Neurofilament Light Chain as a Biomarker of Global Cognition in Individuals With Possible Vascular Mild Cognitive Impairment.

BACKGROUND: Neurofilament Light Chain (NfL) is a biomarker of axonal injury elevated in mild cognitive impairment (MCI) and Alzheimer's disease dementia. Blood NfL also inversely correlates with cognitive performance in those conditions. However, few studies have assessed NfL as a biomarker of global cognition in individuals demonstrating mild cognitive deficits who are at risk for vascular-related cognitive decline. OBJECTIVE: To assess the relationship between blood NfL and global cognition in individuals with possible vascular MCI (vMCI) throughout cardiac rehabilitation (CR). Additionally, NfL levels were compared to age/sex-matched cognitively unimpaired (CU) controls. METHOD: Participants with coronary artery disease (vMCI or CU) were recruited at entry to a 24-week CR program. Global cognition was measured using the Montreal Cognitive Assessment (MoCA) and plasma NfL level (pg/ml) was quantified using a highly sensitive enzyme-linked immunosorbent assay. RESULTS: Higher plasma NfL was correlated with worse MoCA scores at baseline (ß = -.352, P = .029) in 43 individuals with vMCI after adjusting for age, sex, and education. An increase in NfL was associated with worse global cognition (b[SE] = -4.81[2.06], P = .023) over time, however baseline NfL did not predict a decline in global cognition. NfL levels did not differ between the vMCI (n = 39) and CU (n = 39) groups (F(1, 76) = 1.37, P = .245). CONCLUSION: Plasma NfL correlates with global cognition at baseline in individuals with vMCI, and is associated with decline in global cognition during CR. Our findings increase understanding of NfL and neurobiological mechanisms associated with cognitive decline in vMCI.

Modifiable Risk Factors Associated With Cognitive Decline in Late Life Depression: Findings From the Canadian Longitudinal Study on Aging: Facteurs de risque modifiables associés au déclin cognitif dans la dépression en fin de vie : constatations de l'Étude longitudinale canadienne sur le vieillissement.

OBJECTIVE: Depression in later life is associated with a two-fold increased risk of dementia. It is not clear to what extent potentially modifiable risk factors account for this association. METHOD: Older adults (age 50 + ) with objective health measures (n = 14,014) from the Canadian Longitudinal Study on Aging were followed for a mean duration of 35 months. Linear regression analyses were used to determine if clinically significant depression (Centre for Epidemiologic Studies Depression scale score (CESD) ≥ 10) was associated with global cognitive decline, assessed with a neuropsychological battery during follow-up, and if modifiable risk factors mediated this association. RESULTS: Depression was associated with an excess of risk factors for cognitive decline including: vascular disease, hypertension, diabetes, apnoea during sleep, higher body mass index, smoking, physical inactivity and lack of social participation. In regression analyses depression remained independently associated with cognitive decline over time (beta -0.060, P = 0.038) as did cerebrovascular disease (beta -0.197, P < 0.001), HbA1C (beta -0.059, P < 0.001), visual impairment (beta -0.070, P = 0.007), hearing impairment (beta -0.098, P < 0.001) and physical inactivity (beta -0.075, P = 0.014). In mediation analyses, we found that cerebrovascular disease (z = -3.525, P < 0.001), HbA1C (z = -4.976, P < 0.001) and physical inactivity (z = -3.998, P < 0.001) partially mediated the association between depression and cognitive decline. CONCLUSIONS: In this large sample of Canadian older adults incorporating several objective health measures, older adults with depression were at increased risk of cognitive decline and had an excess of potentially modifiable risk factors. Clinicians should pay particular attention to control of diabetes, physical inactivity and risk factors for cerebrovascular disease in older adults presenting with depression as they can contribute to accelerated cognitive decline and may be addressed during routine clinical care.

3D CT Radiomic Analysis Improves Detection of Axillary Lymph Node Metastases Compared to Conventional Features in Patients With Locally Advanced Breast Cancer.

OBJECTIVE: Preoperative detection of axillary lymph node metastases (ALNMs) from breast cancer is suboptimal; however, recent work suggests radiomics may improve detection of ALNMs. This study aims to develop a 3D CT radiomics model to improve detection of ALNMs compared to conventional imaging features in patients with locally advanced breast cancer. METHODS: Retrospective chart review was performed on patients referred to a specialty breast cancer center between 2015 and 2020 with US-guided biopsy-proven ALNMs and pretreatment chest CT. One hundred and twelve patients (224 lymph nodes) met inclusion and exclusion criteria and were assigned to discovery (n = 150 nodes) and testing (n = 74 nodes) cohorts. US-biopsy images were referenced in identifying ALNMs on CT, with contralateral nodes taken as negative controls. Positive and negative nodes were assessed for conventional features of lymphadenopathy as well as for 107 radiomic features extracted following 3D segmentation. Diagnostic performance of individual and combined radiomic features was evaluated. RESULTS: The strongest conventional imaging feature of ALNMs was short axis diameter ≥10 mm with a sensitivity of 64%, specificity of 95%, and area under the curve (AUC) of 0.89 (95% CI, 0.84-0.94). Several radiomic features outperformed conventional features, most notably energy, a measure of voxel density magnitude. This feature demonstrated a sensitivity, specificity, and AUC of 91%, 79%, and 0.94 (95% CI, 0.91-0.98) for the discovery cohort. On the testing cohort, energy scored 92%, 81%, and 0.94 (95% CI, 0.89-0.99) for sensitivity, specificity, and AUC, respectively. Combining radiomic features did not improve AUC compared to energy alone (P = .08). CONCLUSION: 3D radiomic analysis represents a promising approach for noninvasive and accurate detection of ALNMs.

The influence of depression and anxiety on cognition in people with multiple sclerosis: a cross-sectional analysis.

There are conflicting findings about the relationships between depression, anxiety, and cognitive dysfunction in people with multiple sclerosis (MS), and a paucity of research has examined the cumulative influence on cognition of depression plus anxiety. This study aimed to determine whether elevated symptoms of depression and anxiety alone or in combination are associated with worse cognition in people with MS. In this cross-sectional analysis, people with MS consecutively seen at a tertiary neuropsychiatry clinic completed the Hospital Anxiety and Depression Scale for symptoms of depression (HADS-D) and anxiety (HADS-A), and the Minimal Assessment of Cognitive Function in MS for cognitive indices. Accounting for covariates, regression models predicted cognitive indices from scores for HADS-D, HADS-A, and the interaction. Of 831 people with MS, 72% were female, mean age was 43.2 years, and median Expanded Disability Status Scale score was 2.0. Depressive symptoms were independently predictive of lower verbal fluency (Controlled Oral Word Association Test, p < 0.01), verbal learning (California Verbal Learning Test-II (CVLT-II) total learning, p = 0.02), verbal delayed recall (CVLT-II delayed recall, p < 0.01), and processing speed (Symbol Digit Modalities Test, p < 0.01; three-second Paced Auditory Serial Addition Test (PASAT), p = 0.05; two-second PASAT, p = 0.01). Anxiety in people with depression predicted decreased visuospatial function (Judgment of Line Orientation, p = 0.05), verbal learning (p < 0.01), verbal delayed recall (p < 0.01), visuospatial recall (Brief Visuospatial Memory Test-Revised, p = 0.02), and executive function (Delis-Kaplan Executive Function System, p < 0.01). Anxiety alone was not independently predictive of cognition. In conclusion, depression, especially with comorbid anxiety, is associated with cognitive dysfunction in people with MS.

Ultrasound-guided suprainguinal fascia iliaca compartment block and early postoperative analgesia after total hip arthroplasty: a randomised controlled trial.

BACKGROUND: Hip replacement surgery can be painful; postoperative analgesia is crucial for comfort and to facilitate recovery. Regional anaesthesia can reduce pain and postoperative opioid requirements. The role of ultrasound-guided suprainguinal fascia iliaca block for analgesia after elective total hip arthroplasty is not well defined. This randomised trial evaluated its analgesic efficacy. METHODS: Consenting participants (134) scheduled for elective primary total hip arthroplasty under spinal anaesthesia were randomly allocated to receive ultrasound-guided fascia iliaca block with ropivacaine 0.5% or sham block with saline. The primary outcome was opioid consumption in the first 24 h after surgery. Additional outcomes included pain scores at 4, 8, 12, and 16 h, opioid-related side-effects (nausea, vomiting, pruritis), ability to perform physiotherapy on the first postoperative day, and physiotherapist-assessed quadriceps weakness. RESULTS: There were no significant differences in 24-h opioid consumption (block vs sham block, mean difference -3.2 mg oral morphine equivalent, 95% confidence interval -15.3 to 8.1 mg oral morphine equivalent, P=0.55) or any other prespecified outcomes. CONCLUSIONS: In patients undergoing primary total hip arthroplasty, ultrasound-guided suprainguinal fascia iliaca block with ropivacaine did not confer a significant opioid-sparing effect compared with sham block. There were no differences in other secondary outcomes including pain scores, opioid-related side-effects, or ability to perform physiotherapy on the first postoperative day. CLINICAL TRIAL REGISTRATION: www. CLINICALTRIALS: gov (NCT03069183).

Contemporary trends in the incidence and timing of spinal metastases: A population-based study.

Background: Spinal metastases are a significant complication of advanced cancer. In this study, we assess temporal trends in the incidence and timing of spinal metastases and examine underlying patient demographics and primary cancer associations. Methods: In this population-based retrospective cohort study, health data from 2007 to 2019 in Ontario, Canada were analyzed (n = 37, 375 patients identified with spine metastases). Primary outcomes were annual incidence of spinal metastasis, and time to metastasis after primary diagnosis. Results: The age-standardized incidence of spinal metastases increased from 229 to 302 cases per million over the 13-year study period. The average annual percent change (AAPC) in incidence was 2.2% (95% CI: 1.4% to 3.0%) with patients aged ≥85 years demonstrating the largest increase (AAPC 5.2%; 95% CI: 2.3% to 8.3%). Lung cancer had the greatest annual incidence, while prostate cancer had the greatest increase in annual incidence (AAPC 6.5; 95% CI: 4.1% to 9.0%). Lung cancer patients were found to have the highest risk of spine metastasis with 10.3% (95% CI: 10.1% to 10.5%) of patients being diagnosed at 10 years. Gastrointestinal cancer patients were found to have the lowest risk of spine metastasis with 1.0% (95% CI: 0.9% to 1.0%) of patients being diagnosed at 10 years. Conclusions: The incidence of spinal metastases has increased in recent years, particularly among older patients. The incidence and timing vary substantially among different primary cancer types. These findings contribute to the understanding of disease trends and emphasize a growing population of patients who require subspecialty care.

Predictors of SARS-CoV-2 transmission in congregate living settings: a multicenter prospective study.

BACKGROUND: Older adults residing in congregate living settings (CLS) such as nursing homes and independent living facilities remain at increased risk of morbidity and mortality from coronavirus disease 2019. We performed a prospective multicenter study of consecutive severe acute respiratory coronavirus virus 2 (SARS-CoV-2) exposures to identify predictors of transmission in this setting. METHODS: Consecutive resident SARS-CoV-2 exposures across 17 CLS were prospectively characterized from 1 September 2022 to 1 March 2023, including factors related to environment, source, and exposed resident. Room size, humidity, and ventilation were measured in locations where exposures occurred. Predictors were incorporated in a generalized estimating equation model adjusting for the correlation within CLS. RESULTS: Among 670 consecutive exposures to SARS-CoV-2 across 17 CLS, transmission occurred among 328 (49.0%). Increased risk was associated with nursing homes (odds ratio (OR) = 90.8; 95% CI, 7.8-1047.4), Jack and Jill rooms (OR = 2.2; 95% CI, 1.3-3.6), from source who was pre-symptomatic (OR = 11.2; 95% CI, 4.1-30.9), symptomatic (OR = 6.5; 95% CI, 1.4-29.9), or rapid antigen test positive (OR = 35.6; 95% CI, 5.6-225.6), and in the presence of secondary exposure (OR = 6.3; 95% CI, 1.6-24.0). Exposure in dining room was associated with reduced risk (OR = 0.02; 95% CI, 0.005-0.08) as was medium room size (OR = 0.3; 95% CI, 0.2-0.6). Recent vaccination of exposed resident (OR = 0.5; 95% CI, 0.3-1.0) and increased ventilation of room (OR = 0.9; 95% CI, 0.8-1.0) were marginally associated with reduced risk. CONCLUSION: Prospective assessment of SARS-CoV-2 exposures in CLS suggests that source characteristics and location of exposure are most predictive of resident transmission. These findings can inform risk assessment and further opportunities to prevent transmission in CLS.

SARS-CoV-2 antibodies and their neutralizing capacity against live virus in human milk after COVID-19 infection and vaccination: prospective cohort studies.

BACKGROUND: There is limited understanding of the impact of coronavirus disease 2019 (COVID-19) infection and vaccination type and interval on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) human milk antibodies and their neutralizing capacity. OBJECTIVES: These cohort studies aimed to determine the presence of antibodies and live virus neutralizing capacity in milk from females infected with COVID-19, unexposed milk bank donors, and vaccinated females and examine impacts of vaccine interval and type. METHODS: Milk was collected from participants infected with COVID-19 during pregnancy or lactation (Cohort-1) and milk bank donors (Cohort-2) from March 2020-July 2021 at 3 sequential 4-wk intervals and COVID-19 vaccinated participants with varying dose intervals (Cohort-3) (January-October 2021). Cohort-1 and Cohort-3 were recruited from Sinai Health (patients) and through social media. Cohort-2 included Ontario Milk Bank donors. Milk was examined for SARS-CoV-2 antibodies and live virus neutralization. RESULTS: Of females with COVID-19, 53% (Cohort-1, n = 55) had anti-SARS-CoV-2 IgA antibodies in ≥1 milk sample. IgA+ samples (40%) were more likely neutralizing than IgA- samples (odds ratio [OR]: 2.18; 95% confidence interval [CI]: 1.03, 4.60; P = 0.04); however, 25% of IgA- samples were neutralizing. Both IgA positivity and neutralization decreased ∼6 mo after symptom onset (0-100 compared with 201+ d: IgA OR: 14.30; 95% CI: 1.08, 189.89; P = 0.04; neutralizing OR: 4.30; 95% CI: 1.55, 11.89; P = 0.005). Among milk bank donors (Cohort-2, n = 373), 4.3% had IgA antibodies; 23% of IgA+ samples were neutralizing. Vaccination (Cohort-3, n = 60) with mRNA-1273 and shorter vaccine intervals (3 to <6 wk) resulted in higher IgA and IgG than BNT162b2 (P < 0.04) and longer intervals (6 to <16 wk) (P≤0.02), respectively. Neutralizing capacity increased postvaccination (P = 0.04) but was not associated with antibody positivity. CONCLUSIONS: SARS-CoV-2 infection and vaccination (type and interval) impacted milk antibodies; however, antibody presence did not consistently predict live virus neutralization. Although human milk is unequivocally the best way to nourish infants, guidance on protection to infants following maternal infection/vaccination may require more nuanced messaging. This study was registered at clinicaltrials.gov as NCT04453969 and NCT04453982.

Impact of a peer-support programme to improve loneliness and social isolation due to COVID-19: does adding a secure, user friendly video-conference solution work better than telephone support alone? Protocol for a three-arm randomised clinical trial.

INTRODUCTION: The COVID-19 pandemic has forced the implementation of physical distancing and self-isolation strategies worldwide. However, these measures have significant potential to increase social isolation and loneliness. Among older people, loneliness has increased from 40% to 70% during COVID-19. Previous research indicates loneliness is strongly associated with increased mortality. Thus, strategies to mitigate the unintended consequences of social isolation and loneliness are urgently needed. Following the Obesity-Related Behavioural Intervention Trials model for complex behavioural interventions, we describe a protocol for a three-arm randomised clinical trial to reduce social isolation and loneliness. METHODS AND ANALYSIS: A multicentre, outcome assessor blinded, three-arm randomised controlled trial comparing 12 weeks of: (1) the HOspitals WoRking in Unity ('HOW R U?') weekly volunteer-peer support telephone intervention; (2) 'HOW R U?' deliver using a video-conferencing solution and (3) a standard care group. The study will follow Consolidated Standard of Reporting Trials guidelines.We will recruit 24-26 volunteers who will receive a previously tested half day lay-training session that emphasises a strength-based approach and safety procedures. We will recruit 141 participants ≥70 years of age discharged from two participating emergency departments or referred from hospital family medicine, geriatric or geriatric psychiatry clinics. Eligible participants will have probable baseline loneliness (score ≥2 on the de Jong six-item loneliness scale). We will measure change in loneliness, social isolation (Lubben social network scale), mood (Geriatric Depression Score) and quality of life (EQ-5D-5L) at 12-14 weeks postintervention initiation and again at 24-26 weeks. ETHICS AND DISSEMINATION: Approval has been granted by the participating research ethics boards. Participants randomised to standard care will be offered their choice of telephone or video-conferencing interventions after 12 weeks. Results will be disseminated through journal publications, conference presentations, social media and through the International Federation of Emergency Medicine. TRIAL REGISTRATION NUMBER: NCT05228782.

Predictors of later COVID-19 test seeking.

Background: Delays in COVID-19 testing may increase the risk of secondary household and community transmission. Little is known about what patient characteristics and symptom profiles are associated with delays in test seeking. Methods: We conducted a retrospective cohort study of all symptomatic patients diagnosed with COVID-19 and assessed in a COVID Expansion to Outpatients (COVIDEO) virtual care program between March 2020 and June 2021. The primary outcome was later test seeking more than 3 days from symptom onset. Multivariable logistic regression was used to examine predictors of later testing including patient characteristics and symptoms (30 individual symptoms or 7 symptom clusters). Results: Of 5,363 COVIDEO patients, 4,607 were eligible and 2,155/4,607 (46.8%) underwent later testing. Older age was associated with increased odds of late testing (adjusted odds ratio [aOR] 1.007/year; 95% CI 1.00 to 1.01), as was history of recent travel (aOR 1.4; 95% CI 1.01 to 1.95). Health care workers had lower odds of late testing (aOR 0.50; 95% CI 0.39 to 0.62). Late testing was associated with symptoms in the cardiorespiratory (aOR 1.2; 95% CI 1.05, 1.36), gastrointestinal (aOR = 1.2; 95% CI 1.04, 1.4), neurological (aOR 1.1; 95% CI 1.003, 1.3) and psychiatric (aOR 1.3; 95% CI 1.1, 1.5) symptom clusters. Among individual symptoms, dyspnea, anosmia, dysgeusia, sputum, and anorexia were associated with late testing; pharyngitis, myalgia, and headache were associated with early testing. Conclusion: Certain patient characteristics and symptoms are associated with later testing, and warrant further efforts to encourage earlier testing to minimize transmission.

Historique: Les retards à effectuer les tests de dépistage de la COVID-19 peuvent accroître le risque de transmission secondaire dans la famille et la communauté. On ne sait pas vraiment quels sont les caractéristiques des patients et leurs profils de symptômes associés aux retards à se faire dépister. Méthodologie: Les chercheurs ont réalisé une étude de cohorte auprès de tous les patients symptomatiques ayant obtenu un diagnostic de COVID-19 évalués dans le cadre du programme de soins virtuels COVID Expansion to Outpatients (COVIDEO, ou expansion de la COVID aux patients ambulatoires) entre mars 2020 et juin 2021. Le résultat primaire était une demande de dépistage plus de trois jours après l'apparition des symptômes. Les chercheurs ont utilisé la régression logistique multivariable pour examiner les prédicteurs d'un dépistage tardif, y compris les caractéristiques et les symptômes des patients (30 symptômes individuels ou sept grappes de symptômes). Résultats: Des 5 363 patients ayant participé au programme COVIDEO, 4 607 étaient admissibles et 2 155 de ces 4 607 (46,8 %) se sont soumis à un dépistage tardif. Une plus grande probabilité de dépistage tardif était liée à un âge avancé (rapport de cotes corrigé [RCc] 1,007/année, IC à 95 %, 1,00 à 1,01), de même qu'à un voyage récent (RCc = 1,4, IC à 95 %, 1,01 à 1,95). Les travailleurs de la santé étaient moins susceptibles de se faire dépister tardivement (RCc = 0,50, IC à 95 %, 0,39 à 0,62). Le dépistage tardif était associé à des symptômes de la grappe cardiorespiratoire (RCc = 1,2, IC à 95 %, [1,05, 1,36]), gastrointestinale (RCc = 1,2, IC à 95 %, [1,04, 1,4]), neurologique (RCc = 1,1, IC à 95 %, [1,003, 1,3]) et psychiatrique (RCc = 1,3, IC à 95 %, [1,1, 1,5]). Parmi les symptômes individuels, la dyspnée, l'anosmie, la dysgueusie, les expectorations et l'anorexie étaient associées à un dépistage tardif, et la pharyngite, les myalgies et les céphalées, à un dépistage précoce. Conclusion: Certaines caractéristiques des patients et certains symptômes étaient associés à un dépistage tardif, ce qui justifie des efforts supplémentaires pour favoriser un dépistage plus rapide afin de limiter la transmission. Summary: This study of more than 4,000 patients with COVID-19 identified predictors of later test seeking, including older age, recent travel, non-health care worker occupation, cardiorespiratory, gastrointestinal, neurologic and psychiatric symptom clusters, and dyspnea, anosmia, dysgeusia, sputum, and anorexia.

Treatment affects load to failure and microdamage accumulation in healthy and osteolytic rat vertebrae.

Bone turnover and microdamage are impacted by the presence of skeletal metastases which can contribute to increased fracture risk. Treatments for metastatic disease may further impact bone quality. This exploratory study aimed to establish an initial understanding of microdamage accumulation and load to failure in healthy and osteolytic rat vertebrae following focal and systemic cancer treatment (docetaxel (DTX), stereotactic body radiotherapy (SBRT), or zoledronic acid (ZA)). Osteolytic spine metastases were developed in 6-week-old athymic female rats via intracardiac injection of HeLa human cervical cancer cells (day 0). Additional rats served as healthy controls. Rats were either untreated, received SBRT to the T10-L6 vertebrae on day 14 (15 Gy, two fractions), DTX on day 7 or 14, or ZA on day 7. Rats were euthanized on day 21. Tumor burden was assessed with bioluminescence images acquired on day 14 and 21, histology of the excised T11 and L5 vertebrae, and ex-vivo µCT images of the T13-L4. Microstructural parameters (bone volume/total volume, trabecular number, spacing, thickness, and bone mineral density) were measured from L2 vertebrae. Load to failure was measured with axial compressive loading of the L1-L3 motion segments. Microdamage accumulation was labeled in T13 vertebrae with BaSO4 staining and was visualized with high resolution µCT imaging. Microdamage volume fraction was defined as the ratio of BaSO4 to bone volume. DTX administered on day 7 reduced tumor growth significantly (p < 0.05). Microdamage accumulation was found to be increased by the presence of metastases but was reduced by all treatments with ZA showing the largest improvement in HeLa cell injected rats. Load to failure was decreased in untreated and SBRT HeLa cell injected rats compared to healthy controls (p < 0.01). There was a moderate negative correlation between load to failure and microdamage volume fraction in vertebrae from rats injected with HeLa cells (R = -0.35, p = 0.031). Strong correlations were also found between microstructural parameters and load to failure and microdamage accumulation. Several factors, including the presence of osteolytic lesions and use of cancer therapies, influence microdamage accumulation and load to failure in rat vertebrae. Understanding the impact of these treatments on fracture risk of metastatic vertebrae is important to improve management of patients with spinal metastases.

Predicting Patterns of Distant Metastasis in Breast Cancer Patients following Local Regional Therapy Using Machine Learning.

Up to 30% of breast cancer (BC) patients will develop distant metastases (DM), for which there is no cure. Here, statistical and machine learning (ML) models were developed to estimate the risk of site-specific DM following local-regional therapy. This retrospective study cohort included 175 patients diagnosed with invasive BC who later developed DM. Clinicopathological information was collected for analysis. Outcome variables were the first site of metastasis (brain, bone or visceral) and the time interval (months) to developing DM. Multivariate statistical analysis and ML-based multivariable gradient boosting machines identified factors associated with these outcomes. Machine learning models predicted the site of DM, demonstrating an area under the curve of 0.74, 0.75, and 0.73 for brain, bone and visceral sites, respectively. Overall, most patients (57%) developed bone metastases, with increased odds associated with estrogen receptor (ER) positivity. Human epidermal growth factor receptor-2 (HER2) positivity and non-anthracycline chemotherapy regimens were associated with a decreased risk of bone DM, while brain metastasis was associated with ER-negativity. Furthermore, non-anthracycline chemotherapy alone was a significant predictor of visceral metastasis. Here, clinicopathologic and treatment variables used in ML prediction models predict the first site of metastasis in BC. Further validation may guide focused patient-specific surveillance practices.

Gene mutations as a non-invasive measure of adult cochlear implant performance: Variable outcomes in patients with select TMPRSS3 mutations.

BACKGROUND: The cochlear implant (CI) has proven to be a successful treatment for patients with severe-to-profound sensorineural hearing loss, however outcome variance exists. We sought to evaluate particular mutations discovered in previously established sensory and neural partition genes and compare post-operative CI outcomes. MATERIALS AND METHODS: Utilizing a prospective cohort study design, blood samples collected from adult patients with non-syndromic hearing loss undergoing CI were tested for 54 genes of interest with high-throughput sequencing. Patients were categorized as having a pathogenic variant in the sensory partition, pathogenic variant in the neural partition, pathogenic variant in both sensory and neural partition, or with no variant identified. Speech perception performance was assessed pre- and 12 months post-operatively. Performance measures were compared to genetic mutation and variant status utilizing a Wilcoxon rank sum test, with P<0.05 considered statistically significant. RESULTS: Thirty-six cochlear implant patients underwent genetic testing and speech understanding measurements. Of the 54 genes that were interrogated, three patients (8.3%) demonstrated a pathogenic mutation in the neural partition (within TMPRSS3 genes), one patient (2.8%) demonstrated a pathogenic mutation in the sensory partition (within the POU4F3 genes). In addition, 3 patients (8.3%) had an isolated neural partition variance of unknown significance (VUS), 5 patients (13.9%) had an isolated sensory partition VUS, 1 patient (2.8%) had a variant in both neural and sensory partition, and 23 patients (63.9%) had no mutation or variant identified. There was no statistically significant difference in speech perception scores between patients with sensory or neural partition pathogenic mutations or VUS. Variable performance was found within patients with TMPRSS3 gene mutations. CONCLUSION: The impact of genetic mutations on post-operative outcomes in CI patients was heterogenous. Future research and dissemination of mutations and subsequent CI performance is warranted to elucidate exact mutations within target genes providing the best non-invasive prognostic capability.

Progression to malignancy in oral potentially malignant disorders: a retrospective study of 5,036 patients in Ontario, Canada.

OBJECTIVES: Determine the rate of malignant transformation (MT) of oral potentially malignant disorders (OPMDs) and risk factors for transformation. STUDY DESIGN: The OPMD database (2001-2015) from 2 biopsy services in Ontario, Canada, was linked to the Ontario Cancer Registry to determine the rate of progression to oral squamous cell carcinoma (OSCC). Clinical and histologic features of progressed and non-progressed cases were compared to determine risk factors for progression. RESULTS: The MT rate was 6.4% (322/5,036 cases). The mean time for cancer development was 51.2 months. 33.6% of cases (107/322) progressed after over 60 months. The risk of cancer increased with age and was higher in non-smokers. The MT rate was highest in the tongue (11.4%), followed by the floor of mouth (7.1%) and gingiva (6.5%). Histologic grade was associated with progression to cancer (P < .0001). Atypical verrucous-papillary lesions with no or mild dysplasia predominantly affected older patients' gingiva, and the progression rate was significantly higher than conventional mild dysplasia (9.2% vs 3.2%, P = .0002). CONCLUSIONS: Our population-based retrospective study showed that <10% of OPMDs progressed to cancer, which could take many years. Atypical papillary-verrucous proliferation without high-grade dysplasia is a subtype of OPMD requiring further study.

Randomized trial of personalized psychological feedback from a longitudinal online survey and simultaneous evaluation of randomized stepped wedge availability of in-person peer support for hospital staff during the COVID-19 pandemic.

OBJECTIVE: We tested if automated Personalized Self-Awareness Feedback (PSAF) from an online survey or in-person Peer Resilience Champion support (PRC) reduced emotional exhaustion among hospital workers during the COVID-19 pandemic. METHOD: Among a single cohort of participating staff from one hospital organization, each intervention was evaluated against a control condition with repeated measures of emotional exhaustion at quarterly intervals for 18 months. PSAF was tested in a randomized controlled trial compared to a no-feedback condition. PRC was tested in a group-randomized stepped-wedge design, comparing individual-level emotional exhaustion before and after availability of the intervention. Main and interactive effects on emotional exhaustion were tested in a linear mixed model. RESULTS: Among 538 staff, there was a small but significant beneficial effect of PSAF over time (p = .01); the difference at individual timepoints was only significant at timepoint three (month six). The effect of PRC over time was non-significant with a trend in the opposite direction to a treatment effect (p = .06). CONCLUSIONS: In a longitudinal assessment, automated feedback about psychological characteristics buffered emotional exhaustion significantly at six months, whereas in-person peer support did not. Providing automated feedback is not resource-intensive and merits further investigation as a method of support.

Drivers of Emergency Department Use Among Oncology Patients in the Era of Novel Cancer Therapeutics: A Systematic Review.

BACKGROUND: Patients diagnosed with cancer are frequent users of the emergency department (ED). While many visits are unavoidable, a significant portion may be potentially preventable ED visits (PPEDs). Cancer treatments have greatly advanced, whereby patients may present with unique toxicities from targeted therapies and are often living longer with advanced disease. Prior work focused on patients undergoing cytotoxic chemotherapy, and often excluded those on supportive care alone. Other contributors to ED visits in oncology, such as patient-level variables, are less well-established. Finally, prior studies focused on ED diagnoses to describe trends and did not evaluate PPEDs. An updated systematic review was completed to focus on PPEDs, novel cancer therapies, and patient-level variables, including those on supportive care alone. METHODS: Three online databases were used. Included publications were in English, from 2012-2022, with sample sizes of ≥50, and reported predictors of ED presentation or ED diagnoses in oncology. RESULTS: 45 studies were included. Six studies highlighted PPEDs with variable definitions. Common reasons for ED visits included pain (66%) or chemotherapy toxicities (69.1%). PPEDs were most frequent amongst breast cancer patients (13.4%) or patients receiving cytotoxic chemotherapy (20%). Three manuscripts included immunotherapy agents, and only one focused on end-of-life patients. CONCLUSION: This updated systematic review highlights variability in oncology ED visits during the last decade. There is limited work on the concept of PPEDs, patient-level variables and patients on supportive care alone. Overall, pain and chemotherapy toxicities remain key drivers of ED visits in cancer patients. Further work is needed in this realm.

Characterizing PRN Use of Psychotropic Medications for Acute Agitation in Canadian Long-Term Care Residents with Dementia Before and During COVID-19.

Background: Agitation is a disabling neuropsychiatric symptom of dementia. Pro re nata (PRN) injections of psychotropics can be administered for severe acute agitation, but little is known about the frequency of their actual use. Objective: Characterize actual use of injectable PRN psychotropics for severe acute agitation in Canadian long-term care (LTC) residents with dementia and compare use before and during the COVID-19 pandemic. Methods: Residents from two Canadian LTC facilities with orders for PRN haloperidol, olanzapine, or lorazepam between January 1, 2018- May 1, 2019 (i.e., pre-COVID-19) and January 1, 2020- May 1, 2021 (i.e., COVID-19) were identified. Electronic medical records were reviewed to document PRN injections of psychotropic medications and collect data on reason and demographic characteristics. Descriptive statistics were used to characterize frequency, dose, and indications of use, and multivariate regression models were used to compare use between time periods. Results: Of the 250 residents, 45 of 103 (44%) people in the pre-COVID-19 period and 85 of 147 (58%) people in the COVID-19 period with standing orders for PRN psychotropics received ≥1 injections. Haloperidol was the most frequently used agent in both time periods (74% (155/209 injections) pre-COVID-19; 81% (323/398 injections) during COVID-19). Residents in the COVID-19 period were almost two times more likely to receive injections compared with those in the pre-COVID-19 period (odds ratio = 1.96; 95% CI = 1.15-3.34; p = 0.01). Conclusion: Our results suggest that use of PRN injections increased in LTC during the pandemic and contribute to the mounting evidence that agitation worsened during that time.

Boswellic Acids Improve Clinical Cognitive Scores and Reduce Systemic Inflammation in Patients with Mild to Moderate Alzheimer's Disease.

BACKGROUND: Recent therapeutic approaches for Alzheimer's disease (AD) have had limited success. Considering the association of neuroinflammation with AD symptoms as demonstrated in multiple studies, assessment of the clinical efficacy of molecules that reduce systemic or brain inflammation is warranted. OBJECTIVE: This clinical trial assessed whether boswellic acids can improve cognitive and neuropsychiatric symptoms while reducing inflammation in AD patients. METHODS: A double-blind, placebo-controlled, study was conducted on 85 AD patients randomized to boswellic acids (K-Vie™ as the main ingredient in Memowell™) or placebo for 6 months. Clinical Dementia Rating-Sum of Boxes (CDR-SOB) and Mini-Mental State Examination (MMSE) scores were compared to baseline and between groups and constituted the co-primary clinical efficacy endpoints. Secondary outcomes included neuropsychiatric assessment (Neuropsychiatric Inventory-Questionnaire, NPI-Q) and assessment of AD and inflammation biomarkers. RESULTS: Patients on K-Vie™ showed a 3.1- and 1.6-unit improvement in MMSE and CDR-SOB scores, respectively, when compared to patients on placebo. NPI-Q analysis revealed significant improvement in the K-Vie™ but not in the placebo group. Only mild gastrointestinal side effects were reported in a few patients. Patients on K-Vie™ showed improvement in plasma AD biomarkers and reduction of key inflammatory cytokines including IL-6 and TNF. CONCLUSION: Our results support the positive cognitive effects of boswellic acids by reducing the systemic inflammation.

Lipopolysaccharide, Immune Biomarkers and Cerebral Amyloid-Beta Deposition in Older Adults With Mild Cognitive Impairment & Major Depressive Disorder.

OBJECTIVE: Inflammatory activation and increased immune response to lipopolysaccharide occur in both depression and cognitive decline and may link these two conditions. We investigated whether lipopolysaccharide (LPS), LPS binding protein (LBP) and peripheral biomarkers of immune response were associated with increased cerebral deposition of amyloid-beta (Abeta) in older adults with mild cognitive impairment (MCI) and remitted major depressive disorder (rMDD). DESIGN: Cross-sectional analysis. SETTING: Five academic health centers in Toronto. PARTICIPANTS: Older adults with MCI with/without rMDD. MEASUREMENTS: We investigated the associations among serum LPS, LBP, biomarkers of inflammatory activation - Interleukin-6 (IL-6), C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1), and cerebral Abeta deposition quantified by positron emission tomography. RESULTS: Among 133 study participants (82 with MCI and 51 with MCI+rMDD) there was no association between LPS (beta - 0.17, p = 0.8) or LBP (beta - 0.11, p = 0.12) and global deposition of Abeta following adjustment for age, gender, and APOE genotype in multivariable regression analyses. LBP was positively correlated with CRP (r = 0.5, p <0.001) and IL-6 (r = 0.2, p = 0.02) but no inflammatory biomarker was associated with Abeta deposition; rMDD was not associated with deposition of Abeta (beta -0.09, p = 0.22). CONCLUSION: In this cross-sectional analysis, we did not find an association among LPS/LBP, immune biomarkers or rMDD and global deposition of Abeta. Future analyses should assess the longitudinal relationships between peripheral and central biomarkers of immune activation, depression and cerebral Abeta deposition.