Absence Of Response Research Articles

Onset and Progression of Disease in Nonhuman Primates With PDE6C Cone Disorder.

The California National Primate Research Center contains a colony of rhesus macaques with a homozygous missense mutation in PDE6C (R565Q) which causes a cone disorder similar to PDE6C achromatopsia in humans. The purposes of this study are to characterize the phenotype in PDE6C macaques in detail to determine the onset of the cone phenotype, the degree to which the phenotype progresses, if heterozygote animals have an intermediate phenotype, and if rod photoreceptor function declines over time. We analyzed spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF), and electroretinography (ERG) data from 102 eyes of 51 macaques (aged 0.25 to 16 years). Measurements of retinal layers as well as cone and rod function over time were quantitatively compared. Homozygotes as young as 3 months postnatal showed absent cone responses on electroretinogram. Infant homozygotes had reduced foveal outer nuclear layer (ONL) thickness compared with wildtype infants (P < 0.0001). Over 4 years of study, no consistent changes in retinal layer thicknesses were found within 5 adult homozygotes. However, comparisons between infants and adults revealed reductions in foveal ONL thickness suggesting that cone cells slowly degenerate as homozygotes age. The oldest homozygote (11 years) had reduced rod responses. Heterozygotes could not be distinguished from wildtypes in any parameters. These data suggest that, like humans, macaque PDE6C heterozygotes are normal, and homozygote primates have absent cone function and reduced foveal ONL thickness from infancy. Cone photoreceptors probably degenerate over time and macular atrophy can occur. Rod photoreceptor function may wane in late stages.

Orbital apex syndrome in a man with rhino-ocular cerebral mucormycosis: a case report

BackgroundOrbital apex syndrome is a symptom complex of visual loss and ophthalmoplegia resulting from a disease involving the orbital apex. It can be caused by inflammation, infection, and malignancies. Mucormycosis is an infection caused by filamentous saprophytes of the order Mucorales. It is ubiquitous, and the infection can occur from ingesting contaminated food, inhaling spores, or injecting the disrupted skin or wounds. It is mainly a disease of the immunocompromised, affecting patients with poorly controlled diabetes, organ transplant recipients, and patients with hematological malignancies. We present the case of a man with orbital apex syndrome resulting from rapidly spreading rhino-ocular cerebral mucormycosis, who had a poor outcome despite an aggressive combined medical and surgical treatment. This is an unusual cause of orbital apex syndrome.Case presentationA 46-year-old Bangladeshi man presented to the emergency department with a history of toothache and pain in the left eye. On examination, the patient had a left-sided periorbital edema, ptosis, and proptosis. He had complete ophthalmoplegia and absent direct pupillary response in the left eye. Magnetic resonance imaging of the brain and orbit showed bilateral ethmoidal, left frontal, maxillary, and sphenoidal sinusitis with left orbital cellulitis. His left orbit was surgically decompressed and histology confirmed mucormycosis. Despite aggressive treatment, the patient had only a partial improvement in his symptoms.ConclusionsMucormycosis is a rare disease that can easily be misdiagnosed, leading to delayed treatment and disease dissemination. Clinicians must be suspicious of mucormycosis in patients presenting with multiple cranial nerve palsy.

Evaluation of adenoviral vector Ad19a encoding RSV-F as novel vaccine against respiratory syncytial virus

Respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infections in infants and toddlers. Since natural infections do not induce persistent immunity, there is the need of vaccines providing long-term protection. Here, we evaluated a new adenoviral vector (rAd) vaccine based on the rare serotype rAd19a and compared the immunogenicity and efficacy to the highly immunogenic rAd5. Given as an intranasal boost in DNA primed mice, both vectors encoding the F protein provided efficient protection against a subsequent RSV infection. However, intramuscular immunization with rAd19a vectors provoked vaccine-enhanced disease after RSV infection compared to non-vaccinated animals. While mucosal IgA antibodies and tissue-resident memory T-cells in intranasally vaccinated mice rapidly control RSV replication, a strong anamnestic systemic T-cell response in absence of local immunity might be the reason for immune-mediated enhanced disease. Our study highlighted the potential benefits of developing effective mucosal against respiratory pathogens.

Normative values and factors affecting saphenous nerve responses in a south Asian population: a cross-sectional neurophysiological study at a tertiary care hospital in Pakistan

BackgroundThe saphenous nerve, a sensory branch of the femoral nerve, is not commonly included in routine lower extremity nerve conduction studies due to a high frequency of non-recordable responses in healthy subjects. However, saphenous nerve conduction studies are sometimes utilized for the diagnostic assessment of isolated lumbosacral plexus, femoral, or saphenous mononeuropathies. Our study aims to determine normative saphenous nerve response values in a healthy Pakistani population and to investigate their associations with patient body mass index, age, and gender.MethodsThis cross-sectional descriptive study was undertaken over a 3‑month period (May to July 2021) at a neurophysiology department of a tertiary care center in Pakistan. Healthy subjects underwent neurological examination, anthropometric measurements, and bilateral SN nerve conduction studies, with recording of peak-latency, peak-to-peak amplitude and conduction velocity. Statistical analyses and linear regression were conducted to evaluate associations between nerve conduction study variables and patient characteristics. Statistical analyses were also run to assess patient characteristics affecting recordability of saphenous nerve responses. A p-value < 0.05 was considered statistically significant.ResultsAmong 117 subjects, 79.5% (n = 93) had recordable saphenous nerve responses. Median peak-latency, amplitude, and conduction velocity were 3.2 (3.0-3.3) m/s, 7.7 (5.8–9.9) uV, and 44.0 (42.0–47.0) m/s, respectively. Bilaterally absent responses were observed in 20.5% (n = 24) of subjects. Obese participants had a significantly higher number of absent saphenous responses (p = 0.033). Females had shorter peak-latency (p = 0.006) and higher conduction velocity (p = 0.012).ConclusionsSaphenous nerve responses can be used to assess unilateral femoral and saphenous nerve pathologies, provided they are recordable on the asymptomatic side for comparison. Absent bilateral saphenous nerve responses should be interpreted with caution given their prevalence in healthy individuals. Patient characteristics should be taken into consideration when interpreting recordable and nonrecordable saphenous nerve responses.

Nerve conduction studies of sensory nerves with proven vasculitic neuropathy often show an absent electrical response.

In vasculitic neuropathy (VN), it is not known whether nerve conduction studies (NCSs) showing low amplitude sensory nerve action potentials (SNAPs) or those with absent responses have a higher yield in detecting appropriate nerves for pathological confirmation. Our goal was to describe NCS findings of nerves prior to biopsy in patients with VN. We performed a retrospective study between January 2000 and April 2021 in patients with VN who either met pathological definite criteria for VN or criteria for clinically probable VN and had NCS of the sural or superficial radial sensory nerves prior to biopsy of the same nerve. We included 61 patients with VN. The pathological findings showed 37 (60.7%) definite, 14 (23%) probable, and 2 (3.3%) possible VN; eight (13%) samples did not meet Peripheral Nerve Society pathological criteria. Most patients who met definite (20 out of 37, 54%) and probable (9 out of 14, 64%) VN pathological criteria had absent SNAPs. Only three out of eight (37.5%) patients without VN pathological findings had absent SNAPs. There was no statistically significant correlation between pathological diagnosis and SNAP amplitude (χ2 = 1.98, p = .58). Additionally, no association was found between VN pathological criteria and use of immunomodulatory treatment (p = .67) or corticosteroids (p = .52). Most nerves with pathological VN findings showed no response on NCS. In patients with suspected VN, sural or superficial radial sensory nerves with absent responses on NCS are adequate biopsy targets as compared to nerves in which SNAPs can be recorded.

7787 Primary Aldosteronism Medical Treatment Outcomes (PAMO): An International Consensus on Outcome Assessment Criteria and Multicentre Study

Abstract Disclosure: J. Yang: None. J. Burrello: None. J. Goi: None. T.A. Williams: None. W.F. Young: Consulting Fee; Self; Arena Pharmaceuticals, Inc.. Other; Self; Crinetics Pharmaceuticals. P.J. Fuller: None. P. Investigators: None. Primary aldosteronism (PA) is the most common endocrine cause of hypertension. Mineralocorticoid receptor antagonists, at adequate doses, lower blood pressure and cardiovascular risk in patients with PA. However, there is a lack of a standardized approach to medical therapy and subsequent outcomes assessment. We aimed to: 1) establish criteria for assessing outcomes of targeted medical treatment of PA, and 2) evaluate outcomes using these criteria across an international cohort. A panel of 31 PA experts from 31 centres across four continents used the Delphi method, including three rounds of online questionnaires, to reach consensus. Clinical data were then collected from consecutive patients with PA who started targeted medical treatment between 2016 and 2021 at the participating centres. Consensus was reached for six outcomes, including complete, partial, or absent biochemical response, and complete, partial, or absent clinical response. “Complete biochemical response” was defined as “correction of hypokalemia without potassium supplementation, and normalization of plasma renin activity or concentration”; while “absent biochemical response” was defined as “persistent hypokalemia and/or persistently suppressed or low plasma renin activity or concentration without change from baseline”. “Complete clinical response” was defined as “normal blood pressure without additional antihypertensive medications”; while “absent clinical response” was defined as “the same or increased blood pressure compared to before targeted treatment with same or more antihypertensive medications, not counting targeted therapy”. Of 1483 patients (mean age 52y, 48% female) from 28 centers, 232 (16%) had a complete clinical response, and 719 (49%) had a complete biochemical response at the most recent follow-up (median 29 months after treatment initiation). Compared to those with partial or absent clinical response, patients with complete clinical response had a significantly higher proportion of women and lower proportion with diabetes, stroke or left ventricular hypertrophy. They also had a significantly shorter duration of hypertension, lower BMI, higher eGFR and lower defined daily dose of antihypertensives at baseline. In contrast, these differences were not observed in those with a complete, partial or absent biochemical response. The defined daily dose of targeted therapy did not differ across the various response categories. In conclusion, we have established an international expert consensus for standardized criteria to evaluate the response to targeted medical treatment of PA, facilitate comparisons of outcome data and guide clinicians who manage PA. In a retrospective international cohort, less than half of medically-treated patients reached the established biochemical treatment targets. Further work is needed to increase the rate of complete response. Presentation: 6/3/2024

6520 Stimulated Copeptin Measurement in the Evaluation of a Patient Presenting Hypernatremia and Adipsia

Abstract Disclosure: B.R. Assunção: None. M.M. Freire: None. M. De Castro: None. A.C. Moreira: None. P.C. Elias: None. Introduction: Hypernatremia (hyperNA) in patients submitted to neurosurgery involving the hypothalamic region prompts the diagnosis of vasopressin deficiency (AVP-D), typically accompanied by increased thirst, polydipsia and polyuria. Classic adipsic AVP-D is characterized by hypotonic polyuria and no thirst in response to hyperNA. Clinical Case: A 21 yo male patient, followed since he had a surgery for a pilocytic astrocytoma of the third ventricle at 12 yo, presented hyperNA (154 mEq/L) with mild dehydration. He denied increased thirst, polyuria or polydipsia. Further evaluation showed elevated plasma and urinary osmolalities (pOsm: 317 mOsm/Kg; uOsm: 878 mOsm/Kg). The patient was admitted for hydration and fluid balance. Oral water intake (2500-3000L/day) was prescribed. Serum sodium (Na+) decreased from 158 to 133 mEq/L within 72h, and no polyuria was detected at hyper or normonatremic states. A 3% saline infusion test (SIT) was performed with thirst visual scale and plasma copeptin (CP) assessment. Na+ rose from 139 to 150 mEq/L and pOsm from 295 to 321 mOsm/kg, with no rise in thirst scale (4,2 to 4,8 cm). Basal and maximal 3% SIT CP levels were 3.1 and 3.2 pmol/L, respectively, also displaying subnormal values. CP assessed under hypovolemic hyperNA (Na+: 158 mEq/L) was 4.1 pmol/L, suggesting that this patient might have an adispic disorder with subnormal thirst and AVP osmotic responses, explaining the lack of polyuria. Patient was treated with fixed daily fluid intake with a last follow-up Na+ of 141 mEq/L.Discussion: Adipsic AVP-D is characterized by hypotonic polyuria and no thirst in response to hyperNA. However, polyuria, a hallmark of clinical presentation, was not observed in the present case. Other adipsic disorders include upward resetting of the osmotic thresholds for both thirst and AVP release (Type A); sub-normal thirst and AVP responses to osmotic stimuli (Type B); and intact osmoregulation of AVP release with absent thirst response (Type D). The lack of polyuria even in normovolemic conditions and the subnormal thirst and CP responses to normovolemic hyperNA and dehydrate states suggest the present case to be a Type B adipsic disorder. In those patients, the secretion of small amounts of AVP in response to osmotic stimulation explains why they retain the ability to concentrate urine, limiting free water excretion. Treatment is based on a fixed fluid intake of around 2 liters per day. Conclusions: Adipsic AVP-D and other adipsic disorders are extremely rare, presenting a great challenge in the diagnosis and management. To our knowledge, this is the first description of CP assessment in a patient with hyperNA and adipsia. CP might be an important diagnostic approach to adipsic disorders. Presentation: 6/2/2024

Chronic Unilateral Vestibular Hypofunction: Insights into Etiologies, Clinical Subtypes, Diagnostics and Quality of Life.

Background/Objectives: Chronic unilateral vestibular hypofunction (UVH) can lead to disabling vestibular symptoms and a decrease in quality of life. The aim of this study was to investigate etiologies, clinical subtypes, symptoms, and quality of life (QoL) in patients with chronic UVH. Methods: A retrospective study was performed on 251 UVH patients in a tertiary referral center. Inclusion criteria comprised reduced or absent caloric responses, with a caloric asymmetry ratio ≥25%. Patients with central vestibular pathology, symptom duration <3 months, and incomplete responses to questionnaires were excluded. Patient records were assessed for etiologies, secondary vestibular diagnoses, clinical subtypes, and questionnaires related to QoL. Additionally, multiple linear regression analysis was performed to evaluate factors influencing QoL. Results: Thirteen different etiologies were identified, with Menière's Disease as the most prevalent (31%, n = 79). The most frequently reported secondary vestibular diagnoses were benign paroxysmal positional vertigo (BPPV) (21%, n = 54) and persistent postural perceptual dizziness (PPPD) (19%, n = 47). Five distinct clinical subtypes were identified: recurrent vertigo with UVH (47%), rapidly progressive UVH (25%), idiopathic/unknown UVH (18%), slowly progressive UVH (8%), and congenital UVH (2%). Over 80% of UVH patients experienced moderate-to-severe handicap, as indicated by the Dizziness Handicap Inventory. Approximately 20-25% of UVH patients exhibited moderate-to-severe depression and anxiety, based on the Hospital Anxiety and Depression Scale. Multiple linear regression analyses demonstrated that the presence of PPPD significantly reduced QoL in chronic UVH patients. Conclusions: Chronic UVH is a heterogeneous disorder. Secondary vestibular diagnoses like BPPV and PPPD often co-exist and can significantly impact QoL. A structured diagnostic approach and tailored interventions are crucial to address the diverse needs of UVH patients.

Defining lower esophageal sphincter physiomechanical states among esophageal motility disorders using functional lumen imaging probe panometry.

Functional lumen imaging probe (FLIP) panometry assesses esophageal motility in response to controlled volumetric distension. This study aimed to describe the physiomechanical states of the lower esophageal sphincter (LES) in response to serial filling/emptying regimes for esophageal motility disorders. Fourty-five patients with absent contractile response on FLIP and diagnoses of normal motility (n = 6), ineffective esophageal motility (IEM; n = 8), scleroderma (SSc; n = 10), or nonspastic achalasia (n = 21) were included, as were 20 patient controls with normal motility on FLIP and manometry. LES diameter and pressure were measured after stepwise FLIP filling at 60 mL, 70 mL, and emptying to 60 mL with relative changes used to define physiomechanical states. Passive dilatation after FLIP filling occurred in 63/65 (97%) patients among all diagnoses. After FLIP emptying, passive shortening occurred in 12/14 (86%) normal motility/IEM, 10/10 (100%) SSc, 9/21(43%) achalasia, and 16/20 (80%) controls, with auxotonic relaxation seen in 2/14 (14%) normal motility/IEM, 12/21 (57%) achalasia, and 4/20 (20%) controls. After achalasia treatment (LES myotomy), 21/21 (100%) achalasia had passive shortening after FLIP emptying. Physiomechanical states of the LES can be determined via response to FLIP filling and emptying regimes. While passive shortening was the general response to FLIP emptying, auxotonic relaxation was observed in achalasia, which was disrupted by LES myotomy. Further investigation is warranted into the clinical impact on diagnosis and treatment of esophageal motility disorders.

Novel variant in IGHM gene in a patient with agammaglobulinemia: A case report of a preschool child presenting with recurrent pneumonia

Introduction: Agammaglobulinemia is a primary immunodeficiency characterized by absent B cells and originates from X-linked or autosomal mutations affecting B cell maturation. While the most common agammaglobulinemia is X-linked, one well-documented site of autosomal recessive agammaglobulinemia is within the immunoglobulin μ heavy chain protein, encoded by the IGHM gene. Such variants frequently result in clinical presentations of recurrent bacterial infections early in life. Aim: To describe a case of a five-year-old female with agammaglobulinemia resulting from a novel homozygous IGHM variant, presenting with pneumonia complicated by empyema and H. influenzae bacteremia. Methods: Case data was compiled retrospectively from the patient’s medical chart, including relevant laboratory testing for immunoglobulins, quantitative B cell subsets, and genetic testing using a primary immunodeficiency panel. Results: The proband is a 5-year-old female with a history of recurrent pneumonia, presenting with H. influenzae bacteremia in the context of pneumonia complicated by an empyema. Investigations revealed low immunoglobulin levels, absent vaccine responses, and undetectable B cells on flow cytometry. Genetic testing revealed a novel homozygous variant in the IGHM gene: c.775T&gt;C, p.Trp259Arg. Conclusion: Autosomal recessive agammaglobulinemia is a rare but severe, treatable disorder of the immune system which typically presents in early childhood. Hypomorphic mutations, while less commonly reported in the literature, are an important consideration in atypical presentations of primary immunodeficiencies, such as in the case presented. Statement of Novelty: Herein, we report a case of agammaglobulinemia presenting with a novel homozygous variant in the IGHM gene leading to later onset agammaglobulinemia in a 5-year-old female.

Clinical and magnetic resonance imaging features of unilateral thalamic porencephaly in a dog

AbstractA 1‐year‐3‐month‐old, female, neutered labrador retriever was presented with a history of circling behaviour since 2 months of age and a recently detected blindness affecting its right eye. Neurological examination revealed a left‐sided head tilt, compulsive tight circling towards the left, postural reaction deficits in the right thoracic and pelvic limbs, absent menace response in the right eye and ventral positional strabismus of the left eye. The neurological examination findings were localised to the left thalamus. Magnetic resonance imaging of the head revealed porencephaly involving the left dorsal aspect of the thalamus. Furthermore, reduced volume of the left rostral colliculus, crus cerebri and optic chiasm, alongside marked thinning of the left cerebral hemispheric white matter tracts with associated left lateral ventriculomegaly, were present. Based on magnetic resonance imaging features and clinical history, a congenital or perinatal encephaloclastic porencephaly with secondary hypoplasia or atrophy of the associated thalamic projection pathways was prioritised.

THE GENETIC BASIS OF CLINICALLY SUSPECTED ACHROMATOPSIA IN THE UNITED ARAB EMIRATES.

Achromatopsia (ACHM) is a genetically heterogenous relatively stationary congenital autosomal recessive cone disorder characterized typically by photophobia, low vision, nystagmus, hyperopia, grossly normal retinal appearance, and absent photopic responses by full-field electroretinography. Incomplete forms occur as well. This study investigates the genetic basis of clinically suspected ACHM in the United Arab Emirates. Retrospective case series (January 2016-December 2023) of patients with (1) clinically suspected ACHM or (2) mutations in ACHM-associated genes ( CNGA3 , CNGB3 , GNAT2 , PDE6C , PDE6H , AT6 ). Twenty-two clinically suspected patients (19 probands) were identified. Biallelic disease genes and the number of probands were CNGA3 (9), CNGB3 (6), PDE6C (1), GNAT2 (1), RGS9BP (1), and CNNM4 (1). Some mutant alleles were recurrent across different families. Two probands had their diagnoses revised after genetic testing and phenotypic reassessment to RGS9BP -related bradyopsia and CNNM4 -related Jalili syndrome. Three additional cases (making 22 total probands) were identified from ACHM gene mutation review-one each related to PDE6C , to AT6 , and to CNGB3 in concert with CNGA3 (triallelic disease). All three presented with macular discoloration, an atypical finding for classic ACHM. CNGA3 was the single most frequent implicated gene. Bradyopsia and Jalili syndrome can resemble incomplete ACHM. Recurrent mutant alleles may represent founder effects. Macular discoloration on presentation can occur in PDE6C -related disease, AT6 -related disease, and triallelic CNGB3 / CNGA3 -related disease. The possibility for triallelic disease exists and requires genetic counseling beyond that of simple autosomal recessive inheritance.

Cerebrospinal Creatine Kinase BB Isoenzyme: A Biomarker for Predicting Outcome After Cardiac Arrest.

Cerebrospinal fluid creatine kinase BB isoenzyme (CSF CK-BB) after cardiac arrest (CA) has been shown to have a high positive predictive value for poor neurological outcome, but it has not been evaluated in the setting of targeted temperature management (TTM) and modern CA care. We aimed to evaluate CSF CK-BB as a prognostic biomarker after CA. We performed a retrospective cohort study of patients with CA admitted between 2010 and 2020 to a three-hospital health system who remained comatose and had CSF CK-BB assayed between 36 and 84h after CA. We examined the proportion of patients at hospital discharge who achieved favorable or intermediate neurological outcome, defined as Cerebral Performance Category score of 1-3, compared with those with poor outcome (Cerebral Performance Category score 4-5) for various CSF CK-BB thresholds. We also evaluated additive value of bilateral absence of somatosensory evoked potentials (SSEPs). Among 214 eligible patients, the mean age was 54.7 ± 4.8years, 72% of patients were male, 33% were nonwhite, 17% had shockable rhythm, 90% were out-of-hospital CA, and 83% received TTM. A total of 19 (9%) awakened. CSF CK-BB ≥ 230 U/L predicted a poor outcome at hospital discharge, with a specificity of 100% (95% confidence interval [CI] 82-100%) and sensitivity of 69% (95% CI 62-76%). When combined with bilaterally absent N20 response on SSEP, specificity remained 100% while sensitivity increased to 80% (95% CI 73-85%). Discordant CK-BB and SSEP findings were seen in 13 (9%) patients. Cerebrospinal fluid creatine kinase BB isoenzyme levels accurately predicted poor neurological outcome among CA survivors treated with TTM. The CSF CK-BB cutoff of 230 U/L optimizes sensitivity to 69% while maintaining a specificity of 100%. CSF CK-BB could be a useful addition to multimodal neurological prognostication after CA.

Presenteeism Among Healthcare Professionals (HCP) During the COVID-19 Pandemic: Survey of Perceived Barriers

Background: Presenteeism when ill in healthcare personnel (HCP) can contribute to the spread of respiratory illness among HCP and patients. However, during the COVID-19 pandemic and now, there are substantial challenges preventing HCP from staying home when ill. We examined these challenges using the Systems Engineering Initiative for Patient Safety (SEIPS) framework. Method: As part of a larger anonymous electronic survey between 3/11/2022 and 4/12/2022 at an academic tertiary referral center, in inpatient and ambulatory settings where respondents were asked to describe factors impacting presenteeism when ill, we analyzed free-text responses using the SEIPS categories of tasks, tools/technology, person, organization, and physical environment. Result: 522 comments were received in response to the open-ended survey question asking individuals to describe any factors that would assist them in remaining home and/or help them get tested for COVID-19 when they have symptoms of a respiratory illness; 21 were excluded due to absent or incomplete response. Of the remaining responses (N = 501, Figure 1), 82% were associated with a single SEIPS component such as organization (N = 409), while other responses discussed factors that involved two SEIPS components, in no particular order (N = 92). A majority of the responses (N = 324, 55%) reported organizational barriers, frequently citing a strict sick call-in policy as well as a lack of protected time-off for COVID-19 testing or related absences. The next two most commonly identified components were physical environment (N= 88, 15%) and tasks (N = 72, 12%), mentioning barriers such as far distances to testing centers and prolonged waiting periods for testing Results: The person and tools/technology components were less commonly identified, with a frequency of 9% each. Conclusion: A number of systems level factors were identified that may impact the ability of HCP to stay home when ill. Interventions to help overcome HCP perceived barriers to staying home when experiencing respiratory symptoms should focus on the policies and practices within an organization. Communication from leadership should support staying home with respiratory symptoms by creating plans for coverage and back up consistently across all employee types in direct care.

Adolescent high fat diet alters the transcriptional response of microglia in the prefrontal cortex in response to stressors in both male and female mice

Both obesity and high fat diets (HFD) have been associated with an increase in inflammatory gene expression within the brain. Microglia play an important role in early cortical development and may be responsive to HFD, particularly during sensitive windows, such as adolescence. We hypothesized that HFD during adolescence would increase proinflammatory gene expression in microglia at baseline and potentiate the microglial stress response. Two stressors were examined, a physiological stressor [lipopolysaccharide (LPS), IP] and a psychological stressor [15 min restraint (RST)]. From 3 to 7 weeks of age, male and female mice were fed standard control diet (SC, 20% energy from fat) or HFD (60% energy from fat). On P49, 1 h before sacrifice, mice were randomly assigned to either stressor exposure or control conditions. Microglia from the frontal cortex were enriched using a Percoll density gradient and isolated via fluorescence-activated cell sorting (FACS), followed by RNA expression analysis of 30 genes (27 target genes, three housekeeping genes) using Fluidigm, a medium throughput qPCR platform. We found that adolescent HFD induced sex-specific transcriptional response in cortical microglia, both at baseline and in response to a stressor. Contrary to our hypothesis, adolescent HFD did not potentiate the transcriptional response to stressors in males, but rather in some cases, resulted in a blunted or absent response to the stressor. This was most apparent in males treated with LPS. However, in females, potentiation of the LPS response was observed for select proinflammatory genes, including Tnfa and Socs3. Further, HFD increased the expression of Itgam, Ikbkb, and Apoe in cortical microglia of both sexes, while adrenergic receptor expression (Adrb1 and Adra2a) was changed in response to stressor exposure with no effect of diet. These data identify classes of genes that are uniquely affected by adolescent exposure to HFD and different stressor modalities in males and females.

Immune checkpoint regulation is critically involved in canine cutaneous histiocytoma regression.

Canine cutaneous histiocytoma (CCH) is a benign tumor frequently occurring in young dogs which is derived from Langerhans cells (LC). Distinguishing features of this tumor are its spontaneous regression following a rapid tumor growth. Impaired control of immune checkpoints during tumor development and progression is a widespread phenomenon which may result in an absent or ineffective immune response. The interaction between the inflammatory response and the expression of immune checkpoint molecules is only partially described in this tumor type. The aim of this study was to identify immune checkpoint molecules and molecules from the interferon-mediated immune response that are involved in the regression of CCH. Forty-eight CCH derived from dogs ≤ 4 years of age were assigned to one of four groups according to the severity and distribution of lymphocyte infiltration. Using immunohistochemistry and whole-slide image scans of consecutive sections the expression of programmed death protein ligand 1 (PD-L1), CD80, CD86, Survivin, forkhead box protein 3, Ki-67, cleaved caspase-3, CD3, and mx1 were investigated. RNA in-situ hybridization was performed for transcripts of mx1 and interferon-γ. Neoplastic cells showed an expression of PD-L1, CD80, CD86, and Survivin. The density of CD80 expressing cells was negatively correlated with regression while the density of cleaved caspase-3 positive cells increased with regression. Mx1 transcripts and protein were predominantly localized in neoplastic cells while interferon-γ transcripts were most frequently detected in T-cells. The expression of the immune checkpoint molecules CD86 and PD-L1 and particularly the reduced expression of CD80 in groups 3 and 4 indicate an influence of the investigated immune checkpoints on tumor regression. In parallel an activation of the apoptotic cascade during regression is suggested. Finally, the detection of mx1 within the neoplasm pinpoints to a yet undisclosed role of anti-cellular signaling in tumor immunity.

A multicenter, randomized, doubleblind, placebo-controlled trial of amantadine to stimulate awakening in comatose patients resuscitated from cardiac arrest.

We hypothesized that the administration of amantadine would increase awakening of comatose patients resuscitated from cardiac arrest. We performed a prospective, randomized, controlled pilot trial, randomizing subjects to amantadine 100 mg twice daily or placebo for up to 7 days. The study drug was administered between 72 and 120 hours after resuscitation and patients with absent N20 cortical responses, early cerebral edema, or ongoing malignant electroencephalography patterns were excluded. Our primary outcome was awakening, defined as following two-step commands, within 28 days of cardiac arrest. Secondary outcomes included length of stay, awakening, time to awakening, and neurologic outcome measured by Cerebral Performance Category at hospital discharge. We compared the proportion of subjects awakening and hospital survival using Fisher exact tests and time to awakening and hospital length of stay using Wilcoxon rank sum tests. After 2 years, we stopped the study due to slow enrollment and lapse of funding. We enrolled 14 subjects (12% of goal enrollment), seven in the amantadine group and seven in the placebo group. The proportion of patients who awakened within 28 days after cardiac arrest did not differ between amantadine (n=2, 28.6%) and placebo groups (n=3, 42.9%; P>0.99). There were no differences in secondary outcomes. Study medication was stopped in three subjects (21.4%). Adverse events included a recurrence of seizures (n=2; 14.3%), both of which occurred in the placebo group. We could not determine the effect of amantadine on awakening in comatose survivors of cardiac arrest due to small sample size.

Autonomic Dysfunction in Amyotrophic Lateral Sclerosis - A Case-Control Study.

This study aimed to explore autonomic nervous system involvement in amyotrophic lateral sclerosis (ALS) patients by evaluating sympathetic skin response (SSR). The study included 35 sporadic (ALS) patients (cases), and 35 healthy age and sex-matched participants (controls) aged <60 years. SSR was recorded in the electrophysiology lab of the Neurology Department of Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh. Patients with diseases associated with peripheral or autonomic neuropathy were excluded. Prolonged latency (delayed SSR) or an absent response was considered abnormal SSR. SSR was found to be abnormal in 17 (48.6 %) ALS cases, with an absent response in the upper limbs of six cases (17.1%). Abnormal SSR was more prevalent in the lower limbs, with 33 (94.3%) and 20 (57.1%) cases having a delayed or absent response, respectively. In comparison, SSR was normal in all control participants (P-value <0.05). Abnormal SSR was significantly more common in the lower limbs of ALS cases with bulbar palsy than those without bulbar palsy (P-value=0.04). There was no association of SSR with disease severity and duration. ALS is significantly associated with abnormal SSR, indicating autonomic nervous system involvement. There could also be an association between bulbar palsy and abnormal SSR among ALS patients. Further studies should be carried out to determine the association of abnormal SSR with disease severity, duration, and type.

#2862 Genetics and electron microscopy: complementary tools for management of focal segmental glomerulosclerosis?

Abstract Background and Aims Focal segmental glomerular sclerosis (FSGS) defines a histologic lesion that represents a pattern of injury associated to different pathologic conditions affecting both children and adults. It is classified into primary forms, presumably immune-mediated, secondary forms, determined by a maladaptive response to different conditions, genetic and undetermined forms. According to Mayo Clinic classification, primary and secondary forms can de differentiated using electron microscopy (EM), with a podocytes foot process effacement (FPE) ≥80% identifying primary forms. Better understanding the role of Genetics in FSGS and response to treatment in different forms is of vital importance in this rare and multifaceted condition. We analyzed a discrete cohort of patients with FSGS examined both with EM and genetic testing (GT). Main aims of our study were: 1) assessment of GT in primary and secondary forms; 2) analysis of response to therapy according to histologic and genetic classification. Method This is a retrospective observational study on patients that received a histological diagnosis of FSGS, including EM, and underwent NGS genetic testing from January 2020 to June 2023. Primary and secondary forms of FSGS were distinguished by degree of pedicle fusion at EM, according to Mayo Clinic classification. Clinical, laboratory, genetic data and used therapies were recorded. Complete response (CR) to therapy was defined as a reduction of proteinuria to 0.3 g/day, with normalization of albuminemia. Partial response (PR) was defined as halving proteinuria into a sub-nephrotic range and increasing albuminemia up to 3.5 g/dL. Absent response was defined as a persisting nephrotic range proteinuria. Results In the study period, 33 patients receiving a histologic diagnosis of FSGS with EM examination underwent NGS testing. Of these, 25 had available genetic results and were included. Ten patients (40%) were females, 15 (60%) were males; mean age was 40.8 years (SD ±14.5); 20 (80%) were Caucasian, 4 (16%) Black, 1 (4%) Asian. Based on EM, 11 (44%) were classified as primary forms, 14 (56%) as secondary forms. Twelve (48%) patients presented with nephrotic syndrome. Of these, 10 had a primary form. Seven (28%) had nephrotic-range proteinuria without hypoalbuminemia, 6 (24%) had subnephrotic range proteinuria. Six (54.5%) of the primary forms and 8 (57.1%) of the secondary forms had a positive genetic testing (p = 0.78). Among secondary forms, through GT, one diagnosis of Fabry disease and one of Tuberous Sclerosis were made in patients without clear systemic symptoms. Fabry disease was confirmed by presence of zebra bodies at EM. All primary forms received immunosuppressive therapies, all being rituximab-based regimens; all secondary forms received support therapy. Nine (81.1%) primary forms and 9 (64.3%) secondary forms had at least a PR to treatment (4 CR in primary group and 1 CR in secondary group) (p = 0.33). Among primary forms, 5 of 6 patients (83%) with a positive GT had at least a PR with a strong immunosuppressive therapy. In secondary forms group 4 of 8 patients (50%) had at least PR with offered support therapy. Fabry and Tuberous Sclerosis were offered specific treatments with benefit. Conclusion Percentage of positive GT did not differ in primary and secondary forms of FSGS as defined by Mayo Clinic classification. Thus a positive GT should not be considered a unique feature of secondary forms. GT was critical for an unexpected diagnosis of systemic hereditary diseases, thus enabling adequate target therapies. We believe GT should be offered to all patients with FSGS. In primary FSGS, defined according to EM, more than 80% of patients had at least a PR following immunosuppressive therapy, even in patients with positive GT. In conclusion, as clinical presentation and light microscopy are not sufficient for an accurate diagnosis, combining EM and GT is of utmost importance in proper classification and management of FSGS.

#1174 Prevalence and factors contributing to erythropoietin hyporesponsiveness in CKD patients on hemodialysis: a single center, cross sectional study

Abstract Background and Aims Anemia, one of the most frequent early complications of CKD is associated with a reduced QOL, cardiovascular morbidity, accelerated CKD progression, and it is an independent predictor of mortality. The successful management of anemia is a vital part of patient care, that improves clinical outcomes. According to the literature, 90% of renal anemia patients responded in a dose-dependent manner to rHu EPO, whereas the remaining 5–10% of patients had either a blunted or absent response to this agent, despite high-dose therapy. Erythropoietin hyporesponsiveness is a strong, independent predictor of mortality risk. Various factors have been associated with ESA hypo responsiveness in different studies. Both the inability to achieve a target hemoglobin and administration of high dose epoetin -alpha are associated with increased risk of CVD complications. AIMS AND OBJECTIVES Method STUDY PERIOD: December 2021 to DECEMBER 2022 STUDY DESIGN: Observational cross sectional study. SAMPLE SIZE: N = 144: Patients older than 18 years old undergoing hemodialysis for at least 3 months before the study were enrolled. History of inpatient treatment, infection, bleeding or transfusion within the last month, hematologic disorders sickle cell disease, MDS and active malignancies were excluded. Required parameters were recorded on every month follow up;Demographic data, Cause of ESRD, Dialysis vintage, ESAs dose (Unit/week), type, Medications history; Dose (mg/week) of iron preparation &amp; use of medication like ACEi, ARBs, dialysis adequacy(Kt/V), haemogram, Liver function test, Kidney function test Iron profile, Serum parathyroid hormone, Serum calcium &amp; phosphorus, CRP, Anti EPO antibodies(if required). We used the European Best Practice Guideline (EBPG) II definition to define ESA hyporesponsiveness for our study purpose(Increase in erythropoietin dose ≥25% to maintain the same Hgb level or &amp;lt; 1 mg/dL gain in Hgb after 4 weeks. EHRI was calculated by dividing weekly ESA dose per kilogram of body weight (IU/Kg/W) by hemoglobin level (g/dL). Based on EHRI, patients were assigned or divided into 2 groups. Group I (EHRI&amp;lt;16) and Group II (EHRI ≥ 16). Patients in the Group II were labeled as erythropoietin hyporesponsive patients and they were compared with others in order to identify the impact of different factors on ESA. Results Among 144 patients, 80 were male and 64 females and 28.4% were diabetic. Mean EHRI were calculated for all patients and based on EHRI pts were divided into two study groups, Gr-I (EHRI&amp;lt;16) &amp; Gr-II(EHRI ≥16). EHRI ≥16 group was considered as ESA hyporesponsive groups. The study parameters were compared between the groups and its statistical significance measured. The overall prevalence of ESA hyporesponsive in our study was 26.3%. Conclusion The overall prevalence of ESA hyporesponsive in our study was 26.3%. Iron deficiency anemia, inadequate dialysis, chronic inflammation, malnutrition, secondary hyperparathyroidism and increased dialysis vintage were the factors associated with ESA hyporesponsiveness.