Mosaic BRCA1 promoter methylation contribution in hereditary breast/ovarian cancer pedigrees.

PURPOSE: Mosaic BRCA1 promoter methylation (BRCA1meth) increases the risk of early-onset breast cancer, triple-negative breast cancer and ovarian cancer. As mosaic BRCA1meth are believed to occur de novo, their role in family breast/ovarian cancer has not been assessed. PATIENTS: Blood-derived DNA from 20 unrelated affected cases from families with aggregation of breast/ovarian cancer, but with no germline pathogenic variants in BRCA1/2, PALB2 or RAD51C/D, were screened by methylation-sensitive high-resolution melting. CpG analysis was performed by pyrosequencing on blood and buccal swab. Two probands carried a pathogenic variant in a moderate-penetrance gene (ATM and BARD1), and 8 of 18 others (44%) carried BRCA1meth (vs none of the 20 age-matched controls). Involvement of BRCA1 in tumourigenesis in methylated probands was demonstrated in most tested cases by detection of a loss of heterozygosity and a homologous recombination deficiency signature. Among the eight methylated probands, two had relatives with breast cancer with detectable BRCA1meth in blood, including one with high methylation levels in two non-tumour tissues. CONCLUSIONS: The high prevalence of mosaic BRCA1meth in patients with breast/ovarian cancer with affected relatives, as well as this first description of a family aggregation of mosaic BRCA1meth, shows how this de novo event can contribute to hereditary breast/ovarian cancer pedigrees.

Low ambient temperature and incident myocardial infarction with or without obstructive coronary arteries: a Chinese nationwide study.

BACKGROUND AND AIMS: Although non-optimum ambient temperature is a major non-traditional risk factor for acute myocardial infarction, there is no prior knowledge on whether non-optimum ambient temperature could differentially affect myocardial infarction with obstructive coronary artery disease (MI-CAD) and myocardial infarction with non-obstructive coronary arteries (MINOCA). METHODS: Using the Chinese Cardiovascular Association database-Chest Pain Center Registry, a nationwide, time-stratified, case-crossover investigation was conducted from 2015 to 2021. Meteorological data were obtained from an established satellite-based model, and daily exposures were assigned according to the onset of myocardial infarction in each patient. A conditional logistic regression model combined with distributed lag non-linear models (10 days) was used to estimate the exposure-response relationships. RESULTS: A total of 83 784 MINOCA patients and 918 730 MI-CAD patients were included. The risk of MINOCA and MI-CAD associated with low temperature occurred at lag 2 day and lasted to 1 week. Extremely low temperature was associated with a substantially greater odds ratio (OR) of MINOCA [OR 1.58, 95% confidence interval (CI) 1.31-1.90] than MI-CAD (unmatched: OR 1.32, 95% CI 1.23-1.43; equally matched by age and sex: OR 1.25, 95% CI 1.04-1.50), compared with the corresponding reference temperatures (30°C, 35°C, and 30°C). Stronger associations were observed for patients who were aged ≥65 years, female, or resided in the south. There was no significant difference for the impacts of high temperature on MINOCA and MI-CAD. CONCLUSIONS: This nationwide study highlights the particular susceptibility of MINOCA patients to ambient low temperature compared with that of MI-CAD patients.

Tumor mutational burden assessment and standardized bioinformatics approach using custom NGS panels in clinical routine.

BACKGROUND: High tumor mutational burden (TMB) was reported to predict the efficacy of immune checkpoint inhibitors (ICIs). Pembrolizumab, an anti-PD-1, received FDA-approval for the treatment of unresectable/metastatic tumors with high TMB as determined by the FoundationOne®CDx test. It remains to be determined how TMB can also be calculated using other tests. RESULTS: FFPE/frozen tumor samples from various origins were sequenced in the frame of the Institut Curie (IC) Molecular Tumor Board using an in-house next-generation sequencing (NGS) panel. A TMB calculation method was developed at IC (IC algorithm) and compared to the FoundationOne® (FO) algorithm. Using IC algorithm, an optimal 10% variant allele frequency (VAF) cut-off was established for TMB evaluation on FFPE samples, compared to 5% on frozen samples. The median TMB score for MSS/POLE WT tumors was 8.8 mut/Mb versus 45 mut/Mb for MSI/POLE-mutated tumors. When focusing on MSS/POLE WT tumor samples, the highest median TMB scores were observed in lymphoma, lung, endometrial, and cervical cancers. After biological manual curation of these cases, 21% of them could be reclassified as MSI/POLE tumors and considered as "true TMB high." Higher TMB values were obtained using FO algorithm on FFPE samples compared to IC algorithm (40 mut/Mb [10-3927] versus 8.2 mut/Mb [2.5-897], p < 0.001). CONCLUSIONS: We herein propose a TMB calculation method and a bioinformatics tool that is customizable to different NGS panels and sample types. We were not able to retrieve TMB values from FO algorithm using our own algorithm and NGS panel.

Diffuse Midline H3K27-Altered Gliomas in the Spinal Cord: A Systematic Review.

PURPOSE: To systematically review the clinical features, management, and outcomes of diffuse midline H3K27-altered gliomas of the spinal cord (DMG-SCs). METHODS: PubMed, Ovid EMBASE, Scopus, and Web of Science were searched from database inception to 23 September 2023 for histologically confirmed cases of DMG-SC. Patient demographics, tumor characteristics, management information, and survival outcomes were extracted and analyzed. RESULTS: A total of 279 patients from 39 studies were collected. Patients were mostly male (61%), with an average age of 32 years. Patients were treated with surgery, radiotherapy, and chemotherapy combined (31%) or surgery only (24%), and extent of resection was most often subtotal (38%). Temozolomide was the most common chemotherapeutic agent (81%). Radiation therapy was delivered with mean dose of 47 Gy in 23 fractions. At mean follow-up time of 21 months, 13% of patients were alive. Average median overall survival was 24 months (range of 13 to 40 months) with a median progression-free survival of 14 months. Historical WHO grades of 2 or 3 appeared to exhibit a longer average median overall survival time than that of grade 4 DMG-SCs (32 vs. 23 months, p = 0.009). CONCLUSIONS: Outcomes for DMG-SCs are poor overall but appear to be favorable compared to intracranial DMGs. Despite the recent WHO 2021 grade 4 classification for all DMGs, given the differences in overall survival reported based on historical grading systems, future studies on DMG-SCs are needed to further define if DMG-SCs may represent a heterogeneous group of tumors with different prognoses.

Progression-associated molecular changes in basal/squamous and sarcomatoid bladder carcinogenesis.

The aggressive basal/squamous (Ba/Sq) bladder cancer (BLCA) subtype is often diagnosed at the muscle-invasive stage and can progress to the sarcomatoid variant. Identification of molecular changes occurring during progression from non-muscle-invasive BLCA (NMIBC) to Ba/Sq muscle-invasive BLCA (MIBC) is thus challenging in human disease. We used the N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model of Ba/Sq MIBC to study longitudinally the molecular changes leading to the Ba/Sq phenotype and to the sarcomatoid variant using IHC and microdissection followed by RNA-seq at all stages of progression. A shift to the Ba/Sq phenotype started in early progression stages. Pathway analysis of gene clusters with coordinated expression changes revealed Shh signaling loss and a shift from fatty acid metabolism to glycolysis. An upregulated cluster, appearing early in carcinogenesis, showed relevance to human disease, identifying NMIBC patients at risk of progression. Similar to the human counterpart, sarcomatoid BBN tumors displayed a Ba/Sq phenotype and epithelial-mesenchymal transition (EMT) features. An EGFR/FGFR1 signaling switch occurred with sarcomatoid dedifferentiation and correlated with EMT. BLCA cell lines with high EMT were the most sensitive to FGFR1 knockout and resistant to EGFR knockout. Taken together, these findings provide insights into the underlying biology of Ba/Sq BLCA progression and sarcomatoid dedifferentiation with potential clinical implications. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Molecular characterisation of tumours of the lacrimal apparatus.

AIMS: Malignant tumours of the lacrimal apparatus are rare and frequently show a poor prognosis, with no clear therapeutic standards. Characterisation of the genetic landscape of these rare tumours is sparse, and therefore therapeutics generally follow those of their common salivary gland counterparts. To further clarify the pathophysiology and discover potential therapeutic targets, we investigated the genetic landscape of eight tumours of the lacrimal apparatus. METHODS AND RESULTS: DNA and RNA sequencing were performed to identify genetic mutations and gene fusions. Immunohistochemistry, fluorescence in-situ hybridisation and reverse transcription-polymerase chain reaction followed by Sanger sequencing were performed to confirm the identified molecular alterations. Genetic alterations were detected in six tumours. Among five adenoid cystic carcinomas (ACC), four had confirmed alterations of MYB or MYBL1 genes, including a MYB::NFIB fusion, a MYBL1::NFIB fusion, a MYB amplification and a novel NFIB::THSD7B fusion. Mutations in genes encoding epigenetic modifiers, as well as NOTCH1, FGFR2 and ATM mutations, were also identified in ACCs. A carcinoma ex pleomorphic adenoma showed TP53 and CIC mutations and an amplification of ERBB2. A transitional cell carcinoma was associated with HPV16 infection. No genetic alteration was found for one adenocarcinoma, not otherwise specified. CONCLUSIONS: Our study highlights the variety of molecular alterations associated with lacrimal system tumours and emphasises the importance of molecular testing in these tumours, which can reveal potentially targetable mutations. Our results also reinforce the hypothesis of a common physiopathology of all ACCs, regardless of their primary location.

Screening for primary aldosteronism in the diabetic population: a cohort study.

BACKGROUND: Primary aldosteronism (PA) is the most common endocrine cause of hypertension. It is associated with higher cardio-metabolic risk than essential hypertension. Hypertension is common in patients with type 2 diabetes who carry increased cardiovascular risk; however, it is unknown how frequently they are tested for PA. AIM: To assess the extent to which the Endocrine Society's 2016 PA screening guidelines have been applied in a tertiary diabetes care setting and evaluate the demographic, clinical and biochemical characteristics of patients who met screening criteria compared with those who did not. METHODS: This is a retrospective cohort study. Data were collected from 272 patients who attended tertiary diabetes clinics and had two or more blood pressure measurements from January to December 2018. RESULTS: Of 272 patients, 60 (22.1%) had indication(s) for PA screening, but only 14 (23.3%) of 60 were screened using the aldosterone-to-renin ratio (ARR). Five patients who did not meet screening criteria were screened. Only one of 19 patients screened had an abnormal ARR; however, 16 were taking medications known to affect aldosterone and/or renin production. CONCLUSIONS: In a tertiary diabetes outpatient setting, only a minority of patients who fulfilled the Endocrine Society criteria for PA screening were actually screened. Appropriate screening for PA in the diabetic hypertensive population is necessary for the diagnosis and targeted treatment of a highly modifiable cardiovascular risk factor. Further studies are needed to develop feasible strategies to identify patients with PA in this population.

The influence of interradicular anatomy on the predictability of periodontal regenerative therapy of furcation defects: a retrospective, multicenter clinical study.

BACKGROUND: The relationship between the anatomy of the interradicular space and success in regenerative therapy of furcation defects is discussed in this paper. The goal of this retrospective, multicenter clinical study is to clinically evaluate the relationship between the interradicular conformation and regenerative therapy success with the use of a novel measurement method. METHODS: One hundred thirty-eight radiographs of mandibular molars with furcation defects that had been treated with regenerative therapy were collected from six clinical centers. Data on the type of therapy and clinical parameters before and after treatment (follow-up of at least 12 months) were collected. The radiographs (before surgery and at least 12 months postoperatively) were measured with a visual evaluation method by a blind operator using graphics software. RESULTS: Success, defined as a reduction in horizontal and vertical furcation involvement, decrease in probing depths, and increase in clinical attachment level, was statistically assessed on 138 regenerated molars sites and were related to clinical variables such as age, sex, center, and treatment. No correlation was found between success in regenerative therapy and the conformation of the interradicular space, measured with a visual ratio method and a standard linear measurement. At the univariate analysis, the parameters that had a correlation with success were center, extent of furcation involvement, treatment, and sex. The use of enamel matrix derivative (EMD) seemed to be the most favorable therapy, with increase in CAL gain and reduction of vertical or horizontal furcation involvement. CONCLUSIONS: The regenerative outcome was not significantly influenced by the anatomy of furcation. The center, the degree of furcation involvement, sex, and treatment (EMD) were significantly associated with higher success of periodontal regeneration.

A low-carbohydrate diet containing soy protein and fish oil reduces breast but not prostate cancer in C3(1)/Tag mice.

We recently showed that a low-carbohydrate (CHO) diet containing soy protein and fish oil dramatically reduces lung nodules in a mouse model of lung cancer when compared to a Western diet. To explore the universality of this finding, we herein compared this low-CHO diet to a Western diet on in preventing breast and prostate cancer using a mouse model that expresses the SV40 large T-antigen specifically in breast epithelia in females and prostate epithelia in males. We found that breast cancer was significantly reduced with this low-CHO diet and this correlated with a reduction in plasma levels of glucose, insulin, IL-6, TNFα and prostaglandin E2 (PGE2). This also corresponded with a reduction in the Ki67 proliferation index within breast tumors. On the other hand, this low-CHO diet did not reduce the incidence of prostate cancer in the male mice. Although it reduced both blood glucose and insulin to the same extent as in the female mice, there was no reduction in plasma IL-6, TNFα or PGE2 levels, or in the Ki67 proliferation index in prostate lesions. Based on immunohistochemistry studies with antibodies to 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), carnitine palmitoyltransferase Ia (CPT1a) and fatty acid synthase (FAS), it is likely that this difference in response of the two cancer types to this low-CHO diet reflects differences in the glucose dependence of breast and prostate cancer, with the former being highly dependent on glucose for energy and the latter being more dependent on fatty acids.

Military sexual trauma in context: Ethnoracial differences in ecological resources among treatment-seeking veterans.

Veterans who have experienced military sexual trauma (MST) are at increased risk for a host of negative outcomes, including posttraumatic stress disorder, depressive disorders, and substance use disorders. Previous studies have shown racial differences in MST exposure, namely that Black veterans experience MST more frequently than White veterans. One way to help clinicians and researchers understand the impact of these ethnoracial differences in MST exposure is through an applied theory of ecological resources, which has demonstrated ecological factors (e.g., aspects of identity, beliefs, and environmental stressors) contribute to veteran well-being in the aftermath of MST. The present study aimed to examine ethnoracial differences in ecological resources (i.e., available social support, spiritual coping, past-year interpersonal violence, financial sufficiency, and stable living environment). Participants (N = 505) were U.S. veterans who sought care at a Veterans Healthcare Administration clinic in the midwestern United States for mental health issues related to MST. Results demonstrated Black veterans were more likely than White veterans to report being financially insecure, U = 18,091.50, z = -2.04, p = .042, r = .10. Black veterans were also more likely to report spiritual beliefs that assisted with coping, Cramer's V = .19, but less likely to report having a social support system, Cramer's V = .16. These findings highlight the importance of assessing and addressing disparities illuminated by ethnoracial differences in ecological resources and barriers in veterans seeking care for MST.

Atypical evolution of meningiomatosis after discontinuation of cyproterone acetate: clinical cases and histomolecular characterization.

PURPOSE: The long-term use of cyproterone acetate (CPA) is associated with an increased risk of developing intracranial meningiomas. CPA discontinuation most often induces a stabilization or regression of the tumor. The underlying biological mechanisms as well as the reasons why some meningiomas still grow after CPA discontinuation remain unknown. We reported a series of patients presenting CPA-induced meningiomatosis with opposed tumor evolutions following CPA discontinuation, highlighting the underlying histological and genetic features. METHODS: Patients presenting several meningiomas with opposite tumor evolution (coexistence of growing and shrinking tumors) following CPA discontinuation were identified. Clinical and radiological data were reviewed. A retrospective volumetric analysis of the meningiomas was performed. All the growing meningiomas were operated. Each operated tumor was characterized by histological and genetic analyses. RESULTS: Four women with multiple meningiomas and opposite tumor volume evolutions after CPA discontinuation were identified. Histopathological analysis characterized the convexity and tentorial tumors which continued to grow after CPA discontinuation as fibroblastic meningiomas. The decreasing skull base tumor was characterized as a fibroblastic meningioma with increased fibrosis and a widespread collagen formation. The two growing skull base meningiomas were identified as meningothelial and transitional meningiomas. The molecular characterization found two NF2 mutations among the growing meningiomas and a PIK3CA mutation in the skull base tumor which decreased. CONCLUSION: To our knowledge, this is the first report describing an atypical tumor evolution of CPA-associated meningiomas after CPA discontinuation. The underlying biological mechanisms explaining this observation and especially the close relationship between mutational landscapes and embryologic origins of the meninges in CPA-related meningiomas as well as their clonal origin require further research.

Gaining 'authority to operate': student-led emergent volunteers and established response agencies in the Canterbury earthquakes.

There is growing expectation that local volunteers will play a more integrated role in disaster response, yet emergent volunteer groups are often 'outsiders' to crisis management. Questions have been raised, therefore, about how emergent groups can forge relationships with established response agencies. This paper analyses how the Student Volunteer Army, as an emergent group, gained 'authority to operate' after the earthquakes in Canterbury, New Zealand, in 2010-11. It traces how the volunteers accrued authority through multiple sources of permission and credibility and demonstrates the possibility for established response agencies and emergent groups to generate impactful and mutually supportive relationships. However, the analysis also points to two interrelated tensions that can arise, regarding the terms by which emergent groups are recognised, and the 'distance' considered necessary between the two parties. The discussion considers the implications for inclusiveness, risk, and responsibility of further integrations of emergent volunteers in disaster response.

Impact of prenatally diagnosed congenital heart defects on outcomes and management.

Fetal echocardiogram aids in prenatal identification of neonates at high risk for congenital heart defects (CHD). Prenatal detection rates for CHD have increased with improved ultrasound technology, the use of the early fetal echocardiography, and standardization of the performance of the fetal echocardiogram. Accurate prenatal detection of CHD, particularly complex CHD, is an important contributor to improved survival rates for patients with CHD. Early detection allows for families to choose whether or not to continue with pregnancy, referral to pediatric cardiology specialists for patient education, and delivery planning. Better psychosocial supports are needed for families with CHD.

Nanoparticle encapsulated oxytocin increases resistance to induced seizures and restores social behavior in Scn1a-derived epilepsy.

Oxytocin (OT) has broad effects in the brain and plays an important role in cognitive, social, and neuroendocrine function. OT has also been identified as potentially therapeutic in neuropsychiatric disorders such as autism and depression, which are often comorbid with epilepsy, raising the possibility that it might confer protection against the behavioral and seizure phenotypes in epilepsy. Dravet syndrome (DS) is an early-life encephalopathy associated with prolonged and recurrent early-life febrile seizures (FSs), treatment-resistant afebrile epilepsy, and cognitive and behavioral deficits. De novo loss-of-function mutations in the voltage-gated sodium channel SCN1A are the main cause of DS, while genetic epilepsy with febrile seizures plus (GEFS+), also characterized by early-life FSs and afebrile epilepsy, is typically caused by inherited mutations that alter the biophysical properties of SCN1A. Despite the wide range of available antiepileptic drugs, many patients with SCN1A mutations do not achieve adequate seizure control or the amelioration of associated behavioral comorbidities. In the current study, we demonstrate that nanoparticle encapsulation of OT conferred robust and sustained protection against induced seizures and restored more normal social behavior in a mouse model of Scn1a-derived epilepsy. These results demonstrate the ability of a nanotechnology formulation to significantly enhance the efficacy of OT. This approach will provide a general strategy to enhance the therapeutic potential of additional neuropeptides in epilepsy and other neurological disorders.

Urinary Incontinence and Pelvic Organ Prolapse.

The multifactorial pathophysiology of pelvic floor disorder accounts for the coexistence of several pelvic floor disorders in many women. Up to 54% of women with pelvic organ prolapse (POP) report concurrent stress urinary incontinence (SUI). While POP is a risk factor for coexistent SUI, apical and anterior prolapse can also conceal SUI symptoms that are unmasked by POP repair, resulting in de novo SUI postoperatively. It is important for pelvic reconstructive surgeons to consider the relationship between POP and urinary incontinence in presurgical planning and to discuss with patients the risks and advantages of concurrent versus staged anti-incontinence procedures.

Primary cutaneous perivascular epithelioid cell tumors: two cases and a review of the literature.

Report _Case Presentation _Photo Vignette _Letter Authors declare that the contents of this article are their own original unpublished findings. Title: Primary cutaneous perivascular epithelioid cell tumors: two cases and a review of the literature Authors: Jennifer Wong1 DO, Jason Mammino2 DO, Jennifer Seyffert3 DO, Kristen Schmits4 MD, Etan Marks4 MD, Daniel Rivlin3 MD Affiliations: 1Department of Dermatology, LECOM- Larkin Community Hospital, Miami, Florida, USA, 2Department of Dermatology, KCUMB - Advanced Dermatology and Cosmetic Surgery, Orlando, Florida, USA, 3Department of Dermatology, LECOM- Skin and Cancer Associates, Miami Beach, Florida, USA, 4Department of Dermatopathology Advanced Dermatology and Cosmetic Surgery Pathology Laboratory, Delray Beach, Florida, USA Corresponding Author: Jennifer Seyffert DO, 4308 Alton Road, Suite 510, Miami Beach, FL 33140, Tel: 305-674-8865, Fax: 305-674-1459, Email: jseyf12@gmail.com Abstract: Perivascular epithelioid cell tumors, also known as PEComas, are mesenchymal neoplasms which uncommonly originate within the skin, with only 23 cases documented within the literature. These rare neoplasms classically display epithelioid cells composed of granular or clear cytoplasm arranged in sheets, nests, or cords. Their immunoreactivity for melanocytic and smooth muscle markers makes these tumors distinct and unique.[1] We herein present two cases of primary cutaneous PEComas that clinically mimic other common cutaneous neoplasms and illustrate the necessity for clinical-pathologic correlation. A literature review is also presented to compare the different clinical and histological presentations of cutaneous PEComas.

Low carbohydrate diets containing soy protein and fish oil slow the growth of established NNK-induced lung tumors.

We recently found that a diet composed of 15% of total calories as carbohydrate (CHO), primarily as amylose, 35% soy protein and 50% fat, primarily as fish oil (FO) (15%Amylose/Soy/FO) was highly effective at preventing lung nodule formation in a nicotine-derived nitrosamine ketone (NNK)-induced lung cancer model. We asked herein whether adopting such a diet once cancers are established might also be beneficial. To test this, NNK-induced lung nodules were established in mice on a Western diet and the mice were then either kept on a Western diet or switched to various low CHO diets. Since we previously found that sedentary mice develop more lung nodules than active mice, we also compared the effect of exercise in this cancer progression model. We found that switching to a 15%Amylose/Soy/FO diet reduced lung nodules and slowed tumor growth with both 'active' and 'sedentary' mice. Ki67, cleaved caspase 3 and Terminal Deoxynucleotidyl Transferase-Mediated dUTP Nick End Labeling assays suggested that the efficacy of the 15%Amylose/Soy/FO in lowering tumor nodule count and size was not due to a reduction in tumor cell proliferation, but to an increase in apoptosis. The 15%Amylose/Soy/FO diet also significantly lowered liver fatty acid synthase and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 expression, pointing to a global metabolic switch from glycolysis to fatty acid oxidation. Mice fed the 15%Amylose/Soy/FO diet also had significantly reduced plasma levels of interleukin (IL)-1ß, IL-6 and tumor necrosis factor α. These results suggest that the 15%Amylose/Soy/FO diet may slow tumor growth by suppressing proinflammatory cytokines, inducing a metabolic switch away from glycolysis and inducing apoptosis in tumors.

Technology-Enabled Clinical Trials: Transforming Medical Evidence Generation.

The complexity and costs associated with traditional randomized, controlled trials have increased exponentially over time, and now threaten to stifle the development of new drugs and devices. Nevertheless, the growing use of electronic health records, mobile applications, and wearable devices offers significant promise for transforming clinical trials, making them more pragmatic and efficient. However, many challenges must be overcome before these innovations can be implemented routinely in randomized, controlled trial operations. In October of 2018, a diverse stakeholder group convened in Washington, DC, to examine how electronic health record, mobile, and wearable technologies could be applied to clinical trials. The group specifically examined how these technologies might streamline the execution of clinical trial components, delineated innovative trial designs facilitated by technological developments, identified barriers to implementation, and determined the optimal frameworks needed for regulatory oversight. The group concluded that the application of novel technologies to clinical trials provided enormous potential, yet these changes needed to be iterative and facilitated by continuous learning and pilot studies.

Comparative Immunogenicity of Several Enhanced Influenza Vaccine Options for Older Adults: A Randomized, Controlled Trial.

BACKGROUND: Enhanced influenza vaccines may improve protection for older adults, but comparative immunogenicity data are limited. Our objective was to examine immune responses to enhanced influenza vaccines, compared to standard-dose vaccines, in community-dwelling older adults. METHODS: Community-dwelling older adults aged 65-82 years in Hong Kong were randomly allocated (October 2017-January 2018) to receive 2017-2018 Northern hemisphere formulations of a standard-dose quadrivalent vaccine, MF59-adjuvanted trivalent vaccine, high-dose trivalent vaccine, or recombinant-hemagglutinin (rHA) quadrivalent vaccine. Sera collected from 200 recipients of each vaccine before and at 30-days postvaccination were assessed for antibodies to egg-propagated vaccine strains by hemagglutination inhibition (HAI) and to cell-propagated A/Hong Kong/4801/2014(H3N2) virus by microneutralization (MN). Influenza-specific CD4+ and CD8+ T cell responses were assessed in 20 participants per group. RESULTS: Mean fold rises (MFR) in HAI titers to egg-propagated A(H1N1) and A(H3N2) and the MFR in MN to cell-propagated A(H3N2) were statistically significantly higher in the enhanced vaccine groups, compared to the standard-dose vaccine. The MFR in MN to cell-propagated A(H3N2) was highest among rHA recipients (4.7), followed by high-dose (3.4) and MF59-adjuvanted (2.9) recipients, compared to standard-dose recipients (2.3). Similarly, the ratio of postvaccination MN titers among rHA recipients to cell-propagated A(H3N2) recipients was 2.57-fold higher than the standard-dose vaccine, which was statistically higher than the high-dose (1.33-fold) and MF59-adjuvanted (1.43-fold) recipient ratios. Enhanced vaccines also resulted in the boosting of T-cell responses. CONCLUSIONS: In this head-to-head comparison, older adults receiving enhanced vaccines showed improved humoral and cell-mediated immune responses, compared to standard-dose vaccine recipients. CLINICAL TRIALS REGISTRATION: NCT03330132.

Characteristics of Young-Onset and Late-Onset Dementia Patients at a Remote Memory Clinic.

BACKGROUND: Young-onset dementia (YOD) is defined as the onset of dementia symptoms before the age of 65 years and accounts for 2-8% of dementia. YOD patients and their caregivers face unique challenges in diagnosis and management. We aimed to compare the characteristics of rural YOD and late-onset dementia (LOD) patients at a rural and remote memory clinic in Western Canada. METHODS: A total of 333 consecutive patients (YOD = 61, LOD = 272) at a rural and remote memory clinic between March 2004 and July 2016 were included in this study. Each patient had neuropsychological assessment. Health, mood, function, behaviour and social factors were also measured. Both groups were compared using χ2 tests and independent sample tests. RESULTS: YOD patients were more likely to be married, employed, current smokers and highly educated. They reported fewer cognitive symptoms, but had more depressive symptoms. YOD patients were less likely to live alone and use homecare services. YOD caregivers were also more likely to be a spouse and had higher levels of distress than LOD caregivers. Both YOD and LOD patient groups were equally likely to have a driver's licence. CONCLUSIONS: Our findings indicate YOD and LOD patients have distinct characteristics and services must be modified to better meet YOD patient needs. In particular, the use of homecare services and caregiver support may alleviate the higher levels of distress found in YOD patients and their caregivers. Additional research should be directed to addressing YOD patient depression, caregiver distress and barriers to services.