Clinical Characterization Research Articles

Congenital heart disease: clinical characterization in newborns from a referral hospital, Manaus, Amazonas, Brazil

In Brazil, the impact of congenital heart disease (CHD) remains obscured by limited data, especially in the northern region. For this reason, our study seeks to uncover the prevalence and clinical variations of CHD in Manaus, Amazonas. This study followed a cross-sectional model performed in 110 newborns with CHD diagnosed between March 2022 to April 2023. Complex CHD was present in about 80% of the newborns, which increased the risk of requiring multiple surgical interventions. We found and characterized 19 CHD phenotypes, with a higher prevalence of complex CHD cases. We documented 12 fatalities, mostly attributed to septic and cardiogenic shock related to complex CHD with high levels of urea, creatinine, AST, ALT, CRP, GGT, NT-proBNP and acidosis (p<0.001). Our findings suggest a close relationship between CHD and a systemic impact with chronic/acute kidney failure and hepatopathies. Inadequate data from the information system on live births (SINASC) results in underreporting and increased CHD mortality rates, emphasizing the urgency for new strategies to enhance case identification and improve early diagnosis of critical CHD with important systemic repercussions.

Plasma steroid concentrations reflect acute disease severity and normalise during recovery in people hospitalised with COVID-19.

Endocrine systems are disrupted in acute illness, and symptoms reported following coronavirus disease 2019 (COVID-19) are similar to those found with clinical hormone deficiencies. We hypothesised that people with severe acute COVID-19 and with post-COVID symptoms have glucocorticoid and sex hormone deficiencies. Samples were obtained for analysis from two UK multicentre cohorts during hospitalisation with COVID-19 (International Severe Acute Respiratory Infection Consortium/World Health Organisation [WHO] Clinical Characterization Protocol for Severe Emerging Infections in the UK study), and at follow-up 5 months after hospitalisation (Post-hospitalisation COVID-19 study). Plasma steroids were quantified by liquid chromatography-mass spectrometry. Steroid concentrations were compared against disease severity (WHO ordinal scale) and validated symptom scores. Data are presented as geometric mean (SD). In the acute cohort (n = 239, 66.5% male), plasma cortisol concentration increased with disease severity (cortisol 753.3 [1.6] vs. 429.2 [1.7] nmol/L in fatal vs. least severe, p < .001). In males, testosterone concentrations decreased with severity (testosterone 1.2 [2.2] vs. 6.9 [1.9] nmol/L in fatal vs. least severe, p < .001). In the follow-up cohort (n = 198, 62.1% male, 68.9% ongoing symptoms, 165 [121-192] days postdischarge), plasma cortisol concentrations (275.6 [1.5] nmol/L) did not differ with in-hospital severity, perception of recovery, or patient-reported symptoms. Male testosterone concentrations (12.6 [1.5] nmol/L) were not related to in-hospital severity, perception of recovery or symptom scores. Circulating glucocorticoids in patients hospitalised with COVID-19 reflect acute illness, with a marked rise in cortisol and fall in male testosterone. These findings are not observed 5 months from discharge. The lack of association between hormone concentrations and common post-COVID symptoms suggests steroid insufficiency does not play a causal role in this condition.

Abstract B042: Clinical and molecular characterization of Lynch syndrome-associated pancreas adenocarcinoma (PDAC)

Abstract Background: Lynch syndrome (LS) is a pan-cancer predisposition syndrome caused by pathogenic germline alterations (gPVs) in DNA mismatch repair genes (PMS2, MSH6, MLH1, MSH2, EPCAM). It is characterized by microsatellite instability (MSI)/deficient DNA mismatch repair (dMMR) of associated tumors, which predicts immune checkpoint blockade (ICB) response. Clinical and molecular features of LS-PDAC are not well defined. Herein we sought to describe clinical characteristics, MSI prevalence, and ICB response. Methods: Patients (pts) with LS-associated gPV and PDAC who had consented to IRB-approved protocol of matched tumor-normal sequencing (MSK-IMPACT from which MSIsensor status derivable) were included. MiMSI utilized to assess microsatellite stable (MSS) PDACs to account for low tumor content. MMR status defined with immunohistochemistry (IHC). Composite MSI adjudicated as either loss of MMR protein expression by IHC or MSI by MSISensor or MiMSI. FACETS algorithm assessed biallelic MMR gene alteration status. Mutational signature analysis performed on MSI tumors with deconstructSigs. Results: N=29 pts identified with LS-associated gPVs and PDAC: 10 MSH2 (34%), 9 MSH6 (31%), 7 PMS2 (24%), 2 MLH1 (7%), 1 EPCAM (3%). Majority white (24, 83%) and female (15, 52%). At diagnosis 62% pts early-stage disease (8 stage II, 10 stage III), 11 stage IV. Median age at diagnosis: 68 yrs (range 45-88). Eighteen (62%) had first-degree family history of LS spectrum cancers. Four pts had metachronous cancers (2 CRC, 1 uterine, 1 CRC and uterine). Orthogonal tumor testing feasible in 22 pts (76%). MiMSI (conducted for 16) reclassified 4 as MSI that were indeterminate by MSISensor; IHC (conducted for 15) classified 1/8 tumors as dMMR previously MSS on MSISensor. Whole cohort MSI status: 16 composite MSI (59%), 11 MSS (41%), and 2 MS unknown. gPVs in N= 16 with MSI tumors: 9 MSH2, 4 MSH6, 2 MLH1, and 1 PMS2; amongst N= 11 MSS tumors: 6 gMSH6, 4 gPMS2, and 1 EPCAM. Amongst 24 evaluable pts biallelic loss identified in 6 pts with MSI disease. The dominant mutational signature in 4/6 was Clock/aging and not MSI; 2 of these 4 harbored gMSH2, and 2/4 gMSH6. KRAS and TP53 mutations more common in sporadic MSS PDAC than LS-PDAC (p=0.001, p=0.005 respectively); KRAS G12R was enriched in LS PDAC vs sporadic PDAC (31.6% vs 15.3%, p=0.06). N= 13 (47%) received ICB, inclusive of 4 reclassified by MiMSI and 8 with metastatic disease. In evaluable pts with MSI disease, overall response rate 60% (2 CR, 4 PR, 4 SD). N= 1 MSS PDAC had POD as best response. Median ICB duration: 27.7 months (95% CI 9.0, NR). Conclusion: In this LS PDAC cohort we observed a higher proportion of MSH6, MSH2, PMS2 gPVs relative to other cohorts. LS-PDAC MSI arises frequently in association with gMSH2, gMLH1. MSI status determination with orthogonal testing is critical to appropriately select pts for ICB. Outcome to ICB in LS PDAC MSI comparable to other tumor types highlighting the importance of MSI as a predictive biomarker in PDAC. Citation Format: Emily Harrold, Catherine A. O'Connor, David Lin, Andrea Gazzo, Henry Walch, Megha Ranganathan, Amanda Catchings, Sarah Kane, Fergus Keane, Deborah M. Thurtle-Schmidt, Fiyinfolu Balogun, Anna Varghese, Kenneth Yu, David Kelsen, Alicia Latham, Britta Weigelt, Wungki Park, Zsofia Stadler, Eileen M. O'Reilly. Clinical and molecular characterization of Lynch syndrome-associated pancreas adenocarcinoma (PDAC) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B042.

Clinical and genetic characterization of patients with catecholaminergic polymorphic ventricular tachycardia: a case series

AIM: of the study was to evaluate the clinical and genetic characteristics, including the development of adverse events and outcomes in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT).&#x0D; MATERIALS AND METHODS: The clinical phenotype of eight patients with CPVT, two of whom were relatives of probands, was observed over 4 years. The clinical and instrumental study included ECG-12, 24-hour Holter ECG monitoring, genealogical history collection and family history of sudden cardiac death (SCD), transthoracic echocardiography and cardiac magnetic resonance imaging to detect structural myocardial changes, electrophysiologic study according to indications, and ICD monitoring. High-throughput sequencing (NGS) was utilized to search for mutations in genes linked to the onset of channelopathies and other inherited rhythm disorders.&#x0D; RESULTS: In 8 patients, nucleotide variants of pathogenicity classes III-V were identified according to the ACMG (2015) criteria in the RYR2 gene associated with CPVT. Pathogenic (IV-V class) and likely pathogenic (IV class) mutations in the RYR2 gene were found in 6 (75%) probands, variants with uncertain clinical significance (VUS, class III) were found in 2 patients. At the time of diagnosis, transient QTc interval prolongation of more than 480 ms was detected in 4 (50%) patients; bradycardia less than 54 beats/min — in 2 (25%) patients, sequences of supraventricular tachycardia and ventricular tachyarrhythmia — in 2 (25%) patients. The most severe form of the disease with marked clinical manifestations and an episode of clinical death with subsequent resuscitation, as well as a transient QTc interval prolongation exceeding 500 ms was observed in patients with mutations c.11814C A (p.Ser3938Arg, rs794728704); c.463G A (p.Gly155Arg) and c.14876G A (p.Arg4959Gln, rs794728811) in the RYR2 gene. Three (37.5%) patients underwent ICD implantation; one for primary SCD prevention and two for secondary prevention.&#x0D; CONCLUSION: In this study, the spectrum of clinical manifestations in patients with genetically confirmed CPVT was examined. The findings highlight transient QTc interval extensions, significant sinus bradycardia, and sequences of supraventricular tachyarrhythmias, which can escalate into life-threatening ventricular tachyarrhythmias in CPVT patients.

Clinical, Genomic, and Immunological Characterization of RSV Surge in Sydney, Australia, 2022.

The 2022 seasonal respiratory syncytial virus (RSV) epidemic in Sydney, Australia saw an unprecedented number of RSV detections. We aimed to characterize genomic and immunologic factors associated with the surge in RSV cases. Whole genome sequences of RSV were generated from 264 RSV-infected infants and linked to case-matched clinical data from the 2022 southern hemisphere RSV season. We then performed an immunologic analysis of baseline RSV-specific humoral immunity in women of childbearing age before and throughout the coronavirus disease 2019 pandemic. Clinical analysis revealed a high burden of disease across patients of all health backgrounds. More than one-half of RSV-related health care visits by infants resulted in hospitalization, and one-quarter required high-flow respiratory support or a higher level of care. Viral phylogenetic analyses revealed that 2022 Sydney RSV sequences were closely related to viruses that had been circulating globally since 2017, including those detected in recent US outbreaks. Nonsynonymous mutations within the palivizumab and nirsevimab binding sites were detected at low frequencies. There was no difference in baseline RSV-neutralizing antibody titers between 2020 and 2022. Collectively, these findings suggest that neither the emergence of a novel RSV genotype nor hypothesized immune debt was associated with the surge of RSV cases and hospitalizations in 2022. Continued genomic and immunologic surveillance is required to further understand the factors driving outbreaks of RSV globally, and to inform guidelines for the rollout and ongoing use of recently developed immunotherapeutics and vaccines.

Clinical and Molecular Characterization of Mucopolysaccharidosis Type 3A and 3B in a Turkish Series

Introduction: Sanfilippo syndrome or mucopolysaccharidosis type 3 (MPS-3) is a rare condition and its epidemiological data are still not defined. MPS-3 is linked to a deficiency in enzymes involved in heparan sulfate degradation. This biomolecule is neurotoxic and its accumulation underlies the severe central nervous system degeneration observed in this disease. Methods: Here, we describe 15 Turkish patients with MPS-3A or MPS-3B subtypes. Clinical data upon the diagnosis and during the follow-up as well as molecular characterization are reported. Results: Two and ten distinct variants were identified in SGSH and NAGLU gene sequences, respectively. Six variants (NAGLU NM_000263.3:c.532−?_c.764+?del, NAGLU NM_000263.3: c.509G>T, NAGLU NM_000263.3: c.700C>G, NAGLU NM_000263.3:c.507_516 del, NAGLU NM dises_000263.3: c.1354 G>A, NAGLU NM_000263.3: c.200T>C) have been previously published and 6 are novel (SGSH NM_000199.4: c.80T>G, SGSH NM_000199.4: c.7_16del, NAGLU NM_000263.3: c.224_235del, NAGLU NM_000263.3: c.904G>T, NAGLU NM_000263.3: c.626C>T, NAGLU NM_000263.3: c.1241A>G). SGSH NM_000199.4:c.7_16del variation might be caused by a founder effect. Conclusion: Due to the high rate of consanguinity in Turkey, the incidence of Sanfilippo syndrome might be higher compared to other populations worldwide. Our results contribute to the characterization of rare diseases in Turkey and to improve our knowledge of the clinical, molecular, and epidemiological aspects of MPS-3 disease.

Borderline personality disorder: a comprehensive review of diagnosis and clinical presentation, etiology, treatment, and currentcontroversies.

Borderline personality disorder (BPD) was introduced in the DSM-III in 1980. From the DSM-III to the DSM-5, no major changes have occurred in its defining criteria. The disorder is characterized by instability of self-image, interpersonal relationships and affects. Further symptoms include impulsivity, intense anger, feelings of emptiness, strong abandonment fears, suicidal or self-mutilation behavior, and transient stress-related paranoid ideation or severe dissociative symptoms. There is evidence that BPD can be reliably diagnosed and differentiated from other mental disorders by semi-structured interviews. The disorder is associated with considerable functional impairment, intensive treatment utilization, and high societal costs. The risk of self-mutilation and suicide is high. In the general adult population, the lifetime prevalence of BPD has been reported to be from 0.7 to 2.7%, while its prevalence is about 12% in outpatient and 22% in inpatient psychiatric services. BPD is significantly associated with other mental disorders, including depressive disorders, substance use disorders, post-traumatic stress disorder, attention-deficit/hyperactivity disorder, bipolar disorder, bulimia nervosa, and other personality disorders. There is convincing evidence to suggest that the interaction between genetic factors and adverse childhood experiences plays a central role in the etiology of BPD. In spite of considerable research, the neurobiological underpinnings of the disorder remain to be clarified. Psychotherapy is the treatment of choice for BPD. Various approaches have been empirically supported in randomized controlled trials, including dialectical behavior therapy, mentalization-based therapy, transference-focused therapy, and schema therapy. No approach has proved to be superior to others. Compared to treatment as usual, psychotherapy has proved to be more efficacious, with effect sizes between 0.50 and 0.65 with regard to core BPD symptom severity. However, almost half of the patients do not respond sufficiently to psychotherapy, and further research in this area is warranted. It is not clear whether some patients may benefit more from one psychotherapeutic approach than from others. No evidence is available consistently showing that any psychoactive medication is efficacious for the core features of BPD. For discrete and severe comorbid anxiety or depressive symptoms or psychotic-like features, pharmacotherapy may be useful. Early diagnosis and treatment of BPD can reduce individual suffering and societal costs. However, more high-quality studies are required, in both adolescents and adults. This review provides a comprehensive update of the BPD diagnosis and clinical characterization, risk factors, neurobiology, cognition, and management. It also discusses the current controversies concerning the disorder, and highlights the areas in which further research is needed.

Increase in invasive group A streptococcal infections in Milan, Italy: a genomic and clinical characterization.

Group A Streptococcus (GAS) causes multiple clinical manifestations, including invasive (iGAS) or even life-threatening (severe-iGAS) infections. After the drop in cases during COVID-19 pandemic, in 2022 a sharp increase of GAS was reported globally. GAS strains collected in 09/2022-03/2023 in two university hospitals in Milan, Italy were retrospectively analyzed. Clinical/epidemiological data were combined with whole-genome sequencing to: (i) define resistome/virulome, (ii) identify putative transmission chains, (iii) explore associations between emm-types and clinical severity. Twenty-eight isolates were available, 19/28 (67.9%) from adults and 9/28 (32.1%) from pediatric population. The criteria for iGAS were met by 19/28 cases (67.9%), of which 11/19 (39.3%) met the further criteria for severe-iGAS. Pediatric cases were mainly non-invasive infections (8/9, 88.9%), adult cases were iGAS and severe-iGAS in 18/19 (94.7%) and 10/19 (52.6%), respectively. Thirteen emm-types were detected, the most prevalent being emm1 and emm12 (6/28 strains each, 21.4%). Single nucleotide polymorphism (SNP) analysis of emm1.0 and emm12.0 strains revealed pairwise SNP distance always >10, inconsistent with unique transmission chains. Emm12.0-type, found to almost exclusively carry virulence factors speH and speI, was mainly detected in children and in no-iGAS infections (55.6 vs. 5.3%, p = 0.007 and 66.7 vs. 0.0%, p < 0.001, respectively), while emm1.0-type was mainly detected in severe-iGAS (0.0 vs. 45.5%, p = 0.045). This study showed that multiple emm-types contributed to a 2022/2023 GAS infection increase in two hospitals in Milan, with no evidence of direct transmission chains. Specific emm-types could be associated with disease severity or invasiveness. Overall, these results support the integration of classical epidemiological studies with genomic investigation to appropriately manage severe infections and improve surveillance.

Extracting immunological and clinical heterogeneity across autoimmune rheumatic diseases by cohort-wide immunophenotyping

ObjectiveExtracting immunological and clinical heterogeneity across autoimmune rheumatic diseases (AIRDs) is essential towards personalised medicine.MethodsWe conducted large-scale and cohort-wide immunophenotyping of 46 peripheral immune cells using Human Immunology Protocol of...

Molecular, Immunological, and Clinical Characterization of SARS-CoV-2 Infection in Breakthrough-Infected Healthcare Workers During the Last Wave of The Pandemic in Shiraz, Iran

Background: The coronavirus disease 2019 (COVID-19) poses a threat to the global economy and public health. Mutations in the spike protein of the virus can impact the functional characteristics and effectiveness of vaccines. Objectives: This study aimed to analyze mutations in three key regions of the spike protein, investigate clinical presentations, and assess protective immune levels in healthcare workers (HCWs) who had received full vaccine doses but were re-infected. Methods: In this cross-sectional study, 49 breakthrough-infected HCWs were included from November 2021 to May 2022. After confirming COVID-19 reinfection, the SARS-CoV-2 genome was extracted using the ROJE extraction kit, and genetic variation analysis was performed through Sanger sequencing. Blood samples were collected with prior consent, and ELISA tests were performed to determine antibody levels. Clinical presentations were recorded, and independent t-tests revealed no significant gender-based differences in the C-terminal point mutation. Results: In this study, 75.5% (37/49) of the included HCWs were female (P-value &lt; 0.05), and 25 were qualified for PCR and gene sequencing. Mutations were observed in 25, 10, and 1 sequence(s) of the C-terminal domain, N-terminal domain, and RBD regions of the S1 gene, respectively. The mutations had no significant correlation with the patient's gender, age, or occupation, but they were significantly more prevalent in those with underlying diseases. 63.3% (31/49) of patients had high or very high IgG levels, and none had undetectable antibody levels at the time of reinfection. Loss of the sense of smell (69.4% - 34/49), sore throat (65.3% - 32/49), headache (59.2% - 29/49), and cough (57.1% - 28/49) were the most prevalent clinical manifestations (P &gt; 0.05) in breakthrough-infected HCWs, aligning with the pattern of symptoms seen in the Omicron wave. However, the loss of the sense of taste showed significant results concerning clinical manifestation (P &lt; 0.05). The examination of mutations revealed the presence of the Omicron variant in the majority of individuals. Point mutations in the C-terminal region did not significantly vary based on age, gender, or vaccine type. No significant difference was observed between vaccine types and clinical symptoms. Conclusions: In conclusion, this study identified spike protein mutations in reinfections among vaccinated healthcare workers. While mutations were prevalent, no significant correlations were found with demographics or vaccine types. Symptoms resembled the Omicron variant, notably with the loss of the sense of taste as a significant marker. Detectable antibody levels post-reinfection suggest that vaccine-induced immunity remains robust. Continuous monitoring of virus variants is crucial for optimizing vaccination strategies in the face of evolving strains.

Extended phenotypic characterization of a novel Helsmoortel-van der Aa syndrome case series.

The neurodevelopmental disorder known as Helsmoortel-van der Aa syndrome (HVDAS, MIM#616580) or ADNP syndrome (Orphanet, ORPHA:404448) is a multiple congenital anomaly (MCA) condition, reported as a syndrome in 2014, associated with deleterious variants in the ADNP gene (activity-dependent neuroprotective protein; MIM*611386) in several children. First reported in the turn of the century, ADNP is a protein with crucial functions for the normal development of the central nervous system and with pleiotropic effects, explaining the multisystemic character of the syndrome. Affected individuals present with striking facial dysmorphic features and variable congenital defects. Herein, we describe a novel case series of HVDAS Italian patients, illustrating their clinical findings and the related genotype-phenotype correlations. Interestingly, the cutaneous manifestations are also extensively expanded, giving an important contribution to the clinical characterization of the condition, and highlighting the relation between skin abnormalities and ADNP defects.

Multi-organ dysfunction and outcomes in pregnancy associated COVID-19 infection – descriptive review of pathological findings

Objective(s)Comparative clinical and morphological characterization of lesions of the vascular and nervous system in cases of maternal death associated with COVID-19.Study designThe study included autopsy in 12 cases of maternal death with a positive intravital result for SARS-CoV-2 by reverse transcription polymerase chain reaction. For histopathology, tissue samples were taken from the internal organs of each patient. Pieces of organs were fixed and stained according to the standard protocol. The relative number of microvessels with vasculitis and fibers of the peripheral nervous system with infiltration by immune cells was studied. All morphological changes were classified depending on the severity of the damage.ResultsThe average age of patients with a fatal outcome was 35 ± 4.4 years. Time to death after onset of symptoms averaged 16 ± 4.4 days. Dystrophic lesions (necrosis and apoptosis) of the villous and extravillous trophoblast and decidual tissue were observed in the studied placentas. Histopathological signs of mild and severe lesions of the peripheral nervous system in the organs of the gastrointestinal tract were detected in 2 (16.7%) and 10 (83.3%) cases, respectively, in the myocardium in 4 (33.3%) and 8 (66.7%) cases. Histopathological signs of severe damage to the microvascular bed in the organs of the gastrointestinal tract were registered in 9 (75%) cases.Conclusion(s)The main clinical feature of this cohort was that death occurred in a long-term period, in most cases with a negative PCR. The histopathological pattern was a non-acute injury with an immune component of the microvascular bed and the autonomic nervous system with predominant damage to the myocardium and intestines.What does this study add to the clinical workThis study makes it possible to even better study the immunopathological profile in organs and tissues in pregnant women with a fatal outcome when affected by a viral infection, in particular Covid-19. This knowledge can be used when humanity encounters other viral pandemics in the future.

Clinical significance, molecular characterization, and immune microenvironment analysis of coagulation-related genes in clear cell renal cell carcinoma.

Numerous studies have revealed a tight connection between tumor development and the coagulation system. However, the effects of coagulation on the prognosis and tumor microenvironment (TME) of clear cell renal cell carcinoma (ccRCC) remain poorly understood. We employed the consensus clustering method to characterize distinct molecular subtypes associated with coagulation patterns. Subsequently, we examined variations in the overall survival (OS), genomic profiles, and TME characteristics between these subtypes. To develop a prognostic coagulation-related risk score (CRRS) model, we utilized the least absolute shrinkage and selection operator Cox regression and stepwise multivariate Cox regression analyses. We also created a nomogram to aid in the clinical application of the risk score, evaluating the relationships between the CRRS and the immune microenvironment, responsiveness to immunotherapy, and targeted treatment. The clinical significance of PLAUR and its biological function in ccRCC were also further analyzed. There were significant differences in clinical features, prognostic stratification, genomic variation, and TME characteristics between the two coagulation-related subtypes. We established and validated a CRRS using six coagulation-related genes that can be employed as an effective indicator of risk stratification and prognosis estimation for ccRCC patients. Significant variations in survival outcomes were observed between the high- and low-risk groups. The nomogram was proficient in predicting the 1-, 3-, and 5-year OS. Additionally, the CRRS emerged as a novel tool for evaluating the clinical effectiveness of immunotherapy and targeted treatments in ccRCC. Moreover, we confirmed upregulated PLAUR expression in ccRCC samples that was significantly correlated with poor patient prognosis. PLAUR knockdown notably inhibited ccRCC cell proliferation and migration. Our data suggested that CRRS may be employed as a reliable predictive biomarker that can provide therapeutic benefits for immunotherapy and targeted therapy in ccRCC.

Mouse Model of Nitrogen Mustard Ocular Surface Injury Characterization and Sphingolipid Signaling.

Vesicating chemicals like sulfur mustard (SM) or nitrogen mustard (NM) can cause devastating damage to the eyes, skin, and lungs. Eyes, being the most sensitive, have complicated pathologies that can manifest immediately after exposure (acute) and last for years (chronic). No FDA-approved drug is available to be used as medical counter measures (MCMs) against such injuries. Understanding the pathological mechanisms in acute and chronic response of the eye is essential for developing effective MCMs. Here, we report the clinical and histopathological characterization of a mouse model of NM-induced ocular surface injury (entire surface) developed by treating the eye with 2% (w/v) NM solution for 5 min. Unlike the existing models of specific injury, our model showed severe ocular inflammation, including the eyelids, structural deformity of the corneal epithelium and stroma, and diminished visual and retinal functions. We also observed alterations of the inflammatory markers and their expression at different phases of the injury, along with an activation of acidic sphingomyelinase (aSMase), causing an increase in bioactive sphingolipid ceramide and a reduction in sphingomyelin levels. This novel ocular surface mouse model recapitulated the injuries reported in human, rabbit, and murine SM or NM injury models. NM exposure of the entire ocular surface in mice, which is similar to accidental or deliberate exposure in humans, showed severe ocular inflammation and caused irreversible alterations to the corneal structure and significant vision loss. It also showed an intricate interplay between inflammatory markers over the injury period and alteration in sphingolipid homeostasis in the early acute phase.

Clinical Characterization and Underlying Genetic Findings in Brazilian Patients with Syndromic Microcephaly Associated with Neurodevelopmental Disorders.

Microcephaly is characterized by an occipitofrontal circumference at least two standard deviations below the mean for age and sex. Neurodevelopmental disorders (NDD) are commonly associated with microcephaly, due to perturbations in brain development and functioning. Given the extensive genetic heterogeneity of microcephaly, managing patients is hindered by the broad spectrum of diagnostic possibilities that exist before conducting molecular testing. We investigated the genetic basis of syndromic microcephaly accompanied by NDD in a Brazilian cohort of 45 individuals and characterized associated clinical features, as well as evaluated the effectiveness of whole-exome sequencing (WES) as a diagnostic tool for this condition. Patients previously negative for pathogenic copy number variants underwent WES, which was performed using a trio approach for isolated index cases (n = 31), only the index in isolated cases with parental consanguinity (n = 8) or affected siblings in familial cases (n = 3). Pathogenic/likely pathogenic variants were identified in 19 families (18 genes) with a diagnostic yield of approximately 45%. Nearly 86% of the individuals had global developmental delay/intellectual disability and 51% presented with behavioral disturbances. Additional frequent clinical features included facial dysmorphisms (80%), brain malformations (67%), musculoskeletal (71%) or cardiovascular (47%) defects, and short stature (54%). Our findings unraveled the underlying genetic basis of microcephaly in half of the patients, demonstrating a high diagnostic yield of WES for microcephaly and reinforcing its genetic heterogeneity. We expanded the phenotypic spectrum associated with the condition and identified a potentially novel gene (CCDC17) for congenital microcephaly.

A novel bluetongue virus serotype 2 strain isolated from a farmed Florida white-tailed deer (Odocoileus virginianus) arose from reassortment of gene segments derived from co-circulating serotypes in the Southeastern USA.

Bluetongue disease is a reportable animal disease that affects wild and farmed ruminants, including white-tailed deer (WTD). This report documents the clinical findings, ancillary diagnostics, and genomic characterization of a novel reassortant bluetongue virus serotype 2 (BTV-2) strain isolated from a dead Florida farmed WTD in 2022. Our analyses support that this BTV-2 strain likely stemmed from the acquisition of genome segments from co-circulating BTV strains in Florida and Louisiana. In addition, our analyses also indicate that genetically uncharacterized BTV strains may be circulating in the Southeastern USA; however, the identity and reassortant status of these BTV strains cannot be determined based on the VP2 and VP5 genome sequences. Hence, continued surveillance based on complete genome characterization is needed to understand the genetic diversity of BTV strains in this region and the potential threat they may pose to the health of deer and other ruminants.

Viral hepatitis E in pregnant women in Belarus: clinical examples and molecular genetic characterization of the virus

Objective. To conduct a clinical and molecular genetic study of two cases of acute hepatitis E in pregnant women from Belarus.Materials and methods. A total of 227 pregnant women with clinical symptoms of liver damage were included in the study. Blood serum samples were used for detection of antibodies to hepatitis E virus by enzyme-linked immunosorbent assay, virus nucleic acid was detected from fecal samples by reverse transcription nested polymerase chain reaction. The nucleotide sequence was determined on an automated sequencer using the Sanger method. Nucleotide sequences were analyzed, genotyped and evolutionary distances calculated using MEGA X software.Results. Out of 227 sera tested, immunoglobulins of class G to hepatitis E virus were detected in 15, which is 6.61%. M immunoglobulins were also detected in the blood of six pregnant women, which is 2.6%. Two clinically evident cases of acute hepatitis E were identified. One of the two patients ended her pregnancy with antenatal fetal death. Virus nucleic acid was isolated from another woman diagnosed with hepatitis E, who had an episode of nutritional contact with raw minced pork. The virus RNA sequence isolated from this patient’s body is clustered into a common phylogenetic branch with the sequence obtained from the body of a patient from Belarus with a history of kidney transplantation and sequences isolated from the body of a domestic pig in the Republic of Belarus.Conclusion. Hepatitis E virus poses a significant threat to pregnant women. A set of preventive measures against hepatitis E in pregnant women has been proposed.

Could the Construct of Modern-Type Depression Predict Internet Gaming Disorder in Italian Video Gamers? A Case-Control Study.

A new postmodern depression type, named "Modern-Type Depression" (MTD), is emerging in Western countries. MTD is often underdiagnosed, mainly due to potentially higher comorbidity with technology-based addictions, including Internet Gaming Disorder (IGD). However, the definition of the relationship between MTD and IGD is still controversial, as few data have been published thus far. In particular, there are no data specifically investigating the prevalence of MTD within Italian young subjects with IGD, as well as their mutual association. Hence, within the SWATCH (Social Withdrawal and TeCno-mediated mental Health issues) project, our study aimed to identify the prevalence of MTD in a sample of Italian young adults who play video games by providing a clinical characterization of MTD within a group of IGD individuals (IGD+) versus a group without IGD (IGD-) who play video games. Our cross-sectional case-control study recruited a sample of 543 Italian young video-gaming players (aged 18-35) from the larger SWATCH database, stratified as IGD+ versus IGD-. Subjects were administered the 22-item Tarumi's Modern-Type Depression Trait Scale (TACS-22), the Motives for Online Gaming Questionnaire (MOGQ), and the Internet Gaming Disorder Scale-Short Form (IGDS9-SF). Around 21.7% of the total sample was represented by MTD individuals, while within the IGD sample, around 34% of subjects had MTD. Within the MTD group, significantly higher scores at IGDS-9SF (p < 0.001), MOGQ "Escape from reality" (p < 0.001), "Fantasy" (p < 0.001), and MOGQ total score (p = 0.003) were found compared to MTD-. According to the multivariate regression model, controlled for sex and age, higher scores in the TACS-22 were positively predicted by the total score of IGDS9-SF (p = 0.003), the MOGQ "Escape from Reality" subscale (p = 0.014), and MOGQ "Fantasy" (p = 0.011), and negatively predicted by the MOGQ "Competition" subscale (p = 0.035) [F (4538) = 17.265; p < 0.001]. Our findings suggested that MTD displays a strong association with IGD. Video-gaming players who do not have IGD appear to be less prone to MTD; this suggests that further studies could be carried out to specifically investigate whether pathological use of video games could also be determined by the presence of MTD.

Investigation of a linezolid-resistant Staphylococcus epidermidis outbreak in a French hospital: phenotypic, genotypic, and clinical characterization.

We aimed to retrospectively investigate an outbreak of linezolid-resistant Staphylococcus epidermidis (LRSE), at Tours University Hospital between 2017 and 2021. Twenty of the 34 LRSE isolates were included in the study. Antimicrobial susceptibility testing was performed using the disk diffusion method and MICs of last-resort antibiotics were determined using broth microdilution or Etest®. Seventeen of the 20 resistant strains were sent to the French National Reference Centre for Staphylococci to determine the mechanism of resistance to linezolid. The clonal relationship between LRSE strains was assessed by PFGE and the sequence type determined by MLST. We retrospectively evaluated a new typing tool, IR-Biotyper®, and compared its results to PFGE to evaluate its relevance for S. epidermidis typing. Medical records were reviewed, and antibiotic consumption was determined. Search for a cross transmission was performed. All LRSE strains showed high levels of resistance to linezolid (MICs ≥ 256 mg/L) and were multi-drug resistant. Linezolid resistance was associated with the 23S rRNA G2576T mutation and none of the 17 strains analyzed carried the cfr gene. Ninety-five percent of the 20 LRSE studied strains were genetically related and belonged to sequence-type ST2. The dendrogram obtained from IR-Biotyper® showed 87% congruence with the PFGE analysis. Prior to isolation of the LRSE strain, 70% of patients received linezolid. No patients stayed successively in the same room. Linezolid exposure may promote the survival and spread of LRSE strains. At Tours University Hospital, acquisition of the resistant clone may also have been triggered by hand-to-hand transmission by healthcare workers. In addition, IR-Biotyper® is a promising typing tool for the study of clonal outbreaks due to its low cost and short turnaround time, although further studies are needed to assess the optimal analytical parameters for routine use.

Prevalence and prognostic significance of iron deficiency anemia among heart failure patients: A prospective observational study

ABSTRACT Background: Patients with chronic heart failure (CHF) frequently have associated iron deficiency, which may or may not be associated with anemia. Studies to ascertain the impact of repleting iron in patients with CHF and various other prognostic markers are lacking in Indian patients and the Indian context. Objectives: The objective is to study the prevalence of iron deficiency anemia in patients with CHF and its prognostic significance in predicting major adverse cardiovascular events (MACEs) during 6 months of follow-up along with the role of other clinical and demographic variables. Methodology: A prospective, observational, hospital-based study conducted in a government tertiary medical center in south India on patients admitted with the diagnosis of CHF. Full demographic and clinical characterization and all relevant laboratory investigations including iron profile were done per protocol. The incidence of a MACE (rehospitalization for heart failure or death) and its association with iron deficiency was studied at the end of a 6-month follow-up. Results: A total of 388 patients were followed for 6 months. Out of those, 211 patients (54%) developed composite outcomes. Old age, coronary artery disease, atrial fibrillation, previous heart failure history, chronic kidney disease, and reduced left ventricular ejection fraction were independent predictors of composite outcome. The prevalence of anemia in the study population was 71%, and iron deficiency was 63% (20% absolute and 43% relative). Iron deficiency without anemia was also an independent predictor of the composite outcome. Conclusions: This study highlights the underestimated and neglected burden of iron deficiency in CHF patients in India. It also suggests further large-scale studies to characterize this easily treatable condition better and consider routine testing of iron profiles in future Indian guidelines.