Severe Form Research Articles

Quantitative assessment of thalamic damage and serum neurofilament light chain in relapsing-remitting multiple sclerosis

BackgroundThe study assessed group differences in the thalamus microstructural parameters among healthy individuals and relapsing-remitting multiple sclerosis (RRMS) patients and examined the relationship between quantitative MRI (qMRI) parameters and neurological scores, T2 lesion load, and serum neurofilament light chain (sNfL) levels. MethodsA total of 30 patients with RRMS and 26 age- and sex-matched healthy controls were recruited in this study. The qMRI images were obtained from these individuals. T2 lesion load, thalamic volume, and parameters of thalamic subnuclei were estimated. The neurological functions of participants were assessed using a battery of tests. sNfL concentrations were measured using the single molecule array (SIMOA) technique. ResultsT2 relaxometry in the whole thalamus and its subnuclei were increased, and showed an apparent correlation with T2 lesion load and the severity of MS (EDSS, MSSS, 9HPT, T25FW, SDMT). T1 variability was prolonged in most thalamic subnuclei, and it was correlated with the severity of MS (EDSS, 9HPT, SDMT). Thalamic volumetric parameters of MS patients were smaller than those of healthy controls (p < 0.001) and showed an apparent correlation with MS severity. Surprisingly, sNfL levels showed no correlation with T2 relaxometry, T1 variability, or thalamic volumetric parameters. ConclusionQuantitative synthetic MRI, especially, the metric T2 relaxation times provides a surrogate parameter for assessing underlying thalamic and subnuclei damage in the RRMS group. Integrating structural and quantitative MRI allows a better assessment of the neurodegeneration in the normal-appearing thalamus of RRMS.

Exploring Genetic Silencing: RNAi and CRISPR-Cas Potential against Drug Resistance in Malaria

Malaria has been one of the most lethal infectious diseases throughout history, claiming a high number of human lives. The genomic plasticity of &lt;i&gt;Plasmodium falciparum&lt;/i&gt;, the causative agent of the most severe and deadly form of malaria, gives the parasite a constant resistance to drugs developed for its control. Despite efforts to control and even eradicate the disease, these have largely been unsuccessful due to the parasite's continuous adaptations. This study aims to examine the key genes involved in parasite resistance and propose a shift in the combat strategy. Gene silencing techniques offer promise in combating malaria, yet further research is needed to harness their potential for disease control fully. Although there is still a long way to go for the implementation of gene silencing-based therapeutic strategies, this review addresses examples of the use of such techniques in various human diseases and how they could be extrapolated for malaria treatment.

Phase 2 Randomised Study of Bulevirtide as Monotherapy or Combined With Peg-IFNα-2a as Treatment for Chronic Hepatitis Delta.

Bulevirtide (BLV) leads to beneficial virologic and biochemical responses when given alone to treat hepatitis delta virus (HDV) infection, which causes the most severe form of chronic viral hepatitis. We evaluated 48 weeks of BLV monotherapy, BLV + tenofovir disoproxil fumarate (TDF) and BLV + pegylated interferon alfa-2a (Peg-IFNα-2a), with 24-week follow-up. Ninety patients were enrolled into six arms of 15 each (A-F); 60 patients were included in the main randomisation (arms A-D), and 30 patients (arms E-F) were randomised to the extension phase: (A) Peg-IFNα-2a 180 μg once weekly (QW); (B) BLV 2 mg once daily (QD) + Peg-IFNα-2a 180 μg QW; (C) BLV 5 mg QD + Peg-IFNα-2a 180 μg QW; (D) BLV 2 mg QD; (E) BLV 10 mg QD + Peg-IFNα-2a 180 μg QW and (F) BLV 10 mg (5 mg twice daily) + TDF QD. The primary endpoint was undetectable HDV RNA at week (W)72. At W72, 53%, 27%, 7%, 7% and 33% of patients achieved undetectable HDV RNA in arms B, C, D, E and F, respectively, versus 0% in arm A. More arm B versus A patients had a > 1 log10 IU/mL decline in or loss of hepatitis B surface antigen (HBsAg) at W72 (p = 0.017), including four patients with loss of HBsAg. Bile acid elevations were dose-dependent and reversible following the completion of BLV treatment. BLV combined with Peg-IFNα-2a was well tolerated and resulted in high rates of HDV RNA undetectability off-treatment. NCT02888106.

Communicating a diagnosis of Dravet syndrome to parents/caregivers: An international Delphi consensus.

Dravet syndrome is a developmental and epileptic encephalopathy characterized by drug-resistance, lifelong seizures, and significant comorbidities including intellectual and motor impairment. Receiving a diagnosis of Dravet syndrome is challenging for parents/caregivers, and little research has focused on how the diagnosis should be given. A Delphi consensus process was undertaken to determine key aspects for healthcare professionals (HCPs) to consider when communicating a Dravet syndrome diagnosis to parents/caregivers. Following a literature search and steering committee review, 34 statements relating to the first diagnosis consultation were independent- and anonymously voted on (from 1, totally inappropriate, to 9, totally appropriate) by an international group of expert child neurologists, neuropsychiatrists, nurses, and patient advisory group (PAG) representatives. The statements were divided into five chapters: (i) communication during the first diagnosis consultation, (ii) information to be delivered during the first diagnosis consultation, (iii) points to be reiterated at the end of the first diagnosis consultation, (iv) information to be delivered at subsequent consultations, and (v) communication around genetic testing. Statements receiving ≥ 75% of the votes with a score of ≥7 and/or with a median score of ≥8 were considered consensual. The statements were evaluated by 44 HCPs and PAG representatives in the first round of voting; 29 statements obtained strong consensus, 3 received good consensus, and 2 did not reach consensus. The committee reformulated and resubmitted 4 statements for evaluation (42/44 voters): 3 obtained strong consensus and 1 remained not consensual. The final consensual recommendations include guidance on consultation setting, key disease aspects to convey, how to discuss genetic testing results, disease evolution, and the risk of SUDEP, among other topics. It is hoped that this international Delphi consensus will facilitate a better-structured initial diagnosis consultation and offer further support for parents/caregivers at this challenging time of learning about Dravet syndrome. Diagnosis of Dravet syndrome, a rare and severe form of childhood-onset epilepsy, is often challenging to give to parents. This international study developed guidance and recommendations to help healthcare professionals better structure and personalize this disclosure. By following this advice, doctors can provide more tailored support to families, improving their understanding and management of the condition.

Complex PTSD and identification with the aggressor among survivors of childhood abuse.

Childhood abuse (CA) is a risk factor for trauma-related disorders including posttraumatic stress disorder (PTSD) and complex posttraumatic stress disorder (CPTSD). This severe form of interpersonal trauma may result in "identification with the aggressor" (IWA), in which the individual may take on the beliefs, perspectives, and behaviors of the perpetrator. Although previous evidence suggests that IWA may be particularly related to CPTSD as compared to PTSD, there has been no study that investigated this hypothesis. The current study explored the relations between IWA and PTSD and CPTSD symptoms, and the contribution of IWA to the excess probability of PTSD and CPTSD classifications, as compared to no classification. This cross-sectional study was conducted among 320 Israeli adult CA survivors aged 21-63 (M=42.04, SD=10.81). An online survey was completed by a convenience sample of adult CA survivors. Replacing one's agency with that of the perpetrator as part of IWA had a significant effect on both PTSD and CPTSD symptoms (ES=0.36 and 0.24, respectively), and served as a risk factor for both PTSD and CPTSD classifications. Moreover, analysis of the models' predicted values reveals that the predicted probability of CPTSD classification was 3 to 5 times higher than on the probability of PTSD classifications, for low to high values of the replacing one's agency scale, respectively. The current findings suggest that IWA may describe some of the deep and long-lasting detriments of CA on self, and may contribute to the development of CPTSD symptoms.

Severe Liver-Related Outcomes in Patients With Hepatitis Delta: Results From a Multi-Ethnic Multicenter Long-Term Follow-Up Study.

Hepatitis B virus (HBV)-hepatitis delta virus (HDV) coinfection is the most severe form of chronic viral hepatitis, but the factors that determine disease progression and severity are incompletely characterised. This long-term follow-up study aims to identify risk factors for severe liver-related outcomes. In this multicentre national cohort study, data from admission until the last visit between 2001 and 2023 was retrospectively collected from 162 HBV-HDV coinfected patients. The inclusion criteria were HBsAg or HBV DNA positivity, anti-HDV or HDV RNA positivity, and at least one follow-up visit. The median follow-up was 6.2 years (IQR 3.3-10.2). At baseline, 68/152 (44.7%) patients were diagnosed with advanced liver fibrosis. Forty patients (24.7%) had at least one severe liver-related outcome during follow-up. HDV viremia was detectable in 92 patients (64.3%) at last evaluation and was more frequently detectable in patients of European origin (p < 0.001). HDV RNA-positive patients had a 4.7-fold higher risk for severe liver-related outcomes (p < 0.001) and were more frequently diagnosed with advanced fibrosis at baseline (p = 0.007) compared to HDV RNA-negative patients. Multivariate analyses identified HDV RNA positivity, as well as several markers for liver disease severity, such as INR, platelet count, and advanced fibrosis at baseline, and age at admission as independent risk factors for severe liver-related outcomes. In conclusion, almost one in four HBV-HDV coinfected patients developed a severe liver-related outcome during follow-up. Several markers for liver disease severity and HDV RNA positivity were the strongest predictors for outcomes.

Epigenetic memory as crucial contributing factor in directing the differentiation of human iPSC into pancreatic β-cells in vitro.

Impaired insulin secretion contributes to the pathogenesis of type 1 diabetes mellitus through autoimmune destruction of pancreatic β-cells and the pathogenesis of severe forms of type 2 diabetes mellitus through β-cell dedifferentiation and other mechanisms. Replenishment of malfunctioning β-cells via islet transplantation has the potential to induce long-term glycemic control in the body. However, this treatment option cannot widely be implemented in clinical due to healthy islet donor shortage. Emerging β-cell replacement with human-induced pluripotent stem cell (iPSC) provides high remedial therapy hopes. Thus, tremendous progress has been made in developing β-cell differentiation protocols in vitro; however, most of the differentiated iPSC-derived β-cells showed immature phenotypes associated with low efficiency depending on the iPSC lines used, creating a crucial barrier for their clinical implementation. Multiple mechanisms including differences in genetic, cell cycle patterns, and mitochondrial dysfunction underlie the defective differentiation propensity of iPSC into insulin-producing β-cells. Accumulating evidence recently indicated that, following the reprogramming, epigenetic memory inherited from parental cells substantially affects the differentiation capacity of many iPSC lines. Therefore, differences in epigenetic signature are likely to be essential contributing factors influencing the propensity of iPSC differentiation. In this review, we will document the impact of the epigenome on the reprogramming efficacy and differentiation potential of iPSCs and how targeting the epigenetic residual memory could be an additional strategy to improve the differentiation efficiency of existing protocols to generate fully functional hPSC-derived pancreatic β-cells for diabetes therapy and drug screening.

M6A-mRNA Reader YTHDF2 Identified as a Potential Risk Gene in Autism With Disproportionate Megalencephaly.

Among autistic individuals, a subphenotype of disproportionate megalencephaly (ASD-DM) seen at three years of age is associated with co-occurring intellectual disability and poorer prognoses later in life. However, many of the genes contributing to ASD-DM have yet to be delineated. In this study, we identified additional ASD-DM candidate genes with the aim to better define the genetic etiology of this subphenotype of autism. We expanded the previously studied sample size of ASD-DM individuals ten fold by including probands from the Autism Phenome Project and Simons Simplex Collection, totaling 766 autistic individuals meeting the criteria for megalencephaly or macrocephaly and revealing 154 candidate ASD-DM genes harboring de novo protein-impacting variants. Our findings include 14 high confidence autism genes and seven genes previously associated with DM. Five impacted genes have previously been associated with both autism and DM, including CHD8 and PTEN. By performing functional network analysis, we expanded to additional candidate genes, including one previously implicated in ASD-DM (PIK3CA) as well as 184 additional genes connected withASD or DM alone. Using zebrafish, we modeled a de novo tandem duplication impacting YTHDF2, encoding an N6-methyladenosine (m6A)-mRNA reader, in an ASD-DM proband. Testing zebrafish CRISPR knockdown led to reduced head/brain size, while overexpressing YTHDF2 resulted in increased head/brain size matching that of the proband. Single-cell transcriptomes of YTHDF2 gain-of-function larvae point to reduced expression of Fragile-X-syndrome-associated FMRP-target genes globally and in the developing brain, providing insight into the mechanism underlying autistic phenotypes. We additionally discovered a variant impacting a different gene encoding an m6A reader, YTHDC1, in our ASD-DM cohort. Though we highlight only two cases to date, our study provides support for the m6A-RNA modification pathway as potentially contributing to this severe form of autism.

P-1286. Severe Forms Of Rickettsiosis In Comparison With Non-Severe Forms

Abstract Background Rickettsiosis, a relatively benign disease, typically manifests with fever, skin rash, and headache. However, severe forms may occur, changing therefore, the prognosis of the disease. We aimed to study the clinical, biological and therapeutic characteristics of severe forms of rickettsiosis in comparison with non-severe forms. Methods We conducted a retrospective study including all patients hospitalized for rickettsiosis in infectious diseases department between 1996 and 2022. The diagnosis was confirmed by serological tests. Results We encountered 84 cases of severe rickettsiosis (17.8%) and 388 cases of non-severe forms (82.2%). The median age of patients with severe forms was 47[32-64] years and with non-severe forms was 37[25-53] years (p=0.24). Meningeal syndrome (38.1% vs 8.5%; p&amp;lt; 0.001) and vomiting (58.3% vs 41.9%; p=0.006) were significantly more frequent among severe cases. Maculopapular skin rash (57.1% vs 86.8%; p&amp;lt; 0.001) and arthralgia (58.3% vs 76%; p=0.001) were significantly less frequent among severe cases. Leukocytosis was significantly more frequent among severe forms (36.9% vs 20.6%; p=0.001). Elevated C-reactive protein levels (63.1% vs 66.2%; p=0.582), thrombocytopenia (51.8% vs 59.6%; p=0.19) and hepatic cytolysis (60.7% vs 69.8%; p=0.103) were noted among severe and non-severe forms, with no significant difference. Treatment duration was significantly longer among severe forms (10[7-14] days vs 7[5-10] days; p=0.016). Conclusion The diagnosis of severe forms of rickettsiosis should be ruled out in front of meningeal syndrome and vomiting, even in the absence of maculopapular skin rash and arthralgia, especially in the presence of leukocytosis. Disclosures All Authors: No reported disclosures

P-1981. MMCD score for predicting kidney replacement therapy in hospitalized patients with COVID-19 from 2020 to 2022

Abstract Background Acute kidney injury (AKI) requiring kidney replacement therapy (KRT) in its most severe forms is a significant complication of patients with COVID-19. The development of a risk score to predict KRT requirement could optimize health resource allocation. Thus, this study aimed to develop and validate a score to predict the KRT requirement in hospitalized patients with COVID-19 from 2020 to 2022. Area under the receiver operating characteristic curve for the 2021-2022 validation of MMCD score Methods This is a multicenter retrospective cohort of consecutive patients hospitalized for COVID-19, confirmed by laboratory tests, in 40 Brazilian hospitals, from March 2020 to July 2022. Patients under 18 years old, pregnant, in palliative care, or in dialysis therapy at admission were excluded from the study. Predictor variables were selected using generalized additive models (GAM) and the least absolute shrinkage and selection operator (LASSO) regression was used for score derivation. The score was developed in the period from March to July 2020, with temporal and geographic validation from July to September 2020 and new temporal validation from March 2021 to July 2022. The performance of the score was evaluated by the area under the receiver operating characteristic curve (AUROC, with a 95% confidence interval), graphical analysis with intercept and slope test, and Brier score. Calibration for the validation of MMCD score Results The study included 3,680 patients in the development sample, 1,532 in the 2020 temporal validation, 1,378 in the geographic validation, and 9,473 in the 2021-2022 temporal validation. Four predictors were identified: mechanical ventilation at any time during hospitalization, male sex, admission creatinine, and diabetes mellitus. The score named MMCD showed excellent performance in the derivation and validations cohorts (development AUROC 0.929, CI 0.918–0.939, Brier 0.057; 2020 temporal validation AUROC 0.927, CI 0.911–0.941, Brier 0.056; 2020 geographic validation AUROC 0.819, CI 0.792–0.845, Brier 0.122; 2021/2022 temporal validation AUROC 0.916, CI 0.909-0.924, Brier 0.057). Conclusion The MMCD showed excellent predictive ability for KRT in different phases of the pandemic, which can contribute to support more assertive decisions in the allocation of care resources, in addition to efficient clinical management. Disclosures All Authors: No reported disclosures

Intensive Therapeutic Plasma Exchange—New Approach to Treat and Rescue Patients with Severe Form of Yellow Fever

Background: Severe yellow fever (YF) can result in acute liver failure (ALF) and high mortality. The role of therapeutic plasma exchange (TPE) in managing YF-ALF remains unclear. This study evaluated the impact of TPE strategies in severe YF. Methods: This observational case-series study evaluated three groups of patients classified according to treatment: G1 (standard intensive care support [ICS]), G2 (ICS + high-volume-TPE [HV-TPE]), and G3 (ICS + intensive TPE). HV-TPE was performed during 3 consecutive days with extra sessions of one plasma-volume, if necessary, whereas intensive TPE consisted of one plasma volume/session performed twice daily, with additional fresh frozen plasma infusion. Hemostatic agents, including tranexamic acid, platelets, and cryoprecipitate, were administered as needed. TPE was de-escalated based on clinical and laboratory parameters. The primary outcome was mortality. Results: Sixty-six patients were included (G1: 41, G2: 11, G3: 14). Groups had similar baseline characteristics. Mortality was significantly lower in G3 (14%) compared to G2 (82%) and G1 (85%) (p &lt; 0.001). Additionally, G3 patients showed a higher frequency of undetectable YF viral load. Conclusions: Intensive TPE is a feasible and effective intervention for severe YF, achieving an 84% reduction in mortality. The limitations of our results are the small sample size, observational and single-center study. Further studies are warranted to elucidate intensive TPE’s role in YF management.

83. Predictors of Undetectable HDV RNA 48 weeks after completion of finite treatment with Bulevirtide and Pegylated-Interferon Alpha 2a

Abstract Background Chronic Hepatitis Delta (CHD) is the most severe form of viral hepatitis. Bulevirtide (BLV) is a first-in-class entry inhibitor approved in the EU for the treatment of compensated CHD. In MYR204, a Phase 2b study evaluating finite treatment with BLV with or without pegylated interferon alfa-2a (Peg-IFNa), combination treatment with 10mg BLV resulted in higher undetectable HDV RNA rates 24 weeks (W) post end of treatment (EOT) compared with either monotherapy regimen. Here, we present predictors of undetectable HDV RNA at 48W (FU-48) post-EOT.Table 1.Comparison of Key Efficacy Endpoints at EOT vs FU-48 Methods 174 patients with CHD were randomized (1:2:2:2) with stratification of cirrhosis status and received (A) Peg-IFNa for 48W; or (B) BLV 2mg + Peg-IFNa, or (C) BLV 10mg + Peg-IFNa for 48W followed by 48W of monotherapy with BLV 2mg or 10mg, respectively; or (D) BLV 10mg for 96W. All patients were followed up to FU-48. Efficacy endpoints were compared by Fisher’s exact test. The logistic regression model examined if any baseline (BL) characteristics predicted responses at FU-48 with arms B and C. Characteristics with p&amp;lt; 0.05 were considered potential predictors. The MMRM was used to evaluate treatment effect on HDV RNA during initial 48W on-treatment.Figure 1.Selected Characteristics as Potential Predictors of undetectable HDV RNA at FU-48 in patients treated with BLV +Peg-IFNa. Logistic regression analysis was performed on a merged data set of patients that were treated with combination therapy of BLV (either 2 or 10mg) +Peg-IFNa to evaluate predictors of HDV RNA undetectability. P values &amp;lt;0.05 are represented in bold. Results BL characteristics were similar between all arms. Key endpoints such as, HDV RNA undetectability, ALT normalization, and composite response (HDV RNA undetectable and ALT normalization) at EOT and FU-48 are shown in Table 1. Selected potential BL predictors of undetectable HDV RNA at FU-48 included BL HDV RNA &amp;lt; median of 5.54 log10 IU/mL (Odds Ratio (OR): 5.6, p=0.0003), and BL liver stiffness &amp;lt; 11.1kPa (OR: 2.9, p&amp;lt; 0.02) (Fig.1). Time to onset of HDV RNA undetectability (OR: 0.99, p=0.0015), and undetectable by on-treatment 24W (OR:13.5, p&amp;lt; 0.0001) predicted HDV RNA undetectability at FU-48. BLV (2 or 10mg) + Peg-IFNa had a higher weekly decline of HDV RNA compared to Peg-IFNa (LS-means difference: -0.0414 log10IU/mL or -0.0542 log10IU/mL (p&amp;lt; 0.0001), respectively) within the first 48W on-treatment. Conclusion In patients with CHD treated with a finite regimen of BLV + Peg-IFNa early rapid on-treatment viral decline and achievement of HDV RNA undetectability are associated with undetectable HDV RNA at FU-48. Disclosures Tarik Asselah, PhD, Abbvie: Expert Testimony|Abbvie: Investigator|Eiger Pharmaceuticals: Expert Testimony|Eiger Pharmaceuticals: Investigator|Gilead Sciences, Inc.: Expert Testimony|Gilead Sciences, Inc.: Investigator|Janssen: Expert Testimony|Janssen: Investigator|Merck: Expert Testimony|Merck: Investigator|Myr pharmaceutical: Expert Testimony|Myr pharmaceutical: Investigator|Roche: Expert Testimony|Roche: Investigator Fabien Zoulim, MD, PhD, Aligos Therapeutics: consulting fees|Antios Therapeutics: consulting fees|Assembly Biosciences: Grant/Research Support|Assembly Biosciences: consulting fees|Beam Therapeutics: Grant/Research Support|Gilead Sciences, Inc.: consulting fees|Janssen: Grant/Research Support Dana Tedesco, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Private Company) Renee-Claude Mercier, PharmD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Private Company) Dmitry Manuilov, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Private Company) Audrey Lau, MD, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Private Company) Marc Bourliere, MD, PhD, AbbVie: Board Member|AbbVie: Expert Testimony|Gilead Sciences, Inc.: Board Member|Gilead Sciences, Inc.: Expert Testimony|Intercept: Board Member|Intercept: Expert Testimony|Roche: Board Member|Roche: Expert Testimony Vladimir Chulanov, MD, PhD, AbbVie: Advisor/Consultant|AbbVie: Expert Testimony|AstraZeneca: Advisor/Consultant|AstraZeneca: Expert Testimony|Bristol Myers Squibb: Advisor/Consultant|Bristol Myers Squibb: Expert Testimony|Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: Expert Testimony|GSK: Advisor/Consultant|GSK: Expert Testimony|Hepatera: Advisor/Consultant|Hepatera: Expert Testimony|Merck Sharp &amp; Dohme: Advisor/Consultant|Merck Sharp &amp; Dohme: Expert Testimony|Roche: Advisor/Consultant|Roche: Expert Testimony|R-Pharm: Advisor/Consultant|R-Pharm: Expert Testimony

Pneumonia and pregnancy

Acute community-acquired pneumonia (CAP) during pregnancy is a frequently encountered and potentially severe condition. CAP incidence and ecology are unchanged during pregnancy as compared with the overall young adult population. Risk factors specifically identified in pregnant women include advanced gestational age, asthma, anemia and repeated courses of corticosteroid therapy for fetal lung maturation. The clinical presentation of CAP is not altered during pregnancy. Key points in the pregnant host encompass: (i) reduced maternal tolerance to hypoxia, due to physiological adaptations during pregnancy; (ii) heightened severity of some infections, notably viral pneumonias such as influenza, varicella or SARS-CoV-2 pneumonia; (iii) potentially deleterious fetal repercussions of infection and maternal hypoxia, with an increased risk of premature delivery and prematurity; (iv) the need for specific attention to the risk of fetal irradiation in the performance of possibly repeated radiological examinations and (v) therapeutic specificities arising from the possible embryo-fetal toxicity of certain anti-infectious agents. CAP prevention is premised on compliance with universal hygiene measures and on vaccination, which guarantees protection against severe forms of pneumonia not only in the mother (Streptococcus pneumoniae, seasonal flu, chickenpox, COVID-19), but also in the child during the first few months of life (whooping cough, RSV).

P-1545. Evaluation of Clinical Efficacy of Systemic Antibiotics for Treatment of Acute Pyelonephritis in Adults: A Network Meta-Analysis of Randomized Controlled Trials

Abstract Background Acute pyelonephritis, a severe form of urinary tract infection (UTI), poses significant health risks including kidney damage and urosepsis. Current clinical guidelines, last updated in 2010, primarily focus on women with uncomplicated UTIs, leaving a gap in recommendations for broader cases. Our study aims to bridge this gap by conducting an updated literature review to evaluate the efficacy of various antibiotics for acute pyelonephritis. Figure 1: Flow diagram of study selection Methods We conducted a systematic review of PubMed and Embase databases from inception to July 2023. We included randomized controlled trials (RCTs) involving adults (≥18 years) treated for acute pyelonephritis across various care settings. Our review focused on English-language articles examining intravenous (IV), oral, and IV-to-oral antibiotic treatments. Studies reporting outcomes specifically for pyelonephritis were eligible. We performed a frequentist network meta-analysis to evaluate clinical success, microbiological cure, and composite clinical or microbiological cure of different antibiotic therapies.Figure 2:Network plot of RCTs evaluating A) clinical cure, B) microbiological cure, and C) composite outcome of clinical cure or microbiological cure Results We included 37 RCTs (Figure 1). Due to data limitations, we assessed antibiotic classes rather than individual antibiotics (Figure 2). For clinical cure (n=1290, 11 RCTs), both fluoroquinolones (Odds Ratio [OR]: 3.71, 95% confidence interval [CI]: 1.30-10.55; P-score: 0.8215) and cephalosporins (OR: 3.45, 95% CI: 1.30-10.55; P-score: 0.7420) outperformed trimethoprim-sulfamethoxazole (TMP-SMX), with fluoroquinolones ranking highest in efficacy. For microbiological cure (n=1270, 11 RCTs), aminoglycosides (OR: 19.85, 95% CI: 1.62-243.61; P-score: 0.8373), fluoroquinolones (OR: 13.69, 95% CI: 1.73-108.03; P-score: 0.7785), cephalosporins (OR: 10.33, 95% CI: 1.20-88.73; P-score: 0.5395), and carbapenems (OR: 9.92, 95% CI: 1.14-86.61; P-score: 0.5394) were superior to TMP-SMX. Aminoglycosides ranked highest in efficacy. Regarding composite outcomes (n=2164, 6 RCTs), cephalosporins (P-score: 0.9898) and fluoroquinolones (0.7377) ranked highest in efficacy.Figure 3:Efficacy of systemic antibiotics in A) clinical cure, B) microbiological cure, and C) composite outcome of clinical cure or microbiological cure in adult patients with acute pyelonephritis.League tables display the results [OR (95% CI)] of pairwise meta-analysis in the upper right half, when available, and the results of the network meta-analysis in the left lower half. CI, confidence interval; OR, odds ratio; TMP-SMX, trimethoprim-sulfamethoxazole. Conclusion In adults with acute pyelonephritis, fluoroquinolones and cephalosporins demonstrate the highest efficacy probability, while TMP-SMX exhibits the lowest. Further studies are warranted to validate these findings. Disclosures All Authors: No reported disclosures

P-154. Malaria In Tunisia : Eradicated Or Still Endemic ?

Abstract Background Although malaria has been eradicated in Tunisia since 1979, our country remains exposed to the potential risk of resurgence. We aimed to study clinical, laboratory and therapeutic features of malaria. Methods We conducted a retrospective study including all patients hospitalized in the infectious disease department for malaria between 2000 and 2022. Results We encountered 92 cases, among whom 85 were males (92.4%). The mean age was 30±11 years. Fifteen patients received malaria chemoprophylaxis (16.3%). Returned travellers developed symoptoms after 10[5-25] days of returning home. Countries involved in importation were Ivory Coast (31.5%), Mauritania (8.9%) and Senegal (6.5%). The revealing symptoms included fever (90.2%), chills (87%), cephalalgia (79.3%) and diarrhea (26.1%). Arthromyalgia and vomiting were noted 46 cases (50%), each. Thrombopenia (65.2%), elevated C-reactive protein levels (43.5%), lymphopenia (39.1%), anemia (31.5%) and hepatic cytolysis (27.1%) were reported. There were 23 cases of severe malaria (25%). Palsmodium falciparum was identified in 68 cases (74%) and Plasmodium vivax in 8 cases (8.9%). Gametocytes were detected in 8.9% of the cases. Patients were treated with artemether/lumefantrine (71.7%) or quinine (19.6%). The disease evolution was favorable in 90 cases (97.8%). Apyrexia was noted after 2±1 days of treatment. Two patients were dead (2.2%). Conclusion Travellers to malaria endemic countries should be aware of the risk of malaria in order to follow preventive measures and to promptly consult in case of symptoms. An early diagnosis followed by the adequate treatment might prevent severe forms and death. Disclosures All Authors: No reported disclosures

Investigating neuropathological correlates of hyperactive and psychotic symptoms in dementia: a systematic review

IntroductionBehavioral and Psychological Symptoms of Dementia (BPSD) are common neuropsychiatric manifestations that complicate the clinical course of dementia and impact caregiving. Among these, the Hyperactivity–Impulsivity–Irritiability–Disinhibition–Aggression–Agitation (HIDA) and Psychosis (P) domains are particularly challenging to manage. Despite their prevalence, their underlying mechanisms and neuropathological correlates, remain poorly understood. This systematic review aims to elucidate the neuropathological basis of the HIDA and psychosis domains, exploring whether distinct proteinopathies and neural circuit dysfunctions are associated with these symptoms.MethodsThe review follows PRISMA guidelines, with a systematic search conducted across MEDLINE, CENTRAL, and EMBASE databases. Inclusion criteria involved studies exploring the neuropathology of the HIDA and psychosis domains in individuals with dementia. Records were screened using PICO software, and data quality was assessed using the Newcastle-Ottawa Scale (NOS) and CARE guidelines. A narrative synthesis was conducted due to heterogeneity in the data.ResultsFrom 846 records identified, 37 studies met inclusion criteria. Of the 18,823 cases analyzed, the most common diagnoses were Alzheimer's Disease (83.44%), Dementia with Lewy Bodies (5.37%), and Frontotemporal Dementia (13.40%). HIDA-P symptoms were distributed across all clinical diagnoses, with agitation (14.00%), delusions (11.60%), disinhibition (7.61%), and hallucinations (6.83%) being the most frequently reported behaviors. The primary neuropathological diagnosis was Alzheimer's Disease Neuropathologic Change (ADNC), present predominantly in intermediate to severe forms. The neuropathological analysis revealed the co-occurrence of multiple proteinopathies, particularly TAUopathy, TDP-43 pathology, and Lewy-related pathology (LRP), with the latter, in association with ADNC, reported in 15 studies.DiscussionHIDA-P symptoms were linked with overlapping involvement of different neural circuits, particularly the amygdala and the broader limbic system. Evidence suggests that TAUopathy and multiple proteinopathies in key brain regions, such as amygdala, are central to the development of these symptoms. In contrast, the contribution of beta-amyloid and vascular damage appears marginal in the genesis of HIDA and psychotic symptoms. No behavioral symptom is pathognomonic of a specific proteinopathy; rather, the topography and severity of lesions plays a more decisive role than their single molecular composition.Systematic review registrationINPLASY2024100082.

Case Report: Severe acute pancreatitis accompanied by gastric mucosal exfoliation hemorrhage: clinical alerts and novel insights

Acute pancreatitis (AP), a condition marked by its swift progression, substantial individual discrepancies, and profound concealment, poses a formidable challenge. Within its severe form, known as severe acute pancreatitis (SAP), the disease assumes an even more prevalent status, often entwined with dire complications such as pancreatic abscess, circulatory shock, and the direst of all, multiple organ failure. Regrettably, the conjunction of SAP with gastric mucosal exfoliation culminating in massive hemorrhage remains an exceptionally rare phenomenon within the clinical realm. This study delves into a retrospective analysis of a singular, yet remarkable clinical case, where SAP's therapeutic odyssey unexpectedly led to gastric mucosa stripping and catastrophic gastrointestinal bleeding. This paper endeavors to unravel the diagnostic intricacies, explore the treatment modalities, and prognosticate the outcome, all with the ultimate aim of fostering a heightened clinical vigilance and fostering a novel, nuanced understanding of SAP's exceptional complications within the intensive care arena. Furthermore, this study aspires to serve as a beacon of reference, illuminating the path for clinical practitioners confronted with such elusive yet critical scenarios.

Reshaping computational neuropsychiatry beyond synaptopathy.

Computational neuropsychiatry is a leading discipline to explain psychopathology in terms of neuronal message passing, distributed processing, and belief propagation in neuronal networks. Active Inference (AI) has been one of the ways of representing this dysfunctional signal processing. It involves that all neuronal processing and action selection can be explained by maximizing Bayesian model evidence, or minimizing variational free energy. Following these principles, it has been suggest that dysconnection in neuronal network results in aberrant belief updating and erroneous inference, leading to psychiatric and neurologic symptoms. However, there is a classic distinction between disorders of inference (or synaptopathy - including the majority of psychiatric disorders), and disorders of brain function (including vascular neurological pathologies and severe forms of tauopathy and synucleinopathies). This distinction is generally based on the idea that synaptopathies impair neuromodulatory precision weighting, leading to rigid inferences or heightened sensitivity to noise, while disorders of brain function are linked to damage in the nervous system (disconnection). This makes it challenging to apply the logic of the free energy principle. We suggest that this distinction will enable future models of neuropsychiatric symptoms to be improved by considering more than neuronal message passing.

SRAGE as a Prognostic Biomarker in ARDS: Insights from a Clinical Cohort Study

Background and Objectives: Acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury with high mortality, characterized by hypoxemic respiratory failure and diffuse lung damage. Despite advancements in care, no definitive biomarkers have been established for ARDS diagnosis and prognostic stratification. Soluble receptor for advanced glycation end-products (sRAGE), a marker of alveolar epithelial injury, has shown promise as a prognostic indicator in ARDS. This study evaluates sRAGE’s utility in predicting 28-day mortality. Materials and Methods: A retrospective cohort study was conducted at a tertiary care ICU in Serbia from January 2021 to June 2023. Adult patients meeting the Berlin definition of ARDS were included. Exclusion criteria included pre-existing chronic respiratory diseases and prolonged mechanical ventilation before diagnosis. Serum sRAGE levels were measured within 48 h of ARDS diagnosis using enzyme-linked immunosorbent assay (ELISA). Clinical severity scores, laboratory markers, and ventilatory parameters were recorded. Logistic regression and survival analyses were used to assess the prognostic value of sRAGE for 28-day mortality. Results: A cohort of 121 patients (mean age 55.5 years; 63.6% male) was analyzed. Non-survivors exhibited higher median sRAGE levels than survivors (5852 vs. 4479 pg/mL, p = 0.084). The optimal sRAGE cut-off for predicting mortality was &gt;16,500 pg/mL (sensitivity 30.4%, specificity 86.9%). Elevated sRAGE levels were associated with greater disease severity and an increased risk of 28-day mortality in ARDS patients, highlighting its potential as a prognostic biomarker. The main findings, while indicative of a trend toward higher sRAGE levels in non-survivors, did not reach statistical significance. Conclusions: The main findings, while indicative of a trend toward higher sRAGE levels in non-survivors, did not reach statistical significance (p = 0.084). sRAGE demonstrates potential as a prognostic biomarker in ARDS and has moderate correlation with 28-day mortality. Integrating sRAGE with other biomarkers could enhance risk stratification and guide therapeutic decisions. The retrospective design limits the ability to establish causation, underscoring the need for multicenter prospective studies.

Prolonged Corticosteroid Use in the Treatment of Tuberculous Meningoencephalitis: A Case Report

Tuberculous meningoencephalitis is a rare manifestation of Mycobacterium tuberculosis (Mtb), with the most severe form and highest mortality. It can cause multiple complications, and treatment is difficult, as drugs cannot properly diffuse through the haemato-encephalitic barrier. We reported the case of a 17-year-old female patient who was admitted to the emergency room department with a fever for previous two weeks (up to 39 °C), dizziness, difficulty walking, and weight loss. Magnetic resonance imaging indicated possible meningoencephalitis, and a CT scan of the lungs visualised miliary infiltrates in both lungs. After repeated tests, Mtb DNA was found in the bronchial wash, cerebrospinal fluid, faeces, and urine via an Xpert/Rif Ultra test. Treatment was started with isoniazid, rifampicin, ethambutol, pyrazinamide, and corticosteroids as well. Although treatment was initiated within the first few days in the hospital, a reduction in glucocorticoid dosage worsened the patient’s neurological state, making treatment even more challenging. Prolonged use of glucocorticoids led to an improvement in the stage of the condition. Further, over time, the patient’s condition improved. Pulmonary infiltrations were not found after 2.5 months of starting therapy. Conclusions: Timely treatment is crucial for improving the prognosis of patients with miliary tuberculosis and tuberculous meningoencephalitis. Prompt recognition of symptoms and accurate diagnosis are essential to initiate effective treatment strategies. In this patient’s case, prolonged use of corticosteroids reduced neurologic complications, and ongoing treatment gradually improved the patient’s condition.