk factors and mental health symptoms were assessed based on self-reported survey responses. We characterized neighborhoods as low-, moderate-, and high-stress based on gun violence incidence from 2013 to 2020 and the census tract-level Child Opportunity Index. Mixed effects logistic regression and Poisson models were used to examine moderation effects. RESULTS: The 9,814 included patients were 64% female and 64% non-Hispanic Black. The following psychosocial risk factors were associated with two to eight times higher odds of depressive symptoms and suicide risk: exposure to trauma, bullying at school, at-risk substance use, fighting, and retaliation. Adolescents living in high-stress neighborhoods were twice as likely to report fighting and retaliation and reported more psychosocial risk factors than those in low-stress neighborhoods. Odds of mental health symptoms increased with the number of psychosocial risk factors, particularly in youth from low-stress neighborhoods. DISCUSSION: Objective neighborhood characteristics had a significant interaction effect on the relationship between psychosocial risks and depression and suicide risk among adolescents seeking care in a pediatric emergency department.

Suicidal Ideation and Attempts Among Youth With Physical-Mental Comorbidity in Canada: Proposal for an Epidemiological Study.

BACKGROUND: Evidence suggests that having a chronic physical illness (CPI; eg, asthma, diabetes, and epilepsy) is an independent risk factor for suicidality (ie, suicidal ideation or attempts) among youth. Less is known about the mechanisms linking CPI and suicidality. Some evidence suggests that mental illness (eg, depression and anxiety) or neurodevelopmental disorder (eg, attention-deficit/hyperactivity disorder) mediates or moderates the CPI-suicidality association. Missing from the knowledge base is information on the association between having co-occurring CPI and mental illness or neurodevelopmental disorder (MIND) on youth suicidality. OBJECTIVE: This study uses epidemiological data from the 2019 Canadian Health Survey of Children and Youth (CHSCY) to study the intersection of CPI, MIND, and suicidality in youth. We will estimate prevalence, identify predictors, and investigate psychosocial and service use outcomes for youth with CPI-MIND comorbidity versus other morbidity groups (ie, healthy, CPI only, and MIND only). METHODS: Conducted by Statistics Canada, the CHSCY collected data from 47,850 children (aged 1-17 years) and their primary caregiving parent. Measures of youth CPI, MIND, family environment, and sociodemographics are available using youth and parent informants. Information on psychiatric services use is available via parent report and linkage to national administrative health data found in the National Ambulatory Care Reporting System and the Discharge Abstract Database, which allow the investigation of hospital-based mental health services (eg, emergency department visits, hospitalizations, and length of stay in hospital). Questions about suicidality were restricted to youths aged 15-17 years (n=6950), which form our analytic sample. Weighted regression-based analyses will account for the complex survey design. RESULTS: Our study began in November 2023, funded by the American Foundation for Suicide Prevention (SRG-0-008-22). Access to the linked CHSCY microdata file was granted in May 2024. Initial examination of CHSCY data shows that approximately 20% (1390/6950) of youth have CPI, 7% (490/6950) have MIND, 7% (490/6950) seriously considered suicide in the past year, and 3% (210/6950) had attempted suicide anytime during their life. CONCLUSIONS: Findings will provide estimates of suicidality among youth with CPI-MIND comorbidity, which will inform intervention planning to prevent loss of life in this vulnerable population. Modeling correlates of suicidality will advance understanding of the relative and joint effects of factors at multiple levels-information needed to target prevention efforts and services. Understanding patterns of psychiatric service use is vital to understanding access and barriers to services. This will inform whether use matches need, identifying opportunities to advise policy makers about upstream resources to prevent suicidality. Importantly, findings will provide robust baseline of information on the link between CPI-MIND comorbidity and suicidality in youth, which can be used by future studies to address questions related to the impact of the COVID-19 pandemic and associated countermeasures in this vulnerable population of youth. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/57103.

Treatment and Diagnostic Approach for Lhermitte-Duclos Disease and Suspected Cowden Syndrome.

Lhermitte-Duclos disease (LDD) is a rare entity, which may or may not be associated with Cowden syndrome (CS). The authors present a 26-year-old male with a history of emergency treatment due to acute obstructive hydrocephalus and apparent Chiari malformation. In posterior evaluation, mild cerebellar symptoms, mucocutaneous lesions, and a left hemispheric cerebellar lesion were evident. Initially, with the clinical evidence and the radiological study report of a cerebellar tiger-striped lesion, LDD with associated CS was suspected, and a genetic protocol was performed. The protocol included an endoscopy and thyroid ultrasound, and with symptom progression, a new neurosurgical procedure was performed. To complete the approach, we used the clinical criteria for PTEN hamartoma tumor syndrome established in 2013, and CS was diagnosed in the patient. In patients with radiological and clinical suspicion of LDD and CS, it should be mandatory to investigate the presence of other types of tumors due to their association with PTEN hamartomatous tumor syndrome, and in the absence of genetic study, the clinical criteria previously established in the literature should be sufficient to establish the diagnosis.

36-40% of Routine Care Patients With Osteoarthritis or Rheumatoid Arthritis Screen Positive for Anxiety, Depression, and/or Fibromyalgia on a Single MDHAQ.

OBJECTIVE: Osteoarthritis (OA) and rheumatoid arthritis (RA) are associated with similar patient disease burdens and a high prevalence of comorbid anxiety (ANX), depression (DEP), and fibromyalgia (FM). Nonetheless, these comorbidities are infrequently assessed in routine care, in part because multiple questionnaires are not feasibly completed by patients. We analyzed the prevalence of ANX, DEP, and FM in patients with OA versus patients with RA seen in routine care using indices within a single Multidimensional Health Assessment Questionnaire (MDHAQ) and associations with \ Routine Assessment of Patient Index Data 3 (RAPID3) and its component function, pain, and patient global scores. METHODS: A retrospective analysis of MDHAQ data in unselected patients with OA or RA receiving routine care at one setting included four indices within an MDHAQ: MDHAQ ANX screen, MDHAQ DEP screen, Fibromyalgia Assessment Screening Tool, and RAPID3. The prevalence of each comorbidity and associations with RAPID3 and components were analyzed in unadjusted and age-adjusted (Mantel-Haenszel) odds ratios (ORs) and 95% confidence intervals. RESULTS: Overall, 40.4% of 361 patients with OA and 36.3% of 488 patients with RA screened positive for ANX, DEP, and/or FM (8.1% and 7% for all three, respectively). RAPID3 and each component were elevated significantly in patients with any positive screen result for ANX, DEP, and/or FM in both diagnoses (ORs of 2.6-35.8). CONCLUSION: FM, DEP, and/or ANX rates were 40.4% in patients with OA and 36.3% in patients with RA, associated with significantly poorer patient status measures. Each of these three common comorbidities of patient distress may be feasibly screened for on a single MDHAQ in routine care.

Classification of Suicide Attempt Risk Using Environmental and Lifestyle Factors in 3 Large Youth Cohorts.

Importance: Suicide is the third-leading cause of death among US adolescents. Environmental and lifestyle factors influence suicidal behavior and can inform risk classification, yet quantifying and incorporating them in risk assessment presents a significant challenge for reproducibility and clinical translation. Objective: To quantify the aggregate contribution of environmental and lifestyle factors to youth suicide attempt risk classification. Design, Setting, and Participants: This was a cohort study in 3 youth samples: 2 national longitudinal cohorts from the US and the UK and 1 clinical cohort from a tertiary pediatric US hospital. An exposome-wide association study (ExWAS) approach was used to identify risk and protective factors and compute aggregate exposomic scores. Logistic regression models were applied to test associations and model fit of exposomic scores with suicide attempts in independent data. Youth from the Adolescent Brain Cognitive Development (ABCD) study, the UK Millennium Cohort Study (MCS), and the Children's Hospital of Philadelphia emergency department (CHOP-ED) were included in the study. Exposures: A single-weighted exposomic score that sums significant risk and protective environmental/lifestyle factors. Main Outcome and Measure: Self-reported suicide attempt. Results: A total of 40 364 youth were included in this analysis: 11 564 from the ABCD study (3 waves of assessment; mean [SD] age, 12.0 [0.7] years; 6034 male [52.2%]; 344 attempted suicide [3.0%]; 1154 environmental/lifestyle factors were included in the ABCD study), 9000 from the MCS cohort (mean [SD] age, 17.2 [0.3] years; 4593 female [51.0%]; 661 attempted suicide [7.3%]; 2864 environmental/lifestyle factors were included in the MCS cohort), and 19 800 from the CHOP-ED cohort (mean [SD] age, 15.3 [1.5] years; 12 937 female [65.3%]; 2051 attempted suicide [10.4%]; 36 environmental/lifestyle factors were included in the CHOP-ED cohort). In the ABCD discovery subsample, ExWAS identified 99 risk and protective exposures significantly associated with suicide attempt. A single weighted exposomic score that sums significant risk and protective exposures was associated with suicide attempt in an independent ABCD testing subsample (odds ratio [OR], 2.2; 95% CI, 2.0-2.6; P < .001) and explained 17.6% of the variance (based on regression pseudo-R2) in suicide attempt over and above that explained by age, sex, race, and ethnicity (2.8%) and by family history of suicide (6.3%). Findings were consistent in the MCS and CHOP-ED cohorts (explaining 22.6% and 19.3% of the variance in suicide attempt, respectively) despite clinical, demographic, and exposure differences. In all cohorts, compared with youth at the median quintile of the exposomic score, youth at the top fifth quintile were substantially more likely to have made a suicide attempt (OR, 4.3; 95% CI, 2.6-7.2 in the ABCD study; OR, 3.8; 95% CI, 2.7-5.3 in the MCS cohort; OR, 5.8; 95% CI, 4.7-7.1 in the CHOP-ED cohort). Conclusions and Relevance: Results suggest that exposomic scores of suicide attempt provided a generalizable method for risk classification that can be applied in diverse samples from clinical or population settings.

Sex differences in immune protection in mice conferred by heterologous vaccines for pneumonic plague.

Background: Yersinia pestis is the etiological agent of plague, which can manifest as bubonic, septicemic, and/or pneumonic disease. Plague is a severe and rapidly progressing illness that can only be successfully treated with antibiotics initiated early after infection. There are no FDA-approved vaccines for plague, and some vaccine candidates may be less effective against pneumonic plague than bubonic plague. Y. pestis is not known to impact males and females differently in mechanisms of pathogenesis or severity of infection. However, one previous study reported sex-biased vaccine effectiveness after intranasal Y. pestis challenge. As part of developing a safe and effective vaccine, it is essential that potential sex differences are characterized. Methods: In this study we evaluated novel vaccines in male and female BALB/c mice using a heterologous prime-boost approach and monitored survival, bacterial load in organs, and immunological correlates. Our vaccine strategy consisted of two subcutaneous immunizations, followed by challenge with aerosolized virulent nonencapsulated Y. pestis. Mice were immunized with a combination of live Y. pestis pgm- pPst-Δcaf1, live Y. pestis pgm- pPst-Δcaf1/ΔyopD, or recombinant F1-V (rF1-V) combined with adjuvants. Results: The most effective vaccine regimen was initial priming with rF1-V, followed by boost with either of the live attenuated strains. However, this and other strategies were more protective in female mice. Males had higher bacterial burden and differing patterns of cytokine expression and serum antibody titers. Male mice did not demonstrate synergy between vaccination and antibiotic treatment as repeatedly observed in female mice. Conclusions: This study provides new knowledge about heterologous vaccine strategies, sex differences in plague-vaccine efficacy, and the immunological factors that differ between male and female mice.

Use of online food delivery services among adults in five countries from the International Food Policy Study 2018-2021.

Aim: Online food delivery services (OFDS) are popular for purchasing meals prepared outside home, increasing access to energy-dense and nutrient-poor foods. This adversely impacts dietary choices and health outcomes. Our study examined trends in OFDS use in Australia, Canada, Mexico, the United Kingdom (UK), and the United States (US) from 2018 to 2021. Methods: Repeated annual cross-sectional data was sourced from the International Food Policy Study for five countries among adults over 18 years (N = 83,337). Weighted estimates for trends in i) the proportion of the respondent's purchasing meals per week using OFDS, and ii) average number (and standard deviation (SD)) of meals purchased per week using OFDS were assessed. Logistic regression models were fitted. Findings: OFDS use increased among adults between 2018-2021 (Australia: 17 % of respondents purchased at least one meal in the last 7 days using OFDS in 2018 to 25 % in 2021, Canada: 12 % to 19 %, Mexico: 28 % to 38 %, UK: 19 % to 28 %, and US: 17 % to 21 %). Average number of meals purchased per week outside home remained consistent for all countries over time (e.g., in Australia, 2.70 (SD 0.06) meals in 2018 and 2.63 (SD 0.06) in 2021). However, average number of meals purchased using OFDS nearly doubled between 2018 and 2021 (e.g., in Australia, 0.45 (SD 0.03) meals in 2018 to 0.81 (SD 0.04) in 2021). Conclusion: OFDS use is increasing and are substituting the conventional forms of purchasing meals outside home. Nutritional quality of foods sold, marketing practices and purchasing patterns on OFDS deserve further attention.

Using random forest to identify correlates of depression symptoms among adolescents.

PURPOSE: Adolescent depression is a significant public health concern, and studying its multifaceted factors using traditional methods possess challenges. This study employs random forest (RF) algorithms to determine factors predicting adolescent depression scores. METHODS: This study utilized self-reported survey data from 56,008 Canadian students (grades 7-12) attending 182 schools during the 2021/22 academic year. RF algorithms were applied to identify the correlates of (i) depression scores (CESD-R-10) and (ii) presence of clinically relevant depression (CESD-R-10 ≥ 10). RESULTS: RF achieved a 71% explained variance, accurately predicting depression scores within a 3.40 unit margin. The top 10 correlates identified by RF included other measures of mental health (anxiety symptoms, flourishing, emotional dysregulation), home life (excessive parental expectations, happy home life, ability to talk to family), school connectedness, sleep duration, and gender. In predicting clinically relevant depression, the algorithm showed 84% accuracy, 0.89 sensitivity, and 0.79 AUROC, aligning closely with the correlates identified for depression score. CONCLUSION: This study highlights RF's utility in identifying important correlates of adolescent depressive symptoms. RF's natural hierarchy offers an advantage over traditional methods. The findings underscore the importance and additional potential of sleep health promotion and school belonging initiatives in preventing adolescent depression.

Prion Seeding Activity in Plant Tissues Detected by RT-QuIC.

Prion diseases such as scrapie, bovine spongiform encephalopathy (BSE), and chronic wasting disease (CWD) affect domesticated and wild herbivorous mammals. Animals afflicted with CWD, the transmissible spongiform encephalopathy of cervids (deer, elk, and moose), shed prions into the environment, where they may persist and remain infectious for years. These environmental prions may remain in soil, be transported in surface waters, or assimilated into plants. Environmental sampling is an emerging area of TSE research and can provide more information about prion fate and transport once shed by infected animals. In this study, we have developed the first published method for the extraction and detection of prions in plant tissue using the real-time quaking-induced conversion (RT-QuIC) assay. Incubation with a zwitterionic surfactant followed by precipitation with sodium phosphotungstate concentrates the prions within samples and allows for sensitive detection of prion seeding activity. Using this protocol, we demonstrate that prions can be detected within plant tissues and on plant surfaces using the RT-QuIC assay.

Pulmonary Hypertension and Survival among Non-Small Cell Lung Cancer Patients: A Retrospective Cohort Study in the U.S. Military Health System.

Background: Lung cancer is one of the most lethal cancers with survival being closely related to stage and influenced by comorbid illness. The survival implications of pulmonary hypertension (PH) on patients with non-small cell lung cancer (NSCLC) have only been evaluated in small cohorts, with limited long-term follow-up. Methods: We conducted a retrospective cohort study of 7946 patients with NSCLC diagnosed in the MHS. This study evaluated the survival impact of PH in patients diagnosed with NSCLC in the MHS. Patients were classified as having and not having PH. We stratified PH into those diagnosed before the diagnosis of NSCLC and those diagnosed after NSCLC diagnosis. Results: Relative to patients without PH, patients with PH diagnosed before NSCLC had an increased risk of death (HR = 1.15 [95% CI, 1.02-1.29]). The increased risk of death was more obvious for patients with PH diagnosed after NSCLC compared with those without PH (HR = 2.74 [95% CI, 2.51-2.99]). The results were similar when stratified by patient demographics. Conclusions: In the MHS, PH is associated with worsened NSCLC survival, regardless of when it is diagnosed. When PH is diagnosed after NSCLC, it is associated with a marked reduction in survival, and this finding may suggest a potential role for monitoring pulmonary pressures in NSCLC patients. Furthermore, as specific PH therapy exists, some NSCLC patients with PH may be candidates for therapy.

Using Electronic Health Record Data to Determine the Safety of Aqueous Humor Liquid Biopsies for Molecular Analyses.

Purpose: Knowing the surgical safety of anterior chamber liquid biopsies will support the increased use of proteomics and other molecular analyses to better understand disease mechanisms and therapeutic responses in patients and clinical trials. Manual review of operative notes from different surgeons and procedures in electronic health records (EHRs) is cumbersome, but free-text software tools could facilitate efficient searches. Design: Retrospective case series. Participants: A total of 1418 aqueous humor liquid biopsies from patients undergoing intraocular surgery. Methods: Free-text EHR searches were performed using the Stanford Research Repository cohort discovery tool to identify complications associated with anterior chamber paracentesis and subsequent endophthalmitis. Complications of the surgery unrelated to the biopsy were not reviewed. Main Outcome Measures: Biopsy-associated intraoperative complications and endophthalmitis. Results: A total of 1418 aqueous humor liquid biopsies were performed by 17 experienced surgeons. EHR free-text searches were 100% error-free for surgical complications, >99% for endophthalmitis (<1% false positive), and >93.6% for anesthesia type, requiring manual review for only a limited number of cases. More than 85% of cases were performed under local anesthesia without ocular muscle akinesia. Although the most common indication was cataract (50.1%), other diagnoses included glaucoma, diabetic retinopathy, uveitis, age-related macular degeneration, endophthalmitis, retinitis pigmentosa, and uveal melanoma. A 50- to 100-µL sample was collected in all cases using either a 30-gauge needle or a blunt cannula via a paracentesis. The median follow-up was >7 months. There was only one minor complication (0.07%) identified: a case of a small tear in Descemet membrane without long-term sequelae. No other complications occurred, including other corneal injuries, lens or iris trauma, hyphema, or suprachoroidal hemorrhage. There was no case of postoperative endophthalmitis. Conclusions: Anterior chamber liquid biopsy during intraocular surgery is a safe procedure and may be considered for large-scale collection of aqueous humor samples for molecular analyses. Free-text EHR searches are an efficient approach to reviewing intraoperative procedures. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Mitotic kinases are emerging therapeutic targets against metastatic breast cancer.

This review aims to outline mitotic kinase inhibitors' roles as potential therapeutic targets and assess their suitability as a stand-alone clinical therapy or in combination with standard treatments for advanced-stage solid tumors, including triple-negative breast cancer (TNBC). Breast cancer poses a significant global health risk, with TNBC standing out as the most aggressive subtype. Comprehending the role of mitosis is crucial for understanding how TNBC advances from a solid tumor to metastasis. Chemotherapy is the primary treatment used to treat TNBC. Some types of chemotherapeutic agents target cells in mitosis, thus highlighting the need to comprehend the molecular mechanisms governing mitosis in cancer. This understanding is essential for devising targeted therapies to disrupt these mitotic processes, prevent or treat metastasis, and improve patient outcomes. Mitotic kinases like Aurora kinase A, Aurora Kinase B, never in mitosis gene A-related kinase 2, Threonine-Tyrosine kinase, and Polo-kinase 1 significantly impact cell cycle progression by contributing to chromosome separation and centrosome homeostasis. When these kinases go awry, they can trigger chromosome instability, increase cell proliferation, and activate different molecular pathways that culminate in a transition from epithelial to mesenchymal cells. Ongoing clinical trials investigate various mitotic kinase inhibitors as potential biological treatments against advanced solid tumors. While clinical trials against mitotic kinases have shown some promise in the clinic, more investigation is necessary, since they induce severe adverse effects, particularly affecting the hematopoietic system.

Fighting behavior, conflict perceptions, and firearm access among U.S. adolescents in a pediatric emergency department.

OBJECTIVE: Prior evidence demonstrates that both firearm access and fighting can predict future violence and injury in adolescents. We aimed to examine associations between firearm access with fighting behavior and conflict perception in a sample of adolescents in an urban emergency department (ED) setting. METHODS: In 2023, we conducted a secondary analysis of 13,610 adolescent encounters in the ED of a U.S. children's hospital from 2013 to 2020, using a universally applied, self-administered computerized behavioral health survey. We compared patient characteristics by reported firearm access and fighting behavior using chi-squared tests. Generalized estimating equations (GEE) were used to investigate associations between 1) fighting behavior and firearm access, and 2) between fighting behavior and respondent preference to and reporting of fighting incident to law enforcement after adjusting for race and ethnicity, age, and gender. RESULTS: Approximately one-quarter of the sample reported past year fighting. Youth who reported fighting were more likely to report firearm access (AOR = 1.66, 95%CI = [1.49-1.86]). This association strengthened among youth who perceived continued conflict after a fight (AOR = 2.05, 95%CI = [1.73-2.43]). Youth who perceived continued conflict following a fight were more likely to report (AOR = 1.97, 95%CI = [1.65-2.36]) or want to report (AOR = 2.63, 95%CI = [1.81-3.81]) the fight to law enforcement. CONCLUSIONS: Those perceiving continued conflict after a fight were more likely to report access to firearms and endorse retaliation; however, they were more likely to want to report the fight to law enforcement. These findings highlight the potential for more comprehensive ED risk assessment to reduce retaliation and reinjury for adolescents reporting fighting behavior.

Emerging Oral Pharmaceuticals for Dry Age-Related Macular Degeneration: Mechanism of Action, Current Clinical Status, and Future Directions.

Dry age-related macular degeneration (AMD) has been historically managed with lifestyle modifications, monitoring for conversion to wet AMD, and vitamins. Recently there has been a flurry of research focused on discovering new targets to prevent worsening of dry AMD. In 2023, the US Food and Drug Administration approved the first two intravitreal complement inhibitors to slow the rate of geographic atrophy progression. However, serial intravitreal injections for a chronic progressive disease are burdensome for patients and have procedural risks. Therefore, there is significant research to discover novel oral medications to manage dry AMD. Several oral medications are currently in phase 2 and 3 clinical trials for dry AMD, whereas others have had recent readouts on their clinical trials and efficacy. The purpose of this review is to describe the therapeutic pathways currently being investigated and to provide an update on the clinical status of novel oral medications for the management of dry AMD. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Consensus gene modules strategy identifies candidate blood-based biomarkers for primary Sjögren's disease.

Primary Sjögren disease (pSD) is an autoimmune disease characterized by lymphoid infiltration of exocrine glands leading to dryness of the mucosal surfaces and by the production of autoantibodies. The pathophysiology of pSD remains elusive and no treatment with demonstrated efficacy is available yet. To better understand the biology underlying pSD heterogeneity, we aimed at identifying Consensus gene Modules (CMs) that summarize the high-dimensional transcriptomic data of whole blood samples in pSD patients. We performed unsupervised gene classification on four data sets and identified thirteen CMs. We annotated and interpreted each of these CMs as corresponding to cell type abundances or biological functions by using gene set enrichment analyses and transcriptomic profiles of sorted blood cell subsets. Correlation with independently measured cell type abundances by flow cytometry confirmed these annotations. We used these CMs to reconcile previously proposed patient stratifications of pSD. Importantly, we showed that the expression of modules representing lymphocytes and erythrocytes before treatment initiation is associated with response to hydroxychloroquine and leflunomide combination therapy in a clinical trial. These consensus modules will help the identification and translation of blood-based predictive biomarkers for the treatment of pSD.

Analytical validation of a semi-automated methodology for quantitative measurement of SARS-CoV-2 RNA in wastewater collected in northern New England.

Wastewater-based epidemiology (WBE) can be used to monitor the community presence of infectious disease pathogens of public health concern such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Viral nucleic acid has been detected in the stool of SARS-CoV-2-infected individuals. Asymptomatic SARS-CoV-2 infections make community monitoring difficult without extensive and continuous population screening. In this study, we validated a procedure that includes manual pre-processing, automated SARS-CoV-2 RNA extraction and detection workflows using both reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) and reverse transcriptase droplet digital PCR (RT-ddPCR). Genomic RNA and calibration materials were used to create known concentrations of viral material to determine the linearity, accuracy, and precision of the wastewater extraction and SARS-CoV-2 RNA detection. Both RT-qPCR and RT-ddPCR perform similarly in all the validation experiments, with a limit of detection of 50 copies/mL. A wastewater sample from a care facility with a known outbreak was assessed for viral content in replicate, and we showed consistent results across both assays. Finally, in a 2-week survey of two New Hampshire cities, we assessed the suitability of our methods for daily surveillance. This paper describes the technical validation of a molecular assay that can be used for long-term monitoring of SARS-CoV-2 in wastewater as a potential tool for community surveillance to assist with public health efforts.IMPORTANCEThis paper describes the technical validation of a molecular assay that can be used for the long-term monitoring of SARS-CoV-2 in wastewater as a potential tool for community surveillance to assist with public health efforts.

Metabolomic Analysis and Antiviral Screening of a Marine Algae Library Yield Jobosic Acid (2,5-Dimethyltetradecanoic Acid) as a Selective Inhibitor of SARS-CoV-2.

Current small-molecule-based SARS-CoV-2 treatments have limited global accessibility and pose the risk of inducing viral resistance. Therefore, a marine algae and cyanobacteria extract library was screened for natural products that could inhibit two well-defined and validated COVID-19 drug targets, disruption of the spike protein/ACE-2 interaction and the main protease (Mpro) of SARS-CoV-2. Following initial screening of 86 extracts, we performed an untargeted metabolomic analysis of 16 cyanobacterial extracts. This approach led to the isolation of an unusual saturated fatty acid, jobosic acid (2,5-dimethyltetradecanoic acid, 1). We confirmed that 1 demonstrated selective inhibitory activity toward both viral targets while retaining some activity against the spike-RBD/ACE-2 interaction of the SARS-CoV-2 omicron variant. To initially explore its structure-activity relationship (SAR), the methyl and benzyl ester derivatives of 1 were semisynthetically accessed and demonstrated acute loss of bioactivity in both SARS-CoV-2 biochemical assays. Our efforts have provided copious amounts of a fatty acid natural product that warrants further investigation in terms of SAR, unambiguous determination of its absolute configuration, and understanding of its specific mechanisms of action and binding site toward new therapeutic avenues for SARS-CoV-2 drug development.

Location-based clinical and angiographic profile of brain arteriovenous malformations - a single-center observational study.

BACKGROUND: The location of brain arteriovenous malformations (bAVM) is one of the most relevant prognostic factors included in surgical, endovascular and radiosurgical scores. However, their characteristics according to location are seldom described. The goal of this study was to describe the clinical and angiographic characteristics of bAVM classified according to their location. METHODS: This retrospective observational study included patients diagnosed with bAVM and attending a national referral hospital during the period 2010-2020. Data regarding clinical and angiographic variables were extracted, including characteristics on nidus, arterial afferents, venous drainage and associated aneurysms. BAVM were classified in 8 groups according to their location: frontal, temporal, parieto-occipital, periventricular, deep, cerebellar, brainstem and mixed. Data distribution for each group was determined and between-group differences were assessed. RESULTS: A total of 269 bAVM (in 258 patients) were included. The most frequent location was parieto-occipital; and the least frequent, brainstem. Statistically significant differences were observed between groups for most studied variables, including: clinical presentation, functional status at admission; nidus size and density, classification according to the Spetzler-Martin, Buffalo and modified Pollock-Flickinger scales; number, diameter, origin and type of afferents; number, diameter, type and direction of venous drainage, retrograde venous flow; and presence and size of flow-related aneurysms. CONCLUSION: The clinical and angiographic differences observed between brain AVM groups allow the formulation of profiles according to their location.