Pattern Of Dysfunction Research Articles

Rhythmic Contractions of Lymph Vessels and Lymph Flow Are Disrupted in Hypertensive Rats.

Hypertension increases the risk of lymphedema in patients with comorbidities, but whether hypertension directly compromises lymph vessel (LV) function and lymph flow is unclear. We compared the contractions of mesenteric LVs ex vivo and lymph flow in vivo between normotensive and Ang II (angiotensin II)-induced hypertensive rats and explored the ionic basis of contractile patterns. Key studies were recapitulated in spontaneously hypertensive rats and control Wistar-Kyoto rats. Video microscopy continuously recorded the diameters of cannulated rat mesenteric LVs, and high-speed optical imaging estimated mesenteric lymph flow in vivo. Jess capillary Western electrophoresis evaluated expression levels of ion channel proteins. Isolated LVs from Ang II-induced hypertensive rats exhibited dysrhythmic contractions, whereas LVs from both Ang II-induced hypertensive rats and spontaneously hypertensive rats exhibited reduced diastolic diameters and cross-sectional flow. Mesenteric lymph flow in vivo was 2.9-fold lower in Ang II-induced hypertensive rats compared with normotensive rats. Surprisingly, the LVs from Ang II-induced hypertensive rats expressed fewer intact L-type Ca2+ channel pore proteins and more modulatory cleaved C-terminal fragments. However, pharmacological block of voltage-gated K+ channels but not other K+ channel types in control LVs established the pattern of contractile dysfunction observed in hypertension. Jess capillary Western electrophoresis analysis confirmed a loss of Shaker-type KV1.2 channels in LVs from hypertensive rats. We provide initial evidence of lymphatic contractile dysfunction and compromised lymph flow in hypertensive rats, which may be caused by a loss of KV1.2 channels in the lymphatic muscle cells.

Cognition-related connectome gradient dysfunctions of thalamus and basal ganglia in drug-naïve first-episode major depressive disorder

BackgroundSubcortical functional abnormalities are believed to contribute to clinical symptoms and cognitive impairments in major depressive disorder (MDD). By introducing functional gradient mapping, the present study evaluated subcortical gradients in MDD patients and their association with cognitive features. MethodsOrganization patterns and between-group differences in the principal subcortical gradient were investigated in 145 never-treated first-episode MDD patients and 145 healthy controls (HCs) across limbic, thalamic, and basal ganglia (BG) systems and their structural and functional subregions. We also assessed the associations between significant gradient alterations and clinical characteristics and neuropsychological functioning. ResultsOverall, MDD patients showed a relatively compressed and disturbed gradient organization than HCs, with limbic and BG regions located at the two extreme ends of the principal gradient. Specifically, MDD patients had lower principal gradient values in thalamus and limbic system but higher values in BG than HCs. These gradient alterations, associated with intrinsic Euclidian distance and functional connectivity patterns, manifested as spatial rearrangements of gradient values within each respective subregion. Lower gradient values in thalamic subregion projecting to default mode network were associated with higher principal gradient values in BG subregion projecting to ventral attention network, and these gradient alterations were correlated with poorer episodic memory performance in MDD patients. LimitationsThe specific neuropathological mechanisms driving the gradient alterations still require further investigation. ConclusionsOpposing gradient alterations in the thalamic and BG regions synergistically impact episodic memory performance in MDD, revealing an internally differentiated and cognition related pattern of subcortical gradient dysfunction in MDD.

Endogen microvascular dysfunction is associated with worse outcomes in heart transplantation

Abstract Background Cardiac allograft vasculopathy (CAV) affects the health of both epicardial and microvascular blood vessels in heart transplants. Coronary microvascular dysfunction (CMD) has been associated with poor outcomes in the non-transplant population. Two patterns of microvascular dysfunction have been characterized, classical (low stress flow) and endogen (high rest flow). Whether these patterns of microvascular dysfunction are associated with outcomes in the transplant population has not been thoroughly evaluated. Purpose The purpose of the study was to assess the relationship between microvascular dysfunction and adverse outcomes in patients with heart transplants. Methods Patients with no history of angiographic CAV who underwent positron emission tomography myocardial perfusion imaging and were found to have normal perfusion (summed stress score = 0) were included in the study. Patients were then classified by microvascular dysfunction: normal (flow reserve ≥ 2.0) versus abnormal (flow reserve <2.0). Patients were further subclassified based on pattern of microvascular dysfunction, classical (stress myocardial flow <1.7 mL/min/g) and endogen (stress myocardial flow ≥1.7 mL/min/g). The two primary outcomes were all-cause mortality and a composite of death, heart failure hospitalization, acute coronary syndrome, and revascularization. Kaplan-Meier survival and Cox proportional regression were used to assess the relationship between microvascular function and outcomes. Results In total, 359 patients were enrolled in the study, of which 29 (8%) had classical CMD and 78 (22%) had endogen CMD. Patients with endogen CMD were more likely to be women (46%) compared to 31% for normal microvascular function and 24% for classical CMD. During a median follow up period of 2.0 years (Q1 1.7, Q3 2.3), 36 patients had an adverse event and 19 patients died. Endogen CMD was associated with a significantly higher risk of both the composite outcome, HR 2.30 (1.15 – 4.61), and all-cause mortality, 4.19 (1.64 – 10.73). Classical CMD was not associated with either the composite outcome, HR 0.88 (0.20 – 3.84) or death, HR 1.02 (0.12 – 8.33), however assessment of classical CMD was limited by small sample size. Conclusions Endogen-type CMD is associated with worse intermediate-term outcomes in transplant patients compared to normal microvascular function and classical-type CMD, although comparison to classical-type CMD was limited by small sample size.Table 1:DemographicsFigure 1:KM Survival Curves

How different types of cardiomyopathy with hypertrophic phenotype affect left atrial remodeling and function

Abstract Background Left atrial (LA) dysfunction is a common feature in hypertrophic cardiomyopathies. How the underlying etiology and pathophysiology of different cardiomyopathies affects LA remodeling and function remains unexplored. Purpose The aim of our study is to investigate the influence of various cardiomyopathies with hypertrophic phenotype on LA remodeling and function. Methods Patients with left ventricular (LV) hypertrophic phenotype who underwent cardiac magnetic resonance (CMR) were included. A group of patients with a normal CMR was included as a control group. CMR acquisitions used for clinical indication of heart failure diagnosis and etiology were retrospectively analyzed to obtain LA reservoir, conduit, and booster strain, left atrioventricular coupling index (LACI) and LA sphericity. Differences between groups were assessed. To investigate the independent clinical associates of LA reservoir, conduit and booster strain, multivariable linear regression analyses were performed. Results A total of 375 individuals were analyzed including 321 patients diagnosed with LV hypertrophy and 54 patients with a normal CMR. Of the 321 patients with LV hypertrophy, 148 were diagnosed with hypertrophic cardiomyopathy (HCM), 35 with cardiac amyloidosis (CA), 41 with hypertensive cardiomyopathy (HTN) and 97 with severe asymptomatic aortic stenosis (AS). CMR LA characteristic and strain analysis results are summarized in Figure 1. The indexed LA end-systolic volume (iLAVmax), indexed LA end-diastolic volume (iLAVmin) and LA sphericity were larger in patients with CA when compared to other groups (all p<0.05). CA patients displayed more left atrioventricular uncoupling (lower LACI) when compared to individuals with HCM, HTN, AS, and controls (all p<0.001), while no significant differences were observed across other groups. CA patients exhibited lower LA reservoir and booster strains compared to the other groups (all p<0.05), whereas no significant differences were observed across other hypertrophic phenotype diseases. Age, iLAVMax and LACI were independently associated with all the three LA strain components (Figure 2, all p<0.05). Conclusions LA remodeling and function are affected differently across the various etiologies of LV hypertrophy. CA patients exhibit more pronounced atrial involvement, whereas those with HCM, asymptomatic AS, and HTN display similar patterns of atrial dysfunction and remodeling. Additionally, CMR-derived iLAVmax and LACI are independently correlated with LA function.

Imaging the translocator protein 18 kDa within cognitive control and declarative memory circuits in virally-suppressed people with HIV.

Virally-suppressed people with HIV (VS-PWH) show heterogeneity in patterns of cognitive dysfunction. To better understand the relationship between the neuroimmune response and cognition, we used positron emission tomography (PET) to image the translocator protein 18 kDa (TSPO). The study examined HIV-serostatus differences in TSPO as well as associations between regional TSPO and select cognitive processes defined using the Research Domain Criteria (RDoC) framework. Cross-sectional investigation in VS-PWH (n = 25) versus HIV-uninfected individuals (n = 18) of cognitive control and declarative memory, as well as [11C]DPA-713 PET measures of TSPO within cognitive control and declarative memory regions of interest. Group differences in [11C]DPA-713 binding (VT) in cognitive control or declarative memory regions were examined using linear mixed models. Tests of associations between factor-derived cognitive system measures and PET measures were performed, controlling for TSPO genotype. There were no group differences in any of the four factor-derived cognitive system measures. VS-PWH had higher log [11C]DPA-713 VT across cognitive control regions(unstandardized beta coefficient reflecting mean difference [B] = 0.23, SE = 0.11, 95% confidence interval [CI] 0.01, 0.45, P = 0.04) and declarative memory regions (B = 0.24, SE = 0.11, 95%CI 0.02, 0.45, P = 0.03). Higher log [11C]DPA-713 VT in cognitive control regions related to poorer cognitive control in each group, and to worse self-reported cognitive performance in VS-PWH. Log [11C]DPA-713 VT in each declarative memory region did not associate with measured declarative memory. A localized neuroimmune response marked by high TSPO in brain regions that subserve cognitive control may contribute to poorer cognitive control in VS-PWH.

Multiomics Reveals Biological Mechanisms Linking Macroscale Structural Covariance Network Dysfunction With Neuropsychiatric Symptoms Across the Alzheimer’s Disease Continuum

BackgroundThe highly heterogeneity of neuropsychiatric symptoms (NPSs) hinder further exploration of their role in neurobiological mechanisms and Alzheimer’s disease (AD). We aimed to delineate NPS patterns based on brain macroscale connectomics to understand the biological mechanisms of NPSs on the AD continuum. MethodsWe constructed Regional Radiomics Similarity Networks (R2SN) for 550 participants (AD with NPSs [AD-NPS, n=376], AD without NPSs [AD-nNPS, n=111], and normal controls [n=63]) from CIBL study. We identified R2SN connections associated with NPSs, and then cluster distinct subtypes of AD-NPS. An independent dataset (n=189) and internal validation were performed to assess the robustness of the NPS subtypes. Subsequent multiomics analysis were performed to assess the distinct clinical phenotype and biological mechanisms in each NPS subtype. ResultsAD-NPS patients were clustered into severe (n=187), moderate (n=87), and mild NPS (n=102) subtypes, each exhibiting distinct brain network dysfunction patterns. A high level of consistency in clustering NPS was internally and externally validated. Severe and moderate NPSs showed significant cognitive impairment, increased plasma p-Tau181 levels, extensive decreased brain volume and cortical thickness, and accelerated cognitive decline. Gene set enrichment analysis (GSEA) revealed enrichment of differentially expressed genes in ion transport and synaptic transmission with variations for each NPS subtype. Genome-wide association studies (GWAS) analysis defined the specific gene loci for each subtype of AD-NPS (i.e, logical memory), aligning with clinical manifestations and progression patterns. ConclusionsThis study identified and validated three distinct NPS subtypes, underscoring the role of NPSs in neurobiological mechanisms and progression of the AD continuum.

SENSE-Cog Lewy: Investigating the Impact of Sensory Loss on the Diagnosis, Clinical Features and Prognosis of Lewy Body Dementia

Abstract Background Lewy Body Dementia (LBD) accounts for 20% of the nearly 65,000 people with dementia in Ireland, but fewer than 5% of those affected receive a formal diagnosis. LBD includes both Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) and can be characterised by fluctuating and progressive cognitive difficulties, vivid visual hallucinations and REM sleep behaviour disturbances. Sensory function such hearing, vision and olfactory function declines with age—but increasing evidence shows that abnormal patterns of sensory dysfunction can be one of the earliest clinical signs and predictors of progression of neurodegenerative diseases such as Lewy body dementia and Parkinson’s disease dementia. Methods A scoping review was undertaken using Embase, CINAHL, PsychINFO and PubMed. Only reports on people with LBD (DLB and PDD) from any stage, prodromal to late stage were considered. Papers primarily addressing other forms of neurocognitive disorders were excluded. Sensory loss was conceptualised as the loss of smell, vision and hearing. Two reviewers independently assessed each study for inclusion, and disagreements were resolved by a third reviewer. Results Reports on sensory loss in LBD were very few and most often were comparing sensory loss across different dementia types. Strong associations were observed between olfactory loss and particular visual impairment patterns and the severity of both cognitive and non-cognitive DLB symptoms. Olfactory impairment is a potential early biomarker of DLB and PDD and severity of olfactory dysfunction can predict cognitive decline. Visual hallucinations, for example, were found to be closely linked to visual impairment patterns such as pareidolia. Conclusion This study highlights a knowledge gap regarding the patterns of sensory loss in LBD and their relationship with cognitive and non-cognitive LBD symptoms. Sensory assessments represent potentially valuable diagnostic and prognosis tool in LBD, with further research required to understand the aetiological mechanisms underlying sensory impairment in LBD and other dementias.

Anxiety in late-life depression is associated with poorer performance across multiple cognitive domains.

Anxiety is a common comorbid feature of late-life depression (LLD) and is associated with poorer global cognitive functioning independent of depression severity. However, little is known about whether comorbid anxiety is associated with a domain-specific pattern of cognitive dysfunction. We therefore examined group differences (LLD with and without comorbid anxiety) in cognitive functioning performance across multiple domains. Older adults with major depressive disorder (N = 228, ages 65-91) were evaluated for anxiety and depression severity, and cognitive functioning (learning, memory, language, processing speed, executive functioning, working memory, and visuospatial functioning). Ordinary least squares regression adjusting for age, sex, education, and concurrent depression severity examined anxiety group differences in performance on tests of cognitive functioning. Significant group differences emerged for confrontation naming and visuospatial functioning, as well as for verbal fluency, working memory, and inhibition with lower performance for LLD with comorbid anxiety compared to LLD only, controlling for depression severity. Performance patterns identified among older adults with LLD and comorbid anxiety resemble neuropsychological profiles typically seen in neurodegenerative diseases of aging. These findings have potential implications for etiological considerations in the interpretation of neuropsychological profiles.

Dual blockade of IL-4 and IL-13 with dupilumab ameliorates sensorineural olfactory dysfunction in mice with eosinophilic sinonasal inflammation.

Dupilumab, an antibody that binds IL-4Rα and inhibits IL-4 and IL-13 signals, has demonstrated efficacy in chronic rhinosinusitis with nasal polyps (CRSwNP) primarily characterized by type 2 inflammation. Current evidence suggests that the rate of improvement in olfactory dysfunction with dupilumab exceeds that of nasal polyp reduction, yet the underlying mechanism remains undisclosed. We hypothesize that dupilumab may initially ameliorate sensorineural olfactory dysfunction. Male BALB/c mice were intranasally administered ovalbumin and Aspergillus protease for 12 weeks to induce eosinophilic sinonasal inflammation. Dupilumab treatment was also administered. The mice underwent histological assessment, olfactory behavioural test, and gene expression profiling to identify neuroinflammatory markers within the olfactory bulb. Dupilumab treatment resulted in a reduction in the number of mucosal protruding lesions, as well as decreased infiltration of eosinophils and neutrophils, along with a decrease in olfactory sensory neuron injury. Furthermore, there was a downregulation in the mRNA expression related to microglia activation and neuroinflammation in the olfactory bulb. Dupilumab improves the sensorineural pattern of olfactory dysfunction in mice, potentially explaining why olfaction improves more rapidly than polyp reduction in patients with CRSwNP.

Shared and distinct patterns of default mode network dysfunction in major depressive disorder and bipolar disorder: A comparative meta-analysis

BackgroundWhile patients with major depressive disorder (MDD) and bipolar disorder (BD) exhibited default mode network (DMN) dysfunction revealed by aberrant resting-state functional connectivity (rsFC) patterns, previous findings have been inconsistent. Little is known about the similarities and differences in DMN rsFC between MDD and BD. MethodsA voxel-wise meta-analysis of seed-based DMN rsFC studies on MDD or BD was performed using the Seed-based d Mapping software with permutation of subject images (SDM-PSI). Aberrant DMN rsFC in both disorders was investigated separately, followed by conjunction and between-disorder comparison analyses. Functional decoding was performed to implicate the psychophysiological underpinnings of derived brain abnormalities. ResultsThirty-four studies comparing 1316 MDD patients with 1327 HC, and 22 studies comparing 1059 BD patients with 1396 HC were included. Compared to HC, MDD patients exhibited DMN hyperconnectivity with frontolimbic systems, and hypoconnectivity with temporal lobe and posterior cingulate cortex. BD patients displayed increased DMN connectivity with bilateral precuneus, and reduced connectivity with prefrontal cortex and middle temporal gyrus. No common patterns of DMN rsFC abnormalities were observed between MDD and BD. Compared to BD, MDD patients showed DMN hyperconnectivity with triangular part of the left inferior frontal gyrus and left fusiform gyrus. Functional decoding found that patterns of DMN rsFC alteration between MDD and BD were primarily related to action and perception domains. ConclusionDistinct DMN dysfunction patterns in MDD and BD enhance current understanding of the neural substrates of mood disorders and may provide a potential biomarker for differentiation.

Cognitive phenotypes: Unraveling the heterogeneity in cognitive dysfunction among patients with primary brain tumors receiving radiotherapy.

Patients with primary brain tumors demonstrate heterogeneous patterns of cognitive dysfunction, which we explore using latent profile analysis (LPA) to identify cognitive phenotypes and their trajectories in patients receiving radiotherapy (RT). Ninety-six patients completed neuropsychological testing before and post-RT (3, 6, 12-months) on a prospective longitudinal trial, including measures of processing speed, executive function, language, and verbal and visual memory. Models with 2-4 classes were examined. Demographic and clinical data were examined across phenotypes and post-RT cognitive change was evaluated. The optimal model identified three unique cognitive phenotypes including a group of patients with generalized impairments (11.5%), a group with isolated verbal memory impairments (21.9%), and a group with minimal impairments (66.7%). The Verbal Memory phenotype had fewer years of education (p=.007) and a greater proportion of males (p<.001); the Generalized group had a greater proportion of patients with IDH-wild type gliomas and showed greater symptoms of anxiety and poorer quality of life (p-values<.05); and the Minimal Impairment phenotype had higher rates of IDH-Mutant gliomas. Approximately 50% of patients declined on at least one cognitive domain with memory the most vulnerable. Patients that declined reported greater symptoms of depression (p=.007) and poorer quality of life (p=.025). We identified three distinct cognitive phenotypes in patients with primary brain tumors receiving RT, each associated with unique demographic and clinical (e.g., IDH mutational status) profiles, with mood symptoms associated with late cognitive decline. This patient-centered approach enhances our understanding of clinical profiles associated with cognitive dysfunction and treatment-related neurotoxicity.

Association between pembrolizumab-related thyroid adverse events and outcomes in early-stage triple-negative breast cancer patients.

Pembrolizumab-related thyroid dysfunction has been associated with better outcomes in metastatic cancer patients. This study aims to examine the outcomes (pathological complete response (pCR) and event-free survival (EFS)) in early-stage triple-negative breast cancer (TNBC) patients receiving preoperative therapy who developed pembrolizumab-related thyroid dysfunction. Patients were divided into four groups based on the occurrence or not of pembrolizumab-related thyroid dysfunction (group A and D, respectively) and, in case of pre-existing thyroid disorder, based on the need for levothyroxine start/adjustment or not (group B and C, respectively). pCR and EFS in groups A, B, and C were compared to the ones in group D. Sixty-four early-stage TNBC patients were included, and the median follow-up was 16.5 months (IQR 12.0-23.8). Multiple patterns of thyroid irAEs were observed (overt hypothyroidism in 56.3%, subclinical thyrotoxicosis in 28.1%, overt thyrotoxicosis and subclinical hypothyroidism in 21.9%, and 21.9% of patients). No statistical difference was found in pCR (chi-square test, P = 0.611) comparing groups A, B, and C to group D. The median EFS in groups A, B, and C and in group D were 16.5 (IQR 12.0-24.0) and 16.0 (IQR 12.0-22.3) months, respectively (log-rank test, P = 0.671). The percentage of patients obtaining pCR was 85.7% in patients developing pembrolizumab-related overt thyrotoxicosis and 42.1% in remaining patients (chi-square test, P = 0.036). The EFS was 16.0 months (IQR 12.0-25.0) in patients developing pembrolizumab-related overt thyrotoxicosis and 16.0 months (IQR 12.0-23.5) in the remaining patients (log-rank test, P = 0.494). In conclusion, multiple patterns of pembrolizumab-related thyroid dysfunction occur in early-stage TNBC. Patients developing pembrolizumab-related overt thyrotoxicosis are more likely to achieve pCR.

Two new mouse alleles of Ocm and Slc26a5

The genes Ocm (encoding oncomodulin) and Slc26a5 (encoding prestin) are expressed strongly in outer hair cells and both are involved in deafness in mice. However, it is not clear if they influence the expression of each other. In this study, we characterise the auditory phenotype resulting from two new mouse alleles, Ocmtm1e and Slc26a5tm1Cre. Each mutation leads to absence of detectable mRNA transcribed from the mutant allele, but there was no evidence that oncomodulin regulates expression of prestin or vice versa. The two mutants show distinctive patterns of auditory dysfunction. Ocmtm1e homozygotes have normal auditory brainstem response thresholds at 4 weeks old followed by progressive hearing loss starting at high frequencies, while heterozygotes show largely normal thresholds until 6 months of age, when signs of worse thresholds are detected. In contrast, Slc26a5tm1Cre homozygotes have stable but raised thresholds across all frequencies tested, 3 to 42 kHz, at least from 4 to 8 weeks old, while heterozygotes have raised thresholds at high frequencies. Distortion product otoacoustic emissions and cochlear microphonics show deficits similar to auditory brainstem responses in both mutants, suggesting that the origin of hearing impairment is in the outer hair cells. Endocochlear potentials are normal in the two mutants. Scanning electron microscopy revealed normal development of hair cells in Ocmtm1e homozygotes but scattered outer hair cell loss even at 4 weeks old when thresholds appeared normal, indicating that there is not a direct relationship between numbers of outer hair cells present and auditory thresholds.

P095 LEFT VENTRICULAR DIASTOLIC FUNCTION IN HYPERTENSIVE PATIENTS WITH HEART FAILURE WITH PRESERVED EJECTION FRACTION

The aim of this work was to study the prevalence of the left ventricular diastolic dysfunction and indeterminate diastolic function in sinus hypertension individuals with left ventricular hypertrophy and preserved ejection fraction, and its associated factors. Methods. We enrolled 56 patients (aged 62, 95% confidence intervals (CI) 58–65 years, 53.6% men) with uncontrolled in-treated arterial hypertension who underwent transthoracic echocardiography (TTE, Esaote, MyLabEight). Cardiac diastolic dysfunction was defined when more than half of the TTE criteria was met according to the existing algorithm (average E/e‘, septal / lateral e‘, tricuspid regurgitation velocity, left atrium volume) and indeterminate one, when half of the criteria was encountered. A binary logistic regression analysis (Stata 15, USA) was performed to evaluate parameters for indeterminate diastolic function state. Results. TTE detected the left ventricular diastolic dysfunction only in 5.4%, however, 80.0% subjects had indeterminate diastolic function. Associated with the indeterminate diastolic function pattern factors were age and mitral regurgitation (odds ratios (OR) 8.0, 95% CI 2.19-29.25, p=0.002 and OR 1.06, 95% CI 1.01-1.12, p=0.014, respectively), however, not sex, height, weight, body mass index, diabetes, overweight/obese, and E/e‘. After adjustment for age, sex (female vs male) mitral regurgitation was occurred significantly more often in patients with indeterminate diastolic function in multivariate logistic regression model (OR 5.97, 95% CI1.47-24.35, p=0.013). Conclusions. Prevalence of the left ventricular diastolic dysfunction pattern is low (5.4%) and the indeterminate diastolic function is considerable (80.0%) in cohort of hypertensions with preserved ejection fraction with sinus rhythm. Mitral regurgitation identifies as a factor that associated with the indeterminate diastolic function patterns in hypertension patients.

Patterns of Teprotumumab-Induced Hearing Dysfunction: A Systematic Review.

Hearing loss has been reported after administration of the monoclonal antibody teprotumumab. The purpose of this study was to review available evidence regarding the patterns of teprotumumab-related ototoxicity. PubMed, EMBASE, and Cochrane Library. A systematic review was performed using standardized methodology. Studies were included if they included subjects who were prescribed teprotumumab. Exclusion criteria included non-English articles, abstracts, letters/commentaries, case reports, and reviews. Subjects without both pre- and posttreatment audiometric data were also excluded. Bias was assessed using the Mixed Methods Appraisal Tool. From an initial search of 76 articles, 7 studies reporting on 109 unique patients were included. Four studies were level 4 evidence, 1 study was level 3 evidence, and 2 studies were level 2 evidence. Mean age was 55 ± 14 years with a female predominance (64%). The most commonly reported symptoms were hearing loss (22%), followed by fullness (18%) and tinnitus (14%). In total, 41% of patients with available data met criteria for ototoxicity, all exhibiting shifts in the middle frequencies or higher. Fifteen (14%) patients underwent ultrahigh frequency audiometric testing and 8 (53%, 8/15) demonstrated shifts exclusively in this range. Ototoxicity may occur in patients treated with teprotumumab. Hearing loss occurs primarily in higher frequencies, and routine hearing screening with ultrahigh frequency testing may be warranted. The true incidence of ototoxicity with teprotumumab remains unknown, and more data is needed to elucidate underlying mechanisms and develop strategies to minimize risks.

Frequency-specific static and dynamic neural activity indices in children with different attention deficit hyperactivity disorder subtypes: a resting-state fMRI study.

Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders in childhood. Numerous resting-state functional magnetic resonance imaging (rs-fMRI) studies in ADHD have been performed using traditional low-frequency bands (0.01-0.08 Hz). However, the neural activity patterns of frequency subbands in ADHD still require further investigation. The purpose of this study is to explore the frequency-dependent characteristics and neural activity patterns of ADHD subtypes. We selected the ADHD combined type (ADHD-C, N = 25), ADHD inattentive type (ADHD-I, N = 26) and typically developing (TD, N = 28) children from the ADHD-200 Consortium. Based on the slow-5 band (0.01-0.027 Hz) and slow-4 band (0.027-0.073 Hz), we generated static and dynamic fractional amplitude of low-frequency fluctuation (fALFF) and regional homogeneity (ReHo) maps for each participant. A flexible-factorial analysis of variance model was performed on static and temporal dynamic rs-fMRI measurements within two subbands. Results revealed that the orbital-frontal gyrus, precuneus, superior temporal gyrus and angular gyrus were found to have obvious frequency band and group interaction effects. The intrinsic neural activity differences among three groups were more prominent in the slow-5 frequency band compared to the slow-4 band. In addition, the indices of significant interaction regions showed correlations with the progression of the disease and the features in slow-5 showed an advantageous diagnostic performance compared with those in slow-4. The results suggested the intrinsic neural activities of ADHD subtypes were frequency-dependent. The frequency-specific analysis of static and dynamic brain activity may provide a deeper understanding of neurophysiological dysfunction patterns in ADHD subtypes and provide supplementary information for assessing ADHD subtypes.

Prevalence of psychiatric comorbidities and cognitive dysfunction among chronic kidney disease patients in a general hospital.

Chronic kidney disease (CKD) presents a profound clinical challenge, not only affecting physical health but also significantly impacting mental well-being. The complex interplay between CKD and psychiatric morbidities remains understudied. To address the existing gap by investigating the prevalence and patterns of psychiatric morbidity and cognitive dysfunction among CKD patients. This study adopted a cross-sectional and hospital-based study design. It included 72 patients diagnosed with CKD who fulfilled the inclusion and exclusion criteria. Structured clinical interviews, validated assessment tools (GHQ-12, HAD-S, AUDIT, Addenbrooke's Cognitive Examination-III), and a proforma gathered data on socio-demographic factors, illness severity, treatment history, and psychiatric history. 70.1% of participants exhibited psychological distress, indicating a high prevalence of psychiatric morbidity. Anxiety disorders were prevalent, affecting 58.1% of participants, while depression affected 32.3% (12.9% mild, 20.8% moderate, 4.8% severe). Cognitive impairment varied with CKD severity, with Stage 3 showing better scores than Stage 4, and hemodialysis patients exhibiting the most significant decline. This study underscores the substantial burden of psychiatric morbidity and cognitive dysfunction in CKD patients within a general hospital setting. Early identification and integrated interventions in mental health care are crucial for improving CKD patient outcomes and well-being.

Patterns of thyroid gland dysfunction among hospitalized patients with COVID-19 pneumonia

BackgroundSince the onset of the COVID-19 pandemic, multiple studies have reported a bidirectional between COVID-19 and dysfunction of the thyroid gland. These studies have identified various forms of thyroid dysfunction that have been found to affect the severity and outcome of COVID-19 infection. However, the data from these studies have been inconsistent and conflicting. Our objective was to assess the prevalence of various types of thyroid dysfunction among moderate to severe cases of COVID-19 pneumonia. In addition, the study aimed to evaluate the outcome of thyroid dysfunction after recovery from COVID-19 infection.Patient and methodsIn this observational prospective study data on the clinical features of individuals with moderate to severe COVID-19 pneumonia who were admitted to Zagazig University isolation hospitals from April to December 2022 and their laboratory results were gathered and examined. Thyroid function tests, including TSH, FT3, and FT4, were conducted for all patients upon admission. Follow-up testing was performed on patients who initially had aberrant thyroid lab results 90 days after recovering from COVID-19 infection.ResultsThe study comprised a total of 136 patients who had moderate (44.1%) to severe (55.9%) COVID-19 infection. Sick euthyroid syndrome was the most prevalent form of thyroid dysfunction, accounting for 58.7% of patients with thyroid disorders on admission. After 90 days of post-COVID-19 examination, thyroid dysfunction recovery was observed in 61% of cases. A statistically significant correlation was noted between the severity of COVID-19 and the levels of TSH, free T3, and the ratio of free T3 to T4. A large percentage of patients who showed complete recovery had sick euthyroid syndrome. All patients diagnosed with primary hypothyroidism maintained their hypothyroidism condition, whereas those with hyperthyroidism showed complete recovery.ConclusionCOVID-19 patients may experience several patterns of thyroid dysfunction, including nonthyroidal illness syndrome. These dysfunctions are associated with the intensity of the inflammatory response and the severity of the COVID-19 infection. Nevertheless, these alterations are predominantly reversible upon recovery from a COVID-19 infection.

A new phenotype of patients with post-COVID-19 condition is characterised by a pattern of complex ventilatory dysfunction, neuromuscular disturbance and fatigue symptoms.

Patients with post-COVID-19 condition frequently suffer from chronic dyspnoea. The causes and mechanism for dyspnoea in these patients without evidence of structural lung disease are unclear. Patients treated for COVID-19 at Charité University Hospital in Berlin received pulmonary function testing including respiratory muscle strength tests and completed health-related quality-of-life questionnaires during follow-up. Patients with post-COVID-19 condition during outpatient follow-up with fatigue and exertional intolerance (PCF) were compared to patients with post-COVID-19 condition with evidence of chronic pulmonary sequelae (post-COVID-19 restriction (PCR)) as well as to patients without post-COVID-19 condition (NCF). A total of 170 patients presented for follow-up. 36 participants met criteria for PCF, 28 for PCR and 24 for NCF. PCF patients reported dyspnoea in 63.8%. % predicted value of respiratory muscle strength (median (IQR)) was reduced in PCF (55.8 (41.5-75.9)) compared to NCF and PCR (70.6 (66.3-88.9) and 76.8 (63.6-102.2), respectively; p=0.011). A pattern of reduced forced vital capacity (FVC), but normal total lung capacity (TLC), termed complex ventilatory dysfunction defined as TLC - FVC >10% predicted was observed and occurred more frequently in PCF (88.9%) compared to NCF and PCR (29.1% and 25.0%, respectively; p<0.001). Dyspnoea in PCF is characterised by reduced respiratory muscle strength and complex ventilatory dysfunction indicating neuromuscular disturbance as a distinct phenotype among patients with post-COVID-19 condition. These observations could be a starting point for developing personalised rehabilitation concepts.

P-708 melatonin alleviates circadian rhythm disruption-induced enhanced luteinizing hormone pulsatility and ovarian dysfunction in vivo and in vitro

Abstract Study question Is melatonin deficiency a reversible cause of abnormal pattern of luteinizing hormone (LH) pulsatility and ovarian dysfunction caused by circadian rhythm disruption (CRD)? Summary answer Melatonin could rescue the augmented LH pulsatility and reproductive abnormalities caused by CRD. What is known already Melatonin, mainly synthesized and released by pineal gland, engages in regulating circadian rhythms. When circadian rhythms are disrupted, the nocturnal productions of melatonin are suppressed. Evidence suggests that circadian rhythm disruption (CRD) is associated with reproductive dysfunctions, while melatonin plays a vital role for female reproduction as a free radical scavenger and a neuroendocrine regulator. The gonadotrophin-releasing hormone (GnRH) drives pulsatile luteinizing hormone (LH) secretion, which is also essential for fertility. Study design, size, duration We used 90 CBA/CaJ mice to establish the chronic jet-lag model in which mice were exposed to an 8 hr time shift every 3 days. After 8 weeks of jet-lag induction, some of the mice were given melatonin treatment for 4 weeks. Furthermore, we used a perfusion system in vitro to mimic the process of CRD-induce high-frequency GnRH pulses stimulation of LβT2 gonadotrope cells. Participants/materials, setting, methods Repetitive tail-tip blood collection was used to evaluate the pattern of LH pulsatility. Blood plasma samples were collected from 4 mice at 4-hour intervals to measure levels of melatonin. Follicular development was evaluated by ovarian histology. Reproductive hormones was detected by ELISA. Immunohistochemistry and western blot were used to detect the expression of melatonin receptor 1A (MT1). The LβT2 cells were exposed to pulsatile GnRH at high pulse frequencies to mimic augmented pulsatile GnRH stimulation. Main results and the role of chance CRD mice exhibited reproductive-endocrine dysfunction, including irregular estrous cycles, reduced number of corpus lutea (CL), and decreased levels of estradiol and progesterone. Additionally, CRD enhanced the frequency and amplitude of LH pulsatility and pituitary LH beta-subunit expression. Melatonin administration alleviated these CRD-induced reproductive abnormalities and reversed the augmented LH pulsatility. The expression of MT1 decreased in the anterior pituitaries of CRD mice but increased after melatonin treatment, indicating the essential role of MT1 in melatonin’s reversal of CRD-induced enhanced LH pulsatility. Limitations, reasons for caution Further research is needed to validate the applicability and safety of these findings in humans. Wider implications of the findings The results suggest that melatonin may be a beneficial option for patients with reproductive-endocrine abnormalities, particularly those with circadian rhythm disruption. Trial registration number 82101719