Pattern Of Dysfunction Research Articles

(531) Effect of COVID- 19 on Sexual Function and Activities Among Women of Reproductive Age

Abstract Introduction The novel SARS corona virus (SARS COV 2) causing the Corona Virus Disease (COVID--19) was first reported in Wuhan, China in 2019 and became a global pandemic in 2020 with severe health and economic consequences forcing nations to declare nationwide lockdown to limit the ragging pandemic. Different patterns of signs and symptoms as well as complications were reported to have followed COVID-19. Objective The objectives of the study were to describe the prevalence of female sexual dysfunction and pattern of dysfunction and to determine the effect of COVID--19 infection pandemic and lockdown on sexual function and activities among women reproductive age. Methods This was a cross sectional study of women in the reproductive age-group evaluating the sexual health function before, during and after the COVID--19 infection pandemic and lockdown. This was assessed using a structured questionnaire and a modified Female Sexual Function Index (FSFI). A pre-tested interviewer administered questionnaire was administered to 203 women participants and the information collected included socio-demographic and gynaecologic characteristics, COVID--19 experiences, sexual history and function before, during and after the COVID--19 pandemic lockdown. Results Most of the respondents were aged between 20 and 50 years (95%), married (77.7%) and were sexually active at the time of the study (92.6%) and 16.3% of the respondents had COVID-19 infection at least once. Only 43.6% of the sexually active respondents currently have normal overall female sexual function score with the mean FSFI score of 24.5. 71.4% had at least mild hyposexual desire, 54.2% with arousal disorder, 32.1% disorders of lubrication, 43.3% have orgasm related dysfunction, 37.8% have sexual satisfaction related dysfunction and 41.1% have disorders of sexual pain. COVID-19 lockdown may have had effect on sexual activities as 11.3% of respondents were not sexually active before the lockdown, 13.3% during the lockdown whereas only 7.4% after the lockdown suggesting abstinence as a result of the lockdown. Among the sexually active respondents during COVID-19 lockdown mean FSFI score of 23.76 and only 36.9% had normal overall FSFI score. Conclusions Female sexual dysfunction is still prevalent with the most common form being disorders of desire and arousal. COVID-19 lockdown resulted in abstinence from sexual intercourse in some women and sexual function also noted to be reduced among the sexually active women with higher incidence of female sexual dysfunction during the lockdown. Disclosure No

C36 NON–CYCLIC INTERMITTENT PROSTHETIC MITRAL VALVE DYSFUNCTION: A CASE REPORT OF A DIFFICULT DIAGNOSIS CONFIRMED WITH MULTIMODALITY IMAGING

Abstract A 59–year–old man,obese,with history of hypertension, 3 years ago underwent mitral valve (MV) replacement with a mechanical prothesis(Sorin Bicarbon 31) and preservation of the native subvalvular apparatus for severe mitral regurgitation due to anterior leaflet flail. Pre–discharge transthoracic echocardiography (TTE) showed normal prothesis function (mean pressure gradient (PG) 3,2mmHg), no valvular leaks and a normal ejection fraction (EF). Lately, the patient was admitted twice to emergency department for signs of heart failure, solved with increasing dose of oral diuretics. In both cases a TTE showed a normal EF, a trans–prosthetic mean PG of 6,5mmHg and no valvular impairment/leaks. Since the suboptimal TTE acoustic windows, a transesophageal echocardiography (TEE) was recommended. TEE showed a normal motion of both MV discs and no pannus/thrombus or leaks with the use of a 2–beat acquisition protocol. However, with longer observation a pattern of non–cyclic intermittent valve dysfunction was noted: whereas some cardiac cycles showed normal discs’ motion, other cycles demonstrated an emi–disc opening delay or blockage during diastole with significant prolongation of transmitral pressure half–time and higher transvalvular gradient, suggestive of flow impairment. A cine fluoroscopy and a CT assessment were also performed, showing the visible intermittent pattern of valve dysfunction without radiological signs of thrombosis or pannus. At this point, the interference of the MV apparatus with the emidisc was considered the most probable mechanism of dysfunction. A Heart Team decision toward reintervention was taken since the risk of a sudden worsening of the mechanical valve function, with potentially lethal consequences, was considered high. The surgeon at visual inspection confirmed the interference of the subvalvular apparatus with the posterior emidisc motion. The chronic shear stress generated on the mitral remnant likely developed a progressive fibrotic response that determined the thickening of the tissue and the periodical entrapment of the disc. MV prothesis was replaced with resection of the subvalvular apparatus. At dismissal,TTE evaluation showed normal valvular function confirmed at 6 months follow–up. Intermittent prosthetic MV dysfunction is a rare but potentially serious complication of MV replacement with subvalvular apparatus preservation. TEE, cine–fluoroscopy and CT may be useful as complementary tools to detect this rare complication.

Spirometric Lung Functions in Type 2 Diabetes Mellitus: A Hospital-Based Study.

Objective This cross-sectional case-control study was conducted with the aim to analyzespirometric lung functions in type 2 diabetes mellitus (T2DM) patients and to correlate the spirometric dysfunction with (a) duration of diabetes, b) metabolic control of diabetes, and c) microvascular complications of diabetes. Methods Pulmonary function tests (PFTs) were performed in 50 T2DM patients and 50 normal healthy controls aged <80 years by using an electronic spirometer. The PFTs recorded were as follows: forced vital capacity (FVC), forced expiratory volume in one second (FEV1), FEV1%, forced expiratory flow 25 (FEF25), forced expiratory flow 25-75 (FEF25-75), and peak expiratory flow rate (PEFR). The glycated hemoglobin (HbA1c) of all the patients was measured by affinity chromatography using the NycoCard HbA1C kit. The assessment of diabetic microvascular complications was performed as follows: peripheral neuropathy was done using Michigan Neuropathy Screening Instrument (MNSI), diabetic retinopathy using fundus examination, and diabetic nephropathy using solid phase/sandwich-format/immunometric assay using NycoCard U-albumin kit.PFTs of diabetic patients and controls were compared by applying an independent sample t-test. The correlation between FVC and FEV1, and HbA1c and duration of illness in diabetic patients was analyzed by applying the Pearsoncoefficient. Results The cases had low FVC (103.82 ±24.43 vs. 116.08 ±13.66), FEV1 (101.36 ±24.23 vs. 110.26 ±14.39), FEV1%(97.56 ±8.64 vs. 103.84 ±5.06),PEFR (101.52 ±27.18 vs. 116.96 ±14.96), and FEF 25-75 (73.56 ±29.19 vs. 98.40 ±14.45) compared to controls, and the difference was statistically significant. Asignificant negativecorrelation was found between spirometry parameters and duration of illness as well as HbA1c. Spirometric lung dysfunction also negatively correlated with microvascular complications of diabetes. Among various microvascular complications, retinopathy correlated best with various spirometric parameters. Conclusion Based on our findings, T2DM patients had a significant decrease in their spirometric indices. The pattern of spirometric dysfunction was suggestive of "mixedventilatory dysfunction". The studyresultshighlight the need to include PFTs in the periodic check-up as part of thecomprehensive management of diabetic patients. Hence, pulmonary function should be included in the periodic comprehensive diabetic check for the holistic management of these patients.

Machine learning for spatial stratification of progressive cardiovascular dysfunction in a murine model of type 2 diabetes mellitus.

Speckle tracking echocardiography (STE) has been utilized to evaluate independent spatial alterations in the diabetic heart, but the progressive manifestation of regional and segmental cardiac dysfunction in the type 2 diabetic (T2DM) heart remains understudied. Therefore, the objective of this study was to elucidate if machine learning could be utilized to reliably describe patterns of the progressive regional and segmental dysfunction that are associated with the development of cardiac contractile dysfunction in the T2DM heart. Non-invasive conventional echocardiography and STE datasets were utilized to segregate mice into two pre-determined groups, wild-type and Db/Db, at 5, 12, 20, and 25 weeks. A support vector machine model, which classifies data using a single line, or hyperplane, that best separates each class, and a ReliefF algorithm, which ranks features by how well each feature lends to the classification of data, were used to identify and rank cardiac regions, segments, and features by their ability to identify cardiac dysfunction. STE features more accurately segregated animals as diabetic or non-diabetic when compared with conventional echocardiography, and the ReliefF algorithm efficiently ranked STE features by their ability to identify cardiac dysfunction. The Septal region, and the AntSeptum segment, best identified cardiac dysfunction at 5, 20, and 25 weeks, with the AntSeptum also containing the greatest number of features which differed between diabetic and non-diabetic mice. Cardiac dysfunction manifests in a spatial and temporal fashion, and is defined by patterns of regional and segmental dysfunction in the T2DM heart which are identifiable using machine learning methodologies. Further, machine learning identified the Septal region and AntSeptum segment as locales of interest for therapeutic interventions aimed at ameliorating cardiac dysfunction in T2DM, suggesting that machine learning may provide a more thorough approach to managing contractile data with the intention of identifying experimental and therapeutic targets.

An alternative mechanism for skeletal muscle dysfunction in long-term post-viral lung disease.

Chronic lung disease is often accompanied by disabling extrapulmonary symptoms, notably skeletal muscle dysfunction and atrophy. Moreover, the severity of respiratory symptoms correlates with decreased muscle mass and in turn lowered physical activity and survival rates. Previous models of muscle atrophy in chronic lung disease often modeled chronic obstructive pulmonary disease (COPD) and relied on cigarette smoke exposure and LPS stimulation, but these conditions independently affect skeletal muscle even without accompanying lung disease. Moreover, there is an emerging and pressing need to understand the extrapulmonary manifestations of long-term post-viral lung disease (PVLD) as found in COVID-19. Here, we examine the development of skeletal muscle dysfunction in the setting of chronic pulmonary disease caused by infection due to the natural pathogen Sendai virus using a mouse model of PVLD. We identify a significant decrease in myofiber size when PVLD is maximal at 49 days after infection. We find no change in the relative types of myofibers, but the greatest decrease in fiber size is localized to fast-twitch-type IIB myofibers based on myosin heavy chain immunostaining. Remarkably, all biomarkers of myocyte protein synthesis and degradation (total RNA, ribosomal abundance, and ubiquitin-proteasome expression) were stable throughout the acute infectious illness and chronic post-viral disease process. Together, the results demonstrate a distinct pattern of skeletal muscle dysfunction in a mouse model of long-term PVLD. The findings thereby provide new insights into prolonged limitations in exercise capacity in patients with chronic lung disease after viral infections and perhaps other types of lung injury.NEW & NOTEWORTHY Our study used a mouse model of post-viral lung disease to study the impact of chronic lung disease on skeletal muscle. The model reveals a decrease in myofiber size that is selective for specific types of myofibers and an alternative mechanism for muscle atrophy that might be independent of the usual markers of protein synthesis and degradation. The findings provide a basis for new therapeutic strategies to correct skeletal muscle dysfunction in chronic respiratory disease.

Longitudinal Olfactory Patterns in Multiple Sclerosis: A Scoping Review and Implication for Use in Management of Disease.

Although studies regarding multiple sclerosis (MS) and olfactory dysfunction (OD) have been previously described and summarized, there is not a sole review of longitudinal studies regarding the matter. This review examines the existing literature investigating MS and its effect on olfaction. In addition, the role of OD in the diagnosis and prognosis of MS is explored. A scoping review of the literature was performed covering longitudinal studies investigating MS and OD. Systematic searches of PubMed, Google Scholar, Web of Science, Embase, PsycInfo, Cumulative Index to Nursing and Allied Health Literature, AgeLine, and MEDLINE were performed using terms that encompassed MS and olfaction. The aim of this review was to build on the existing literature by summarizing only findings that were demonstrated longitudinally. Of 6938 articles identified from the search, 9 met the inclusion criteria: longitudinal observation of relapsing-remitting or progressive MS. Olfaction was measured and scored using various testing arrays, and these scores were then correlated with a multitude of clinical markers. Across all studies, patients with MS demonstrated increased OD. Longitudinally, 2 contrasting patterns were identified: (1) clinical markers of acute inflammation correlated with an increased odor threshold and (2) clinical markers of neurodegeneration, or progression of disease, correlated with a decreased ability to discriminate and identify odors. These studies suggest that olfaction is a dynamic, dependent variable of neurodegeneration, correlating with inflammation and clinical markers. This opens the door for future exploration of olfaction's relationship with MS diagnosis, characterization, and therapeutic response.

The cGAS-STING Pathway: A Ubiquitous Checkpoint Perturbing Myocardial Attributes.

As an innate immune route of defense against microbial infringement, cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS)- stimulator of interferon genes (STING) signaling does not simply participate in amplifying inflammatory responses via releasing type-I interferon (IFN) or enhance the expression of pro-inflammatory genes, but also interplays with multifarious pathophysiological activities, such as autophagy, apoptosis, pyroptosis, ferroptosis, and senescence in a broad repertoire of cells like endothelial cells, macrophages and cardiomyocyte. Thus, the cGAS-STING pathway is closely linked with aberrant heart morphologically and functionally via these mechanisms. The past few decades have witnessed an increased interest in the exact relationship between the activation of the cGAS-STING pathway and the initiation or development of certain cardiovascular diseases (CVD). A group of scholars has gradually investigated the perturbation of myocardium affected by the overactivation or suppression of the cGAS-STING. This review focuses on how the cGAS-STING pathway interweaves with other pathways and creates a pattern of dysfunction associated with cardiac muscle. This sets treatments targeting the cGAS-STING pathway apart from traditional therapeutics for cardiomyopathy and achieves better clinical value.

Positive Tetrahydrocurcumin-Associated Brain-Related Metabolomic Implications.

Tetrahydrocurcumin (THC) is a metabolite of curcumin (CUR). It shares many of CUR's beneficial biological activities in addition to being more water-soluble, chemically stable, and bioavailable compared to CUR. However, its mechanisms of action have not been fully elucidated. This paper addresses the preventive role of THC on various brain dysfunctions as well as its effects on brain redox processes, traumatic brain injury, ischemia-reperfusion injury, Alzheimer's disease, and Parkinson's disease in various animal or cell culture models. In addition to its strong antioxidant properties, the effects of THC on the reduction of amyloid β aggregates are also well documented. The therapeutic potential of THC to treat patterns of mitochondrial brain dysmorphic dysfunction is also addressed and thoroughly reviewed, as is evidence from experimental studies about the mechanism of mitochondrial failure during cerebral ischemia/reperfusion injury. THC treatment also results in a dose-dependent decrease in ERK-mediated phosphorylation of GRASP65, which prevents further compartmentalization of the Golgi apparatus. The PI3K/AKT signaling pathway is possibly the most involved mechanism in the anti-apoptotic effect of THC. Overall, studies in various animal models of different brain disorders suggest that THC can be used as a dietary supplement to protect against traumatic brain injury and even improve brain function in Alzheimer's and Parkinson's diseases. We suggest further preclinical studies be conducted to demonstrate the brain-protective, anti-amyloid, and anti-Parkinson effects of THC. Application of the methods used in the currently reviewed studies would be useful and should help define doses and methods of THC administration in different disease conditions.

Combined effects of GBA mutations and STN-DBS negatively impact executive function in Parkinson’s disease (P4-11.004)

Combined effects of GBA mutations and STN-DBS negatively impact executive function in Parkinson’s disease (P4-11.004)

Cognitive and MRI Profiles in Primary and Secondary Progressive Multiple Sclerosis (P13-3.002)

<h3>Objective:</h3> We examined the neuropsychological profile of primary progressive (PP) and secondary progressive (SP) multiple sclerosis (MS) patients and investigated the relationship between cognitive functioning with structural and functional MRI abnormalities. <h3>Background:</h3> Studies comparing frequency and patterns of cognitive dysfunction between PPMS and SPMS have yielded conflicting results. <h3>Design/Methods:</h3> One-hundred eighty-three MS patients (60 PPMS and 123 SPMS) and 75 age- and sex-matched healthy controls underwent 3.0T MRI. MS patients were administered the Brief Repeatable Battery of Neuropsychological tests (BRB-N) and were classified as cognitively impaired if they scored below the 5^th percentile of the normative sample on at least two tests. Four cognitive domain z-scores were determined from normative data, and then averaged to obtain a measure of global cognition (z-BRB-N). Using hierarchical linear regression analysis, the contribution of lesion volumes, normalized brain volumes, white matter fractional anisotropy (FA) and mean diffusivity (MD) abnormalities, and resting state (RS) functional connectivity (FC) alterations to global cognition in PPMS and SPMS was investigated. <h3>Results:</h3> Patients with PPMS and SPMS had similar z-scores in all investigated cognitive domains. Compared to PPMS, SPMS showed decreased FA and increased MD in the fornix, and lower RS FC within the basal ganglia network. The frequency of cognitive impairment was 31.7% in PPMS and 41.3% in SPMS (p=0.19). In PPMS, poorer cognitive performance (e.g., lower z-BRB-N) was associated with decreased FA of the medial lemniscus (ΔR²=0.11; p=0.011) and lower normalized gray matter volume (ΔR²=0.29; p&lt;0.001). In SPMS, poorer cognitive performance was associated with decreased FA of the fornix (ΔR²=0.35; p&lt;0.001) and lower normalized white matter volume (ΔR²=0.05; p=0.034). <h3>Conclusions:</h3> PPMS and SPMS had similar neuropsychological profile. Cognitive dysfunction in PPMS and SPMS was related to distinct patterns of structural MRI abnormalities and involvement of different white matter tracts, while RS FC alterations did not contribute to explain their global cognitive functioning. <b>Disclosure:</b> Damiano Mistri has nothing to disclose. Ms. Cacciaguerra has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Ms. Cacciaguerra has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for BMS Celgene. Ms. Cacciaguerra has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi. Ms. Cacciaguerra has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for BIOMEDIA. Paola Valsasina has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for ACCMED. Elisabetta Pagani has nothing to disclose. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bristol Myers Squibb . Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi Genzyme. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Maria Assunta Rocca has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva. The institution of Maria Assunta Rocca has received research support from Italian Ministry of Health, MS Society of Canada and Fondazione Italiana Sclerosi Multipla. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA).

Neurologic Manifestations of Long COVID Differ Based on Acute COVID-19 Severity.

To characterize neurologic manifestations in post-hospitalization Neuro-PASC (PNP) and non-hospitalized Neuro-PASC (NNP) patients. Prospective study of the first 100 consecutive PNP and 500 NNP patients evaluated at a Neuro-COVID-19 clinic between 5/2020 and 8/2021. PNP were older than NNP patients (mean 53.9 vs 44.9 y; p < 0.0001) with a higher prevalence of pre-existing comorbidities. An average 6.8 months from onset, the main neurologic symptoms were "brain fog" (81.2%), headache (70.3%), and dizziness (49.5%) with only anosmia, dysgeusia and myalgias being more frequent in the NNP compared to the PNP group (59 vs 39%, 57.6 vs 39% and 50.4 vs 33%, all p < 0.003). Moreover, 85.8% of patients experienced fatigue. PNP more frequently had an abnormal neurologic exam than NNP patients (62.2 vs 37%, p < 0.0001). Both groups had impaired quality of life in cognitive, fatigue, sleep, anxiety, and depression domains. PNP patients performed worse on processing speed, attention, and working memory tasks than NNP patients (T-score 41.5 vs 55, 42.5 vs 47 and 45.5 vs 49, all p < 0.001) and a US normative population. NNP patients had lower results in attention task only. Subjective impression of cognitive ability correlated with cognitive test results in NNP but not in PNP patients. PNP and NNP patients both experience persistent neurologic symptoms affecting their quality of life. However, they harbor significant differences in demographics, comorbidities, neurologic symptoms and findings, as well as pattern of cognitive dysfunction. Such differences suggest distinct etiologies of Neuro-PASC in these populations warranting targeted interventions. ANN NEUROL 2023;94:146-159.

Immune profiling in Puerto Rican injection drug users with and without HIV-1 infection.

Antiretroviral therapy has been effective in suppressing HIV viral load and enabling people living with HIV to experience longer, more conventional lives. However, as people living with HIV are living longer, they are developing aging-related diseases prematurely and are more susceptible to comorbidities that have been linked to chronic inflammation. Coincident with HIV infection and aging, drug abuse has also been independently associated with gut dysbiosis, microbial translocation, and inflammation. Here, we hypothesized that injection drug use would exacerbate HIV-induced immune activation and inflammation, thereby intensifying immune dysfunction. We recruited 50 individuals not using injection drugs (36/50 HIV+) and 47 people who inject drugs (PWID, 12/47 HIV+). All but 3 of the HIV+ subjects were on antiretroviral therapy. Plasma immune profiles were characterized by immunoproteomics, and cellular immunophenotypes were assessed using mass cytometry. The immune profiles of HIV+/PWID-, HIV-/PWID+, and HIV+/PWID+ were each significantly different from controls; however, few differences between these groups were detected, and only 3 inflammatory mediators and 2 immune cell populations demonstrated a combinatorial effect of injection drug use and HIV infection. In conclusion, a comprehensive analysis of inflammatory mediators and cell immunophenotypes revealed remarkably similar patterns of immune dysfunction in HIV-infected individuals and in people who inject drugs with and without HIV-1 infection.

Identifying patterns of neurocognitive dysfunction through direct comparison of children with leukemia, central nervous system tumors, and sickle cell disease.

To quantify and compare the magnitude and type of neurocognitive dysfunction in at-risk children with central nervous system (CNS) tumors, acute lymphoblastic leukemia (ALL), and sickle cell disease (SCD) using a common instrument and metric to directly compare these groups with each other. Fifty-three participants between the ages of 7 and 12 years (n=27 ALL, n=11 CNS tumor, n=15 SCD) were enrolled and assessed using the NIH Toolbox Cognition Battery (NIHTCB). Participants with ALL or CNS tumor were 0-18 months posttherapy, while participants with SCD possessed the SS or Sβ0 genotype, took hydroxyurea, and had no known history of stroke. Independent sample t-tests showed that participants with ALL and CNS tumor experienced greatest deficits in processing speed (ALL d=-0.96; CNS tumor d=-1.2) and inhibitory control and attention (ALL d=-0.53; CNS tumor d=-0.97) when compared with NIHTCB normative data. Participants with SCD experienced deficits in cognitive flexibility only (d=-0.53). Episodic memory was relatively spared in all groups (d=-0.03 to -0.32). There were no significant differences in function when groups were compared directly with each other by analysis of variance. Use of a common metric to quantify the magnitude and type of neurocognitive dysfunction across at-risk groups of participants by disease shows that participants perform below age-expected norms in multiple domains and experience dysfunction differently than one another. This approach highlights patterns of dysfunction that can inform disease- and domain-specific interventions.

Patterns and prevalence of cognitive dysfunction in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, in which cognitive dysfunction is common, but poorly understood. This study aims to characterize the prevalence and patterns of cognitive dysfunction in SLE. SLE patients (n = 95) and demographically matched healthy controls (n = 48) underwent cross-sectional cognitive testing using the 1-hr conventional neuropsychological test battery recommended by the American College of Rheumatology for use in SLE. We used standard deviations (SD) from the healthy control group to define impairment. For each cognitive test we compared SLE and control groups using independent samples t-tests (or alternatives when needed). We performed cluster analysis using a machine learning algorithm to look for patterns of cognitive dysfunction. The SLE group performed significantly worse than healthy controls on every cognitive test. The largest differences were in the domains of verbal fluency, working memory and attention, while fine motor and psychomotor speed were the least affected domains. As expected, the prevalence of cognitive dysfunction varied depending on the SD cut-off used, with 49% of participants being >1.5 SD below the healthy control mean in at least two cognitive domains. Heat mapping showed variability in the pattern of dysfunction between individual patients and cluster analysis confirmed the presence of two clusters of patients, which were those significantly impaired versus those having preserved cognition. Cognitive dysfunction is common in SLE but markedly heterogeneous across both cognitive domains and across the SLE group. Cluster analysis supports the use of a binary definition of cognitive dysfunction in SLE.

Functional network interactions in patients with schizophrenia with persistent auditory verbal hallucinations: A multimodal MRI fusion approach using three-way pICA

Over the last decade, there have been an increasing number of functional magnetic resonance imaging (fMRI) studies examining brain activity in schizophrenia (SZ) patients with persistent auditory verbal hallucinations (AVH) using either task-based or resting-state fMRI (rs-fMRI) paradigms. Such data have been conventionally collected and analyzed as distinct modalities, disregarding putative crossmodal interactions. Recently, it has become possible to incorporate two or more modalities in one comprehensive analysis to uncover hidden patterns of neural dysfunction not sufficiently captured by separate analysis. A novel multivariate fusion approach to multimodal data analysis, i.e., parallel independent component analysis (pICA), has been previously shown to be a powerful tool in this regard. We utilized three-way pICA to study covarying components among fractional amplitude of low-frequency fluctuations (fALFF) for rs-MRI and task-based activation computed from an alertness and a working memory (WM) paradigm of 15 SZ patients with AVH, 16 non-hallucinating SZ patients (nAVH), and 19 healthy controls (HC). The strongest connected triplet (false discovery rate (FDR)-corrected pairwise correlations) comprised a frontostriatal/temporal network (fALFF), a temporal/sensorimotor network (alertness task), and a frontoparietal network (WM task). Frontoparietal and frontostriatal/temporal network strength significantly differed between AVH patients and HC. Phenomenological features such as omnipotence and malevolence of AVH were associated with temporal/sensorimotor and frontoparietal network strength. The transmodal data confirm a complex interplay of neural systems subserving attentional processes and cognitive control interacting with speech and language processing networks. In addition, the data emphasize the importance of sensorimotor regions modulating specific symptom dimensions of AVH.

Banff 2016 Global Assessment and Quantitative Scoring for T Cell-Mediated Liver Transplant Rejection are Interchangeable.

Histopathological assessment of liver biopsies is the current "gold standard" for diagnosing graft dysfunction after liver transplantation (LT), as graft dysfunction can have nonspecific clinical presentations and inconsistent patterns of liver biochemical dysfunction. Most commonly, post-LT, graft dysfunction within the first year, is due to acute T-cell mediated rejection (TCMR) which is characterised histologically by the degree of portal inflammation (PI), bile duct damage (BDD), and venous endothelial inflammation (VEI). This study aimed to establish the relationship between global assessment, which is the global grading of rejection using a "gestalt" approach, and the rejection activity index (RAI) of each component of TCMR as described in revised Banff 2016 guidelines. Liver biopsies (n = 90) taken from patients who underwent LT in 2015 and 2016 at the Australian National Liver Transplant Unit were identified from the electronic medical records. All biopsy slides were microscopically graded by at least two assessors independently using the revised 2016 Banff criteria. Data were analysed using IBM SPSS v21. A Fisher-Freeman-Halton test was performed to assess the correlation between the global assessment and the RAI scores for each TCMR biopsy. Within the cohort, 60 (37%, n = 164) patients underwent at least 1 biopsy within 12 months after LT. The most common biopsy outcome (total n = 90) was acute TCMR (64, 71.1%). Global assessment of TCMR slides strongly positively correlated with PI (p value <0.001), BDD (p value <0.001), VEI (p value <0.001), and total RAI (p value <0.001). Liver biochemistry of patients with TCMR significantly improved within 4 to 6 weeks post-biopsy compared to the day of the biopsy. In acute TCMR, global assessment and total RAI are strongly correlated and can be used interchangeably to describe the severity of TCMR.

Patterns of Renal Dysfunction and Profile of Kidney Biopsies in Hematopoietic Stem Cell Transplant Recipients

Introduction: Post hematopoietic stem cell transplant (HSCT), kidney can be subjected to injury by various causes. Of these, graft versus host disease (GvHD) affecting the kidney is an under-recognized entity with no clear guidelines on its diagnosis, clinicopathological manifestations, and outcomes. Material and Methods: Out of 2,930 patients who underwent HSCT at our center between 2005 and 2020, kidney biopsy was performed in 19 allogenic and 5 autologous recipients. Results: The mean age of the cohort at transplant was 33.2 ± 7 years, and 15 (62%) were males. Median time to kidney biopsy from HSCT was 14 (IQR, 9–30) months. Aplastic anemia was the most common underlying hematological disease (54.2%). All 19 allogenic recipients were classified based on clinicopathological manifestations into either thrombotic microangiopathy (TMA, 12/19 [63%]) or nephrotic syndrome (NS, 7/19 [37%]) pattern. Glomerular tuft “mesangiolysis” was the dominant pattern of injury noted in 9/12 cases of TMA pattern. There was a predominance of acute microangiopathic changes restricted primarily to the glomerular compartment. Of the 7 patients with NS pattern, membranous nephropathy was seen in 4 (57%) and minimal change disease in 3 (43%) patients. Thirty-nine percent (7/18) stained positive for C4d which was predominantly glomerular. Allogenic recipients who did not receive immunosuppression (IS) for renal disease had a lower eGFR at biopsy, a longer latency between withdrawal of GvHD prophylaxis and biopsy, and were significantly at a higher risk of kidney failure (IS: 2/11, 18.1% vs. no IS: 2/6, 33.3%, p = 0.04). “Associated extra-renal GvHD” occurred in 11/19 (57.9%) allogenic recipients. Patients with “associated extra-renal GvHD” had significantly more deaths (6/11, 60% vs. 0, p = 0.02) but comparable renal outcomes. Conclusion: Renal GvHD can present with or without “associated extra-renal GvHD” after a prolonged period of withdrawal of GvHD prophylaxis, requiring careful diagnostic vigilance and consideration of IS.

Timing matters: Sex differences in inflammatory and behavioral outcomes following repetitive blast mild traumatic brain injury

BackgroundRepetitive blast-related mild traumatic brain injury (mTBI) caused by exposure to high explosives is increasingly common among warfighters as well as civilians. While women have been serving in military positions with increased risk of blast exposure since 2016, there are few published reports examining sex as a biological variable in models of blast mTBI, greatly limiting diagnosis and treatment capabilities. As such, here we examined outcomes of repetitive blast trauma in female and male mice in relation to potential behavioral, inflammatory, microbiome, and vascular dysfunction at multiple timepoints. MethodsIn this study we utilized a well-established blast overpressure model to induce repetitive (3x) blast-mTBI in both female and male mice. Acutely following repetitive exposure, we measured serum and brain cytokine levels, blood–brain barrier (BBB) disruption, fecal microbial abundance, and locomotion and anxiety-like behavior in the open field assay. At the one-month timepoint, in female and male mice we assessed behavioral correlates of mTBI and PTSD-related symptoms commonly reported by Veterans with a history of blast-mTBI using the elevated zero maze, acoustic startle, and conditioned odorant aversion paradigms. ResultsRepetitive blast exposure resulted in both similar (e.g., increased IL-6), and disparate (e.g., IL-10 increase only in females) patterns of acute serum and brain cytokine as well as gut microbiome changes in female and male mice. Acute BBB disruption following repetitive blast exposure was apparent in both sexes. While female and male blast mice both exhibited acute locomotor and anxiety-like deficits in the open field assay, only male mice exhibited adverse behavioral outcomes that lasted at least one-month. DiscussionRepresenting a novel survey of potential sex differences following repetitive blast trauma, our results demonstrate unique similar yet divergent patterns of blast-induced dysfunction in female vs. male mice and highlight novel targets for future diagnosis and therapeutic development.

Assessing the Impact of Persistent HIV Infection on Innate Lymphoid Cells Using InVitro Models.

Pathogens that persist in their host induce immune dysfunctions even in the absence of detectable replication. To better understand the phenotypic and functional changes that persistent infections induce in sentinel innate immune cells, we developed human PBMC-based HIV models of persistent infection. Autologous nonactivated PBMCs were cocultured with chronically infected, acutely infected, or uninfected cells and were then analyzed by unsupervised high-dimensional flow cytometry. Using this approach, we identified prevalent patterns of innate immune dysfunctions associated with persistent HIV infections that at least in part mirror immune dysfunctions observed in patients. In one or more models of chronic infection, bystander CD16+ NK cells expressing markers of activation, such as CD94, CD45RO, CD62L, CD69, CD25, and immune checkpoints PD1, Tim3, TIGIT, NKG2A and Lag3, were significantly reduced. Conversely, helper ILC subsets expressing PDL1/PDL2 were significantly enriched in chronic infection compared with either uninfected or acute infection, suggesting that chronic HIV-1 infection was associated with an inhibitory environment for bystander ILC and NK subsets. The cell-based models of persistent infection that we describe here provide versatile tools to explore the molecular mechanisms of these immune dysfunctions and unveil the contribution of innate immunity in sustaining pathogen persistence.

LEFT VENTRICULAR DIASTOLIC DYSFUNCTION AND ITS PATTERN IN TYPE 2 DIABETIC PATIENTS WITH AND WITHOUT MICROALBUMINURIA

Objective: To find out and compare left ventricular diastolic dysfunction and its pattern among patients with type-2 diabetes mellitus (T2DM) with and without micro-albuminuria. Methodology: This comparative cross section study was conducted in the outpatient department of Peshawar Institute of Cardiology from August 2021 to January 2022. A total of 228 T2DM normotensive patients, aged 30 to 65 years were enrolled and divided into two groups. Group-A contained 114 T2DM with no-albuminuria and Group-B had 114 T2DM micro-albuminuria patients. Socio-demographic, anthropometric, laboratory character­istics and echocardiographic parameters of all patients were noted. Qualitative variables were analyzed using chi-square test while quantitative variables were analyzed using t-test. P value &lt;0.05 was considered statistically significant. Results: Out of a total of 228 patients, 122 (53.5%) were male. Overall, mean age was noted to be 49.18+8.8 years. In comparison to group-A, duration of diabetes was significantly more among patients of group-B (p&lt;0.001). Renal functions were significantly preserved in Group-A in comparison to Group-B (p=0.003) as shown by eGFR. Left ventricular diastolic dysfunction was found to be 49.1% among patients of Group-A in comparison to 71.1% in Group-B and pattern of left ventricular diastolic dysfunction showed a significant difference between patients of both study groups (0.004). Conclusion: Left ventricular diastolic dysfunction was significantly high among T2DM patients with micro-albu­minuria. Significant associations were found in terms altered left ventricular diastolic echocardiographic features among T2DM patients with micro-albuminuria.