Engineered CD47 protects T cells for enhanced antitumour immunity.

Adoptively transferred T cells and agents designed to block the CD47-SIRPα axis are promising cancer therapeutics that activate distinct arms of the immune system1,2. Here we administered anti-CD47 antibodies in combination with adoptively transferred T cells with the goal of enhancing antitumour efficacy but observed abrogated therapeutic benefit due to rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors. Anti-CD47-antibody-mediated CAR T cell clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered the CD47 variant CD47(Q31P) (47E), which engages SIRPα and provides a 'don't eat me' signal that is not blocked by anti-CD47 antibodies. TCR or CAR T cells expressing 47E are resistant to clearance by macrophages after treatment with anti-CD47 antibodies, and mediate substantial, sustained macrophage recruitment to the tumour microenvironment. Although many of the recruited macrophages manifested an M2-like profile3, the combined therapy synergistically enhanced antitumour efficacy. Our study identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T-cell-directed therapeutics with those designed to activate macrophages. It delivers a therapeutic approach that is capable of simultaneously harnessing the antitumour effects of T cells and macrophages, offering enhanced potency against solid tumours.

New-onset seizures: an unusual neurologic manifestation of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory condition primarily affecting the musculoskeletal system but can often involve other organ systems as well. Rheumatoid meningitis is a rare central nervous system (CNS) manifestation of RA characterized by pachymeningeal and leptomeningeal enhancement. Herein, we present a case of a 64-year-old male who presented with left lower extremity weakness and witnessed seizures. The diagnostic work-up, including lumbar puncture, brain MRI and meningeal biopsy ruled out malignancy and were consistent with the diagnosis of rheumatoid meningitis. The patient was discharged on high-dose steroids along with anti-seizure medications. On subsequent follow-up visits, the patient remained seizure-free.

Perivascular space burden interacts with APOE-ε4 status on cognition in older adults.

Enlarged perivascular spaces (ePVS) may adversely affect cognition. Little is known about how basal ganglia ePVS interact with apolipoprotein (APOE)-ε4 status. Vanderbilt Memory and Aging Project participants (n = 326, 73 ± 7, 59% male) underwent 3 T brain MRI at baseline to assess ePVS and longitudinal neuropsychological assessments. The interaction between ePVS volume and APOE-ε4 carrier status was related to baseline outcomes using ordinary least squares regressions and longitudinal cognition using linear mixed-effects regressions. ePVS volume interacted with APOE-ε4 status on cross-sectional naming performance (ß = -0.002, p = 0.002), and executive function excluding outliers (ß = 0.001, p = 0.009). There were no significant longitudinal interactions (p-values>0.10) except for Coding excluding outliers (ß = 0.002, p = 0.05). While cross-sectional models stratified by APOE-ε4 status indicated greater ePVS related to worse cognition mostly in APOE-ε4 carriers, longitudinal models stratified by APOE-ε4 status showed greater ePVS volume related to worse cognition among APOE-ε4 non-carriers only. Results indicated that greater ePVS volume interacts with APOE-ε4 status on cognition cross-sectionally. Longitudinally, the association of greater ePVS volume and worse cognition appears stronger in APOE-ε4 non-carriers, possibly due to the deleterious effects of APOE-ε4 on cognition across the lifespan.

Sex and Education Modify the Association Between Subjective Cognitive Decline and Amyloid Pathology.

Background: Subjective cognitive decline (SCD) may be an early risk factor for dementia, particularly in highly educated individuals and women. This study examined the effect of education and sex on the association between SCD and Alzheimer's disease (AD) biomarkers in non-demented older adults. Method: Vanderbilt Memory and Aging Project participants free of clinical dementia or stroke (n=156, 72±6 years, 37% mild cognitive impairment, 33% female) completed fasting lumbar puncture, SCD assessment, and Wide Range Achievement Test-III Reading subtest to assess reading level at baseline as a a proxy for educational quality. Cerebrospinal fluid (CSF) biomarkers for AD (ß-amyloid 42 (Aß42), Aß42/40 ratio, phosphorylated tau (p-tau), tau, and neurofilament light (NfL)) were analyzed in batch. Linear mixed effects models related SCD to CSF AD biomarkers and follow-up models assessed SCD x sex, SCD x reading level , and SCD x education interactions on AD biomarkers. Result: In main effect models, higher SCD was associated with lower Aß42 and Aß42/40 ratio (p-values<0.004). SCD was not associated with tau, p-tau, or NfL levels ( p- values>0.38). SCD score interacted with sex on Aß42/40 ratio ( p =0.03) but no other biomarkers ( p -values>0.10). In stratified models, higher SCD was associated with lower Aß42/40 ratio in men ( p =0.0003) but not in women ( p =0.48). SCD score interacted with education on Aß42 ( p =0.005) and Aß42/40 ratio ( p =0.001) such that higher education was associated with a stronger negative association between SCD and amyloid levels. No SCD score x reading level interaction was found (p-values> 0.51) though significant associations between SCD and amyloid markers were seen in the higher reading level group (p-values<0.004) but not the lower reading level group (p-values>0.12) when stratified by a median split in reading level. Conclusion: Among community-dwelling older adults free of clinical dementia, higher SCD was associated with greater cerebral amyloid accumulation, one of the earliest pathological AD changes. SCD appears most useful in detecting early AD-related brain changes in men and individuals with higher quantity and quality of education. SCD was not associated with CSF markers of tau pathology or neurodegeneration. These findings suggest that considering sex and education is important when assessing SCD in older adults.

Clinical and demographic factors modify the association between plasma phosphorylated tau-181 and cognition.

INTRODUCTION: Plasma phosphorylated tau181 (p-tau181) associations with global cognition and memory are clear, but the link between p-tau181 with other cognitive domains and subjective cognitive decline (SCD) across the clinical spectrum of Alzheimer's disease (AD) and how this association changes based on genetic and demographic factors is poorly understood. METHODS: Participants were drawn from the Alzheimer's Disease Neuroimaging Initiative and included 1185 adults aged >55 years with plasma p-tau181 and neuropsychological test data. Linear regression models related plasma p-tau181 to neuropsychological composite and SCD scores with follow-up models examining plasma p-tau181 interactions with cognitive diagnosis, APOE ε4 carrier status, age, and sex on cognitive outcomes. RESULTS: Higher plasma p-tau181 was associated with worse memory, executive functioning, and language abilities, and greater informant-reported SCD. Visuospatial abilities and self-report SCD were not associated with plasma p-tau181. Associations were generally stronger in MCI or dementia, APOE ε4 carriers, women, and younger participants. DISCUSSION: Higher levels of plasma p-tau181 are associated with worse neuropsychological test performance across multiple cognitive domains; however, these associations vary based on disease stage, genetic risk status, age, and sex.

Lupus Podocytopathy: A Rare Cause of Nephrotic Syndrome in Patients with Systemic Lupus Erythematosus.

Lupus podocytopathy, a unique form of lupus nephritis, mimics minimal change disease (MCD) or primary focal segmental glomerulosclerosis (FSGS) and represents approximately 1% of lupus nephritis biopsies. Lupus podocytopathy is characterized by diffuse epithelial cell foot process effacement without immune complex deposition or with only mesangial immune complex deposition. We present the case of a young woman with systemic lupus erythematosus (SLE) who presented with nephrotic syndrome and acute kidney injury (AKI) and was subsequently diagnosed with lupus podocytopathy.

Neurodiversity and National Security: How to Tackle National Security Challenges with a Wider Range of Cognitive Talents.

National security organizations need highly skilled and intellectually creative individuals who are eager to apply their talents to address the nation's most pressing challenges. In public and private discussions, officials and experts addressed the need for neurodiversity in the national security community. They described missions that are too important and too difficult to be left to those who use their brains only in typical ways. Neurodivergent is an umbrella term that covers a variety of cognitive diagnoses, including (but not exclusive to) autism spectrum disorder, attention deficit disorder (ADD) and attention-deficit/hyperactivity disorder (ADHD), dyslexia, dyscalculia, and Tourette's syndrome. Neurodivergent individuals are already part of the national security workforce. The purpose of this study is to understand the benefits that people with neurodivergence bring to national security; the challenges in recruiting, working with, and managing a neurodiverse workforce; and the barriers in national security workplaces that prevent agencies from realizing the full benefits of neurodiversity. To carry out this research, the authors conducted a review of primary, secondary, and commercial literature; they conducted semistructured interviews and held discussions with government officials, researchers and advocates for the interests of neurodivergent populations, and representatives from large organizations that have neurodiversity employment programs; and they synthesized findings from across these tasks to describe the complex landscape for neurodiversity in large organizations in general and in national security specifically.

Evidence of Cardiac Involvement in a Patient With Necrotizing Autoimmune Myopathy (NAM).

Necrotizing autoimmune myopathy (NAM) is a rare inflammatory myopathy primarily affecting skeletal muscles. Cardiac involvement has been reported in immune-mediated necrotizing myopathy (IMNM), but its extent remains poorly understood. We present a unique case of a 68-year-old male with anti-signal recognition particle (SRP) antibody-positive NAM initially presenting with elevated troponin levels. Our case demonstrates cardiac involvement as the presenting feature of NAM, which is a unique feature of inflammatory myopathy.

Baseline grey matter volumes and white matter hyperintensities predict decline in functional activities in older adults over a 5-year follow-up period.

INTRODUCTION: Functional independence is an essential predictor of quality of life in aging, yet few accessible predictors of functional decline have been identified. This study examined associations between baseline structural neuroimaging markers and longitudinal functional status. METHODS: Linear mixed effects models with follow-up time interaction terms related baseline grey matter volume and white matter hyperintensities (WMHs) to functional trajectory, adjusting for demographic and medical covariates. Subsequent models assessed interactions with cognitive status and apolipoprotein E (APOE) ε4 status. RESULTS: Smaller baseline grey matter volumes, particularly in regions commonly affected by Alzheimer's disease (AD), and greater baseline WMHs were associated with faster functional decline over a mean 5-year follow-up. Effects were stronger in APOE-ε4 carriers on grey matter variables. Cognitive status interacted with most MRI variables. DISCUSSION: Greater atrophy in AD-related regions and higher WMH burden at study entry were associated with faster functional decline, particularly among participants at increased risk of AD.

A Case of Concurrence of Clonorchis Sinensis and Pancreatic Adenocarcinoma-A Diagnostic Dilemma.

Clonorchis Sinensis, a common liver fluke, is known to cause biliary disease and can present with a wide array of symptoms. It's mostly found in Asian countries due to consumption of undercooked or raw fish. Although Cholangiocarcinoma is a known serious complication of this disease, Pancreatic neoplasms are rare and have seldom been reported. Here, we report a case of an 80-year-old man who presents with pancreatic adenocarcinoma associated with Clonorchis Sinensis infection.

Syncope Following Treatment of UTI: A Case of Acute Hemolytic Anemia, Methemoglobinemia and Acute Renal Dysfunction Following Phenazopyridine Use in a Patient With G6PD Deficiency.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive genetic disorder which commonly affects males. It is due to a defect in the red blood cell enzyme, G6PD. Lack of G6PD makes the RBCs vulnerable to oxidant stress resulting in hemolysis. The severity of hemolytic anemia varies among individuals with G6PD deficiency. Here we present a case of an 80-year-old man admitted with syncope and jaundice. He was treated with phenazopyridine for a UTI 2 weeks ago. Subsequent investigation revealed G6PD deficiency as well as methemoglobinemia. Historically, phenazopyridine has been associated with causing methemoglobinemia and triggering hemolysis in G6PD deficient individuals. However, only a few cases have been reported in the last 60 years, making it a very rare occurrence.

Whole blood transcript and protein abundance of the vascular endothelial growth factor family relate to cognitive performance.

The vascular endothelial growth factor (VEGF) family of genes has been implicated in the clinical development of Alzheimer's Disease (AD). A previous study identified associations between gene expression of VEGF family members in the prefrontal cortex and cognitive performance and AD pathology. This study explored if those associations were also observed in the blood. Consistent with previous observations in brain tissue, higher blood gene expression of placental growth factor (PGF) was associated with a faster rate of memory decline (p=0.04). Higher protein abundance of FMS-related receptor tyrosine kinase 4 (FLT4) in blood was associated with biomarker levels indicative of lower amyloid and tau pathology, opposite the direction observed in brain. Also, higher gene expression of VEGFB in blood was associated with better baseline memory (p=0.008). Notably, we observed that higher gene expression of VEGFB in blood was associated with lower expression of VEGFB in the brain (r=-0.19, p=0.02). Together, these results suggest that the VEGFB, FLT4, and PGF alterations in the AD brain may be detectable in the blood compartment.

Polygenic resilience score may be sensitive to preclinical Alzheimer's disease changes.

Late-onset Alzheimer's disease (LOAD) is a polygenic disorder with a long prodromal phase, making early diagnosis challenging. Twin studies estimate LOAD as 60-80% heritable, and while common genetic variants can account for 30% of this heritability, nearly 70% remains "missing". Polygenic risk scores (PRS) leverage combined effects of many loci to predict LOAD risk, but often lack sensitivity to preclinical disease changes, limiting clinical utility. Our group has built and published on a resilience phenotype to model better-than-expected cognition give amyloid pathology burden and hypothesized it may assist in preclinical polygenic risk prediction. Thus, we built a LOAD PRS and a resilience PRS and evaluated both in predicting cognition in a dementia-free cohort (N=254). The LOAD PRS had a significant main effect on baseline memory (ß=-0.18, P=1.68E-03). Both the LOAD PRS (ß=-0.03, P=1.19E-03) and the resilience PRS (ß=0.02, P=0.03) had significant main effects on annual memory decline. The resilience PRS interacted with CSF Aß on baseline memory (ß=-6.04E-04, P=0.02), whereby it predicted baseline memory among Aß+ individuals (ß=0.44, P=0.01) but not among Aß- individuals (ß=0.06, P=0.46). Excluding APOE from PRS resulted in mainly LOAD PRS associations attenuating, but notably the resilience PRS interaction with CSF Aß and selective prediction among Aß+ individuals was consistent. Although the resilience PRS is currently somewhat limited in scope from the phenotype's cross-sectional nature, our results suggest that the resilience PRS may be a promising tool in assisting in preclinical disease risk prediction among dementia-free and Aß+ individuals, though replication and fine-tuning are needed.

Enlarged perivascular space burden associations with arterial stiffness and cognition.

Enlarged perivascular spaces (ePVS) are difficult to quantify, and their etiologies and consequences are poorly understood. Vanderbilt Memory and Aging Project participants (n = 327, 73 ± 7 years) completed 3T brain MRI to quantify ePVS volume and count, longitudinal neuropsychological assessment, and cardiac MRI to quantify aortic stiffness. Linear regressions related (1) PWV to ePVS burden and (2) ePVS burden to cross-sectional and longitudinal neuropsychological performance adjusting for key demographic and medical factors. Higher aortic stiffness related to greater basal ganglia ePVS volume (ß = 7.0×10-5, p = 0.04). Higher baseline ePVS volume was associated with worse baseline information processing (ß = -974, p = 0.003), executive function (ß = -81.9, p < 0.001), and visuospatial performances (ß = -192, p = 0.02) and worse longitudinal language (ß = -54.9, p = 0.05), information processing (ß = -147, p = 0.03), executive function (ß = -10.9, p = 0.03), and episodic memory performances (ß = -10.6, p = 0.02). Results were similar for ePVS count. Greater arterial stiffness relates to worse basal ganglia ePVS burden, suggesting cardiovascular aging as an etiology. ePVS burden is associated with adverse cognitive trajectory, emphasizing the clinical relevance of ePVS.

Oestrogen And Progesterone Receptors' Expression Pattern In Fibro-Adenoma Of The Female Breast.

BACKGROUND: Fibro-adenoma is the most common benign condition of the female breast comprising about 68% of all breast lumps. Fibroadenoma is an independent risk factor for the development of breast cancer. Complex fibroadenoma has a 2-3-fold increased risk ratio and simple fibroadenoma has 1.49 times increased risk ratio of developing cancer than the normal population over a period of 20 years. This study aimed to qualitatively check the frequency of oestrogen receptor-positive and progesterone receptor-positive cases of fibroadenoma in our region. METHODS: This cross-sectional study was conducted in the pathology department of Ayub Medical College, Abbottabad from June 2020 to December 2021. Biopsy confirmed cases of fibroadenoma were examined using immune-histochemical stains to score qualitatively the expression pattern of ER and PR. Data was analyzed and assessed using SPSS version 25. A p-value of ≤0.05 was considered statistically significant. RESULTS: The mean age of patients who presented with fibro-adenoma was 24.5±9.29 years with a median age of 21.5 years. In most cases, oestrogen receptor expression was mild 23 (54.76%) whereas progesterone receptor expression was severe 19 (45.23%). On chi-square test, the pattern of progesterone receptor expression for the category of hormone intake showed significant differences. Whereas, the pattern of oestrogen receptor expression for the categories of marital status, history of hormone intake, history of menstrual cycle and type of fibroadenoma showed no statistically significant difference. CONCLUSIONS: Further study into the pathogenesis of fibroadenoma is required to understand the role of ER and PR and explore the therapeutic potential of such drugs that affects these receptors. Cabling.

Diagnosis of Adrenocortical Carcinoma with Hypercortisolism in a Patient Presenting with Hypokalemic Metabolic Alkalosis.

Adrenocortical carcinoma (ACC) is a rare malignancy with an estimated annual incidence of 0.7-2 cases per million. Most patients present with steroid hormone excess or abdominal mass effects, but 15% of patients with ACC are diagnosed incidentally. A careful history, physical exam, and pertinent lab investigations are necessary to reach the diagnosis. Surgical resection is the cornerstone of treatment in localized ACC; however, systemic chemotherapy with mitotane is preferred in patients with widespread disease or those who are not ideal candidates for surgery.

RNASE6 is a novel modifier of APOE-ε4 effects on cognition.

Apolipoprotein E4 (APOE-ε4), the strongest common genetic risk factor for Alzheimer's disease (AD), contributes to worse cognition in older adults. However, many APOE-ε4 carriers remain cognitively normal throughout life, suggesting that neuroprotective factors may be present in these individuals. In this study, we leverage whole-blood RNA sequencing (RNAseq) from 324 older adults to identify genetic modifiers of APOE-ε4 effects on cognition. Expression of RNASE6 interacted with APOE-ε4 status (p = 4.35 × 10-8) whereby higher RNASE6 expression was associated with worse memory at baseline among APOE-ε4 carriers. This interaction was replicated using RNAseq data from the prefrontal cortex in an independent dataset (N = 535; p = 0.002), suggesting the peripheral effect of RNASE6 is also present in brain tissue. RNASE6 encodes an antimicrobial peptide involved in innate immune response and has been previously observed in a gene co-expression network module with other AD-related inflammatory genes, including TREM2 and MS4A. Together, these data implicate neuroinflammation in cognitive decline, and suggest that innate immune signaling may be detectable in blood and confer differential susceptibility to AD depending on APOE-ε4.

Subacute Thyroiditis After Receiving Inactivated Virus Vaccine for COVID-19.

The spread of SARS-COVID 19 infection has resulted in accelerated efforts at development and dissemination of vaccines throughout the globe. These vaccines have different mechanisms of actions and their efficacy and side effects are being monitored. There have been rare reports in literature of thyroid dysfunction after COVID-19 vaccine administration. Sub-acute thyroiditis is one such complication which can arise as a rare side-effect of vaccination. This has also been reported as a symptom of COVID-19 infection. Clinical features include fever, neck pain, palpitations and weight loss. We report sub-acute thyroiditis in a 50-year-old male who presented with symptoms suggestive of thyroid abnormality one day after receiving the inactivated COVID-19 vaccine (CoronaVac Sinovac-Biotech Ltd).

Pseudo Hyperaldosteronism Secondary to Herbal Medicine Use.

Glycyrrhizic acid, better known as licorice, is commonly found in various food and cosmetic products. Excessive consumption is known to cause a syndrome of apparent mineralocorticoid excess or pseudo hyperaldosteronism. Patients typically present with resistant hypertension and hypokalemia mimicking symptoms of primary hyperaldosteronism however laboratory workup will reveal low or normal levels of plasma renin and aldosterone in the serum. While diagnosis of licorice toxicity is relatively straight forward, the challenge lies in determining the culpable agent. We report the case of a Chinese man who initially presented with resistant hypertension and hypokalemia refractory to therapy and was later diagnosed with pseudo hyperaldosteronism secondary to licorice toxicity.

Axonal Injury Partially Mediates Associations Between Increased Left Ventricular Mass Index and White Matter Damage.

BACKGROUND AND PURPOSE: Left ventricular (LV) mass index is a marker of subclinical LV remodeling that relates to white matter damage in aging, but molecular pathways underlying this association are unknown. This study assessed if LV mass index related to cerebrospinal fluid (CSF) biomarkers of microglial activation (sTREM2 [soluble triggering receptor expressed on myeloid cells 2]), axonal injury (NFL [neurofilament light]), neurodegeneration (total-tau), and amyloid-ß, and whether these biomarkers partially accounted for associations between increased LV mass index and white matter damage. We hypothesized higher LV mass index would relate to greater CSF biomarker levels, and these pathologies would partially mediate associations with cerebral white matter microstructure. METHODS: Vanderbilt Memory and Aging Project participants who underwent cardiac magnetic resonance, lumbar puncture, and diffusion tensor imaging (n=142, 72±6 years, 37% mild cognitive impairment [MCI], 32% APOE-ε4 positive, LV mass index 51.4±8.1 g/m2, NFL 1070±588 pg/mL) were included. Linear regressions and voxel-wise analyses related LV mass index to each biomarker and diffusion tensor imaging metrics, respectively. Follow-up models assessed interactions with MCI and APOE-ε4. In models where LV mass index significantly related to a biomarker and white matter microstructure, we assessed if the biomarker mediated white matter associations. RESULTS: Among all participants, LV mass index was unrelated to CSF biomarkers (P>0.33). LV mass index interacted with MCI (P=0.01), such that higher LV mass index related to increased NFL among MCI participants. Associations were also present among APOE-ε4 carriers (P=0.02). NFL partially mediated up to 13% of the effect of increased LV mass index on white matter damage. CONCLUSIONS: Subclinical cardiovascular remodeling, measured as an increase in LV mass index, is associated with neuroaxonal degeneration among individuals with MCI and APOE-ε4. Neuroaxonal degeneration partially reflects associations between higher LV mass index and white matter damage. Findings highlight neuroaxonal degeneration, rather than amyloidosis or microglia, may be more relevant in pathways between structural cardiovascular remodeling and white matter damage.