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Holocarboxylase synthase (HCS) deficiency is an extremely rare metabolic disorder typically presenting as severe neonatal metabolic acidosis, lethargy, hypotonia, vomiting, and seizures. This report describes two siblings in a family with late-onset forms of HCS deficiency. The younger sister presented at the age of 11 years and manifested as acute metabolic acidosis, which promptly resolved following rehydration and biotin administration. The results of the organic urine profile confirmed multiple carboxylase deficiency, and genetic testing revealed a novel pathogenic variant in the HLCS gene (NM_000411.8) in the homozygous state: c.995A>G; p. (Gln332Arg). No further decompensation was observed for her during the 3-year follow-up period. His older brother was diagnosed at the age of 23 years-old through biochemical tests, without any history of acidotic decompensation. A mini-review of HCS deficiency with late onset (>1 year) or early onset (<1 month) revealed that splice variants are associated with late onset, while both variants p. (Leu216Arg) and p. (Leu237Pro) are associated with early onset. However, the majority of genotypes do not show a clear correlation with the timing of HCS deficiency onset. The most significant point here is the description of extremely late-onset cases of HCS deficiency. This can prompt metabolic investigations and raise suspicion of this rare disease in cases of unexplained metabolic acidosis, even beyond early childhood. [ABSTRACT FROM AUTHOR]

Objective: Late-onset systemic lupus erythematosus (LoSLE) is known to possess characteristics different from those of early-onset SLE (EoSLE), thereby making their diagnosis difficult. This study aimed to assess the characteristic features of LoSLE in Japan, a model country with a super-aged society. Methods: Data were obtained from the Lupus Registry of Nationwide Institutions, which includes a multicenter cohort of patients with SLE in Japan who satisfied the 1997 American College of Rheumatology revised classification criteria for SLE. Data were compared between patients with LoSLE (≥50 years old at onset) and EoSLE (<50 years old at onset). To identify factors associated with LoSLE, binary logistic regression was used for the multivariate analysis, and missing values were complemented by multiple imputations. We also conducted a sub-analysis for patients diagnosed within 5 years of onset. Results: Out of 929 enrolled patients, 34 were excluded owing to a lack of data regarding onset age. Among the 895 remaining patients, 100 had LoSLE, whereas 795 had EoSLE. The male-to-female ratio was significantly higher in the LoSLE group than in the EoSLE group (0.32 vs 0.11, p < 0.001). With respect to SLEDAI components at onset, patients with LoSLE exhibited a higher frequency of myositis (11.9% vs 3.75%, p = 0.031), lower frequency of skin rash (33.3% vs 67.7%, p < 0.001), and lower frequency of alopecia (7.32% vs 24.7%, p = 0.012). No significant differences in overall disease activity at onset were observed between the two groups. Regarding medical history, immunosuppressants were more commonly used in EoSLE. A multivariate analysis revealed that a higher male proportion and a lower proportion of new rash at onset were independent characteristic features of LoSLE. We also identified late onset as an independent risk factor for a high SDI score at enrollment and replicated the result in a sub-analysis for the population with a shorter time since onset. Conclusions: We clarified that LoSLE was characterized by a higher male proportion, a lower frequency of skin rash and a tendency to organ damage. Now that the world is faced with aging, our results may be helpful at diagnosis of LoSLE. [ABSTRACT FROM AUTHOR]

Background: Young-onset AD (YOAD) typically occurs before the age of 65 and affects less than 6% of all people diagnosed with AD. There is a lack of research on differences between decision-making capacity and awareness according to age at onset of dementia. Objective: We investigated the relationship between decision-making capacity and awareness domains in people with young- (YOAD) and late-onset Alzheimer's disease (LOAD). Methods: A cross-sectional study included 169 consecutively selected people with AD and their caregivers (124 people with LOAD and 45 people with YOAD). Results: People with YOAD were more cognitively impaired, but more aware of their cognitive deficits and health condition, with moderate effect sizes. All people with AD presented deficits in the domains of decision-making capacity, with more impairment in understanding. There was a relationship between understanding and awareness domains, such that awareness was particularly important for decision-making capacity in the YOAD group. Conclusions: Better awareness involved better understanding in the YOAD group. Clinically, our findings shed light on the need to consider the differences in the domains of awareness and their relationship with other clinical aspects such as decision-making capacity according to age at onset of AD. Furthermore, our data can suggest hypotheses for larger and more robust prospective studies. [ABSTRACT FROM AUTHOR]

Outcome and predictors of early- and late-onset septic shock are still controversial. The aim of the study was to compare the relevant predictors of 28-day mortality in early- and late-onset septic shock and other non-septic critical illnesses. We conducted a prospective, observational, pilot study. A group of 46 patients with early septic shock and 42 nonseptic critically ill patients from the emergency department and 56 patients with late septic shock from the hospital were enrolled. On admission to the ICU, the most important potential predictors of 28-day mortality were assessed. In terms of predicting 28-day mortality, a higher mNUTRIC score was the only common predictor for all three groups. Multi-drug resistant (MDR) bacterial aetiology was a common predictor in both forms of septic shock. Older age, female gender, increased neutrophilto-lymphocyte ratio (NLR) and increased need for vasoactive agents were common predictors in late septic shock and non-septic critically ill patients. Increased red blood cell distribution width coefficient of variation (RDW-CV) was predictor in early septic shock and non-septic critically ill patients. Central venous-arterial carbon dioxide difference (Pcv-aCO2) was predictor in patients with early septic shock. Inflammatory index and MDR carrier status were predictors in non-septic critically ill patients. A higher mNUTRIC score is a predictor of 28-day mortality in early and late septic shock and in critically ill non-septic patients. MDR aetiology was predictive of 28-day all-cause mortality in both types of septic shock, and Pcv-aCO2 was predictive in patients with early septic shock. [ABSTRACT FROM AUTHOR]

Abstract Background Cognitive and behavioral changes in ALS are featured as an integral part of the disease. A noticeable proportion of ALS patients present with a full-blown picture of frontotemporal dementia, which is considered the most common form of cognitive impairment in ALS. Results A total of 30 ALS cases and 30 sex, age and education matched healthy controls were enrolled; their sociodemographic data were statistically insignificant as regards (age, sex, education). Regarding cognitive and behavioral assessment using the ECAS-EG, both ECAS mean total score and subdomains mean scores were significantly lower in ALS patients compared to controls (p-value

Background: Cognitive and behavioral changes in ALS are featured as an integral part of the disease. A noticeable proportion of ALS patients present with a full-blown picture of frontotemporal dementia, which is considered the most common form of cognitive impairment in ALS. Results: A total of 30 ALS cases and 30 sex, age and education matched healthy controls were enrolled; their sociodemographic data were statistically insignificant as regards (age, sex, education). Regarding cognitive and behavioral assessment using the ECAS-EG, both ECAS mean total score and subdomains mean scores were significantly lower in ALS patients compared to controls (p-value < 0.001), with statistically significant relation between ALS clinical staging and ECAS total scores (p-value < 0.001). Furthermore, it was found that mean scores of nearly all ECAS domains are lower in early-onset group with longer duration of illness than late onset with short duration of illness but with a non-statistically significant difference. Conclusion: ALS causes significant cognitive impairment, with relation between functional status and clinical staging of the disease with the severity of cognitive and behavioral dysfunctions and although early-onset cases had lower score on ECAS compared to those with late onset, but it was non-significant. [ABSTRACT FROM AUTHOR]

The clinical course and serological profile of the late-age onset systemic sclerosis (LAO SSc) and the early-age onset SSc (EAO SSc) was compared. The study enrolled 157 patients that fulfilled the American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) classification criteria for systemic sclerosis (SSc). Among them, 69 had diffuse cutaneous SSc (dcSSc) and 88 limited cutaneous SSc (lcSSc). Within this population, 39 patients developed the disease over the age of 60 years old (LAO SSc) and 118 prior to that age (EAO SSc). The subtype of SSc, the incidence of internal organ involvement, the prevalence of malignancy, mortality, and serological profile were compared between both groups. The LAO SSc was observed in 39 of total 157 patients with SSc and exhibited a notably higher prevalence of pulmonary arterial hypertension (p = 0.014), heart involvement (p = 0.0014), and renal involvement (p = 0.0002). The occurrence of arthralgias was less common in the LAO SSc group (p = 0.02) than in the EAO SSc group. Furthermore, in the LAO SSc group, the prevalence of anti –RNA polymerase III antibodies (p = 0.008) and antiPM/Scl antibodies (p = 0.048) were significantly lower than in the EAO SSc group. On the other hand, higher anti-Th/To antibody levels (p = 0.014) were recorded in the LAO SSc group. Approximately 25% of SSc patients experienced a delayed onset of the disease after the age of 60 years old. Some clinical and serological features of late-onset SSc were markedly different from that in early-onset disease. Particularly noteworthy is the fact that involvement of internal organs such as heart and kidneys, as well as pulmonary arterial hypertension were much more often observed among patients with LAO SSc which in our suggestion may be referred to age-related co-morbidities. Key Points • Significant differences in clinical and serological profile of the disease were found between late-age onset (LAO) and early-age onset (EAO) SSc. • Incidence of dcSSc as well as prevalence of anti–RNA polymerase III and anti-PM/Scl antibodies were found to be lower in patients over 60 years old compared to those before 60, but regardless of the age of the disease onset. • Internal organ morbidity, notably pulmonary arterial hypertension, renal impairment and heart disease were significantly more common in elder SSc patients as well as in those with late disease onset. • These findings may suggest an impact of age-related co-morbidities on the course of late-age onset SSc. [ABSTRACT FROM AUTHOR]

Anderson–Fabry Disease (AFD) is a rare, X-linked lysosomal storage disorder caused by a mutation in the α-Galactosidase A gene resulting in α-Galactosidase A enzyme (α-Gal A) deficiency. The metabolic defect leads to the progressive accumulation of glycosphingolipids and the structural and functional impairment of affected organs. Due to the inheritance pattern, male patients are hemizygous with more severe manifestations of the disease as compared to females who, in most cases, are heterozygous with delayed and variable clinical presentation caused by uneven X-chromosome inactivation. Fabry disease cases are often identified by targeted screening programs in high-risk groups, such as in patients with end-stage renal disease, premature stroke, or unexplained cardiomyopathy. Here, we describe a unique case of a homozygous female patient identified by a nationwide screening program in hypertrophic cardiomyopathy patients. Before the systematic screening, the patient had a diagnosis of hypertrophic obstructive cardiomyopathy and was treated accordingly, including with alcohol septal ablation to reduce the obstructive gradient. The confirmation of Fabry disease led to the discovery of the same variant in several members of her family. The identified variant was c.644A>G, p.Asn215Ser (p.N215S), which is known to cause predominant cardiac involvement with late onset of the disease. This variant is amenable to oral therapy with the small-molecule chaperone migalastat, which was started and then interrupted due to the recurrence of the patient's migraine and then re-initiated again after two years. During this period, the patient received enzyme replacement therapy with agalsidase beta but developed progressively worsening venous access. Our case illustrates the importance of the systematic screening of patients with clinical evidence of hypertrophic cardiomyopathy in whom the routine diagnostic process fails to discover Fabry disease, in particular variants with late-onset cardiac manifestations. Many of the late-onset variants are amenable to orally active therapy with migalastat, which significantly improves the comfort of the treatment. Its long-term results are being analyzed by a large international "Follow-me" registry, which was designed to verify the validity of pivotal trials with migalastat in Fabry disease. [ABSTRACT FROM AUTHOR]

Early-onset Alzheimer's disease (EOAD), defined as Alzheimer's disease onset before 65 years of age, has been significantly less studied than the "classic" late-onset form (LOAD), although EOAD often presents with a more aggressive disease course, caused by variants in the APP, PSEN1, and PSEN2 genes. EOAD has significant differences from LOAD, including encompassing diverse phenotypic manifestations, increased genetic predisposition, and variations in neuropathological burden and distribution. Phenotypically, EOAD can be manifested with non-amnestic variants, sparing the hippocampi with increased tau burden. The aim of this article is to review the different genetic bases, risk factors, pathological mechanisms, and diagnostic approaches between EOAD and LOAD and to suggest steps to further our understanding. The comprehension of the monogenic form of the disease can provide valuable insights that may serve as a roadmap for understanding the common form of the disease. [ABSTRACT FROM AUTHOR]

Holocarboxylase synthase (HCS) deficiency is an extremely rare metabolic disorder typically presenting as severe neonatal metabolic acidosis, lethargy, hypotonia, vomiting, and seizures. This report describes two siblings in a family with late-onset forms of HCS deficiency. The younger sister presented at the age of 11 years and manifested as acute metabolic acidosis, which promptly resolved following rehydration and biotin administration. The results of the organic urine profile confirmed multiple carboxylase deficiency, and genetic testing revealed a novel pathogenic variant in the HLCS gene (NM_000411.8) in the homozygous state: c.995A>G; p. (Gln332Arg). No further decompensation was observed for her during the 3-year follow-up period. His older brother was diagnosed at the age of 23 years-old through biochemical tests, without any history of acidotic decompensation. A mini-review of HCS deficiency with late onset (>1 year) or early onset (

Anderson–Fabry Disease (AFD) is a rare, X-linked lysosomal storage disorder caused by a mutation in the α-Galactosidase A gene resulting in α-Galactosidase A enzyme (α-Gal A) deficiency. The metabolic defect leads to the progressive accumulation of glycosphingolipids and the structural and functional impairment of affected organs. Due to the inheritance pattern, male patients are hemizygous with more severe manifestations of the disease as compared to females who, in most cases, are heterozygous with delayed and variable clinical presentation caused by uneven X-chromosome inactivation. Fabry disease cases are often identified by targeted screening programs in high-risk groups, such as in patients with end-stage renal disease, premature stroke, or unexplained cardiomyopathy. Here, we describe a unique case of a homozygous female patient identified by a nationwide screening program in hypertrophic cardiomyopathy patients. Before the systematic screening, the patient had a diagnosis of hypertrophic obstructive cardiomyopathy and was treated accordingly, including with alcohol septal ablation to reduce the obstructive gradient. The confirmation of Fabry disease led to the discovery of the same variant in several members of her family. The identified variant was c.644A>G, p.Asn215Ser (p.N215S), which is known to cause predominant cardiac involvement with late onset of the disease. This variant is amenable to oral therapy with the small-molecule chaperone migalastat, which was started and then interrupted due to the recurrence of the patient’s migraine and then re-initiated again after two years. During this period, the patient received enzyme replacement therapy with agalsidase beta but developed progressively worsening venous access. Our case illustrates the importance of the systematic screening of patients with clinical evidence of hypertrophic cardiomyopathy in whom the routine diagnostic process fails to discover Fabry disease, in particular variants with late-onset cardiac manifestations. Many of the late-onset variants are amenable to orally active therapy with migalastat, which significantly improves the comfort of the treatment. Its long-term results are being analyzed by a large international “Follow-me” registry, which was designed to verify the validity of pivotal trials with migalastat in Fabry disease.

Identified as the pathogenic genes of Alzheimer's disease (AD), APP, PSEN1, and PSEN2 mainly lead to early-onset AD, whose course is more aggressive, and atypical symptoms are more common than sporadic AD. Here, a novel missense mutation, APP E674Q (also named “Shanghai APP”), was detected in a Chinese index patient with typical late-onset AD (LOAD) who developed memory decline in his mid-70s. The results from neuroimaging were consistent with AD, where widespread amyloid β deposition was demonstrated in 18F-florbetapir Positron Emission Tomography (PET). APP E674Q is close to the β-secretase cleavage site and the well-studied Swedish APP mutation (KM670/671NL), which was predicted to be pathogenic in silico. Molecular dynamics simulation indicated that the E674Q mutation resulted in a rearrangement of the interaction mode between APP and BACE1 and that the E674Q mutation was more prone to cleavage by BACE1. The in vitro results suggested that the E674Q mutation was pathogenic by facilitating the BACE1-mediated processing of APP and the production of Aβ. Furthermore, we applied an adeno-associated virus (AAV)-mediated transfer of the human E674Q mutant APP gene to the hippocampi of two-month-old C57Bl/6 J mice. AAV-E674Q-injected mice exhibited impaired learning behavior and increased pathological burden in the brain, implying that the E674Q mutation had a pathogenicity that bore a comparison with the classical Swedish mutation. Collectively, we report a strong amyloidogenic effect of the E674Q substitution in AD. To our knowledge, E674Q is the only pathogenic mutation within the amyloid processing sequence causing LOAD.

Aim: To determine the prevalence of group B Streptococcus (GBS) carriage among parturient women and neonates, and the relative risk of vertical transmission, the relative risk of early and late‐onset GBS and the pooled incidence of early‐late‐onset GBS infection. Methods: A systematic search of relevant cohort studies from three electronic databases to identify all relevant studies published up to 7 November 2022. The review was conducted in accordance with PRISMA guidelines. Estimates were pooled using random‐effects meta‐analyses. Results: A total of 54 articles with 355 787 matched pairs of parturient women and neonates from 30 countries were included in the analysis. The pooled prevalence of GBS colonisation was 17.1% among the pregnant women and 1.0% among neonates. The pooled prevalence of vertical transmission of GBS was 4.5% and the pooled relative risk of GBS colonisation of neonates born to mothers with GBS was 9.9. Conclusion: We support the implementation of targeted intrapartum antibiotic prophylaxis for all women who are positive for GBS as well as women with risks factors for early onset GBS in their infants regardless of their GBS colonisation status. [ABSTRACT FROM AUTHOR]

Background: Generally infrequent, multiple sclerosis (MS) with late onset (LOMS) is characterized by an onset over the age of 50 and a mainly progressive course, while relapsing–remitting (RR) forms are less frequently observed and explored. This study aimed to characterize a large cohort of MS patients with RRMS at onset to assess the baseline factors related to the worst disability trajectories and explore the role of LOMS. Methods: The data were extracted from the Italian MS Register (IMSR). Disability trajectories, defined using at least two and up to twenty expanded disability status scale (EDSS) assessments annually performed, were implemented using group-based trajectory models (GBTMs) to identify different groups with the same trajectories over time. MS profiles were explored using multinomial logistic regression. Results: A total of 16,159 RR patients [1012 (6.26%) presented with LOMS] were analyzed. The GBTM identified four disability trajectories. The group with the most severe EDSS trend included 12.3% of the patients with a mean EDSS score > 4, which increased over time and exceeded 6 score. The group with medium severity EDSS trend comprised 21.9% of the patients and showed a change in EDSS > 3 scores over time. The largest group with 50.8% of patients reported a constant EDSS of 2 score. Finally, the benign group comprised 14.9% of the patients with a low and constant EDSS of 1 score over time. The probability of being in the worst groups increased if the patient was male; had LOMS or experienced brainstem, spinal, or supratentorial symptoms. Conclusions: Four MS severity profiles among RRMS patients in the IMSR have been reported, with LOMS being associated with a rapid worsening of EDSS scores. These findings have important implications for recognizing and managing how older age, aging, and age-related factors interact with MS and its evolution. [ABSTRACT FROM AUTHOR]

Objective: To analyze the different clinical features of patients with early-onset (EO-NMOSDs) and late-onset neuromyelitis optica spectrum diseases (LO-NMOSDs). Methods: A total of 51patients with neuromyelitis optica spectrum disease who were diagnosed in our hospital for the first time from January 2015 to December 2022 were included in the First Affiliated Hospital of Hainan Medical College and divided into 22 cases in the EO-NMOSDs group and 29 cases in the LO-NMOSDs group according to whether the age of onset was ≥ 50 years old. The basic data, Extended Disability Status Scale (EDSS) score, blood and cerebrospinal fluid test indicators of the two groups were statistically analyzed. Results: There were no significant differences in demographic characteristics, clinical features and serum AQP-4 antibody positivity rate between the two groups (all P>0.05), and there were significant differences in triglycerides (TG), low-density lipoprotein (LDL), apolipoprotein A (APOA), apolipoprotein B (APOB) and lipoprotein a (P=0.010, P=0.048, P=0.014, P=0.061, P=0.001, respectively), and cerebrospinal fluid LDH, There were significant differences between microprotein quantification and EDSS score (P=0.018, P=0.034, P=0.025, respectively), and the level of microprotein quantification in cerebrospinal fluid of LO-NMOSDs had a certain correlation with the degree of disability (r=0.52, P<0.03). Conclusion: LO-NMOSDs and EONMOSDs group patients have similar demographic characteristics, serum AQP-4 antibody positive rate and clinical features, but compared with EO-NMOSDs, patients in LO-NMOSDs group are prone to abnormal lipid metabolism, higher trace proteins in cerebrospinal fluid and more likely to be disabled, and among LO-NMOSDs, the higher the trace protein in the cerebrospinal fluid, the more severe the disability status of patients. [ABSTRACT FROM AUTHOR]

Neonatal sepsis is traditionally classified as early-onset sepsis (EOS) and late-onset sepsis (LOS) disease categories. This paradigm was based on observed epidemiological data from high income settings. However, increasing availability of microbiology results from diverse settings challenges these assumptions, necessitating re-examination of neonatal sepsis classifications. To review the literature describing the aetiology of EOS and LOS in hospitalized neonates with stratification of pathogen spectrum by low- (LIC), middle- (MIC) and high-income (HIC) country settings, to critically re-examine the continued appropriateness of the 'EOS vs. LOS' sepsis paradigm in all settings. PubMed was searched for peer-reviewed English full-text articles published from inception up until 8 August 2022. Studies often report on either EOS or LOS, rather than both. We identified only 49 original articles reporting on pathogen distribution of both EOS and LOS in the same hospital setting. Clear differences in sepsis aetiology were shown between LIC, MIC and HIC settings, with increasing importance of Klebsiella pneumoniae and decreasing importance of Group B Streptococcus in the first 72 hours of life in LIC and MIC. The concept of 'EOS vs. LOS' may be less useful for predicting the pathogen spectrum of neonatal sepsis in LIC and MIC, but the paradigm has shaped reporting of neonatal sepsis, and our understanding. Future neonatal sepsis reporting should utilize strengthening the reporting of observational studies in epidemiology for newborn infection (STROBE-NI) reporting guidelines and clearly describe timing of infection by day, and variation in pathogen spectrum across the neonatal period. Data identified in this review challenge the generalizability of the prevailing EOS/LOS paradigm in LIC and MIC. [ABSTRACT FROM AUTHOR]

A 4-year-old boy presented with acute-onset autoimmune cytopenia with severe, persistent lymphopenia, autoimmune thyroiditis, elevated IgE and glucose 6-phosphate dehydrogenase enzyme deficiency. In immunologic evaluation, lower T, B and natural killer cells and higher levels of adenosine deaminase (ADA) metabolites were observed. The compound heterozygous novel ADA gene mutations causing ADA deficiency were detected. Successful immunologic and metabolic cure was achieved with enzyme replacement therapy, followed by reduced intensity conditioning hematopoietic stem cell transplantation from a matched unrelated donor. An interesting aspect of this patient is the detection of novel compound heterozygous mutations without consanguinity and a secondary outcome is the recovery of glucose 6-phosphate dehydrogenase deficiency after hematopoietic stem cell transplantation. [ABSTRACT FROM AUTHOR]

Abstract Background Much longitudinal research has been carried out on non-suicidal self-injury (NSSI) during the last decades, but there still is a lack of studies of the individual developmental pathways of NSSI from adolescence into young adulthood. The aim of the present study was to investigate individual developmental pathways of repetitive non-suicidal self-injury (repNSSI) from adolescence into young adulthood, including adolescent predictors and psychological outcomes in young adulthood. Three developmental pathways were targeted: stable adolescence-limited repNSSI; repNSSI prolonged into young adulthood; and late-onset repNSSI; with no repNSSI as comparison. Methods Data were taken from a cohort of compulsory school students (N = 1064) in grades 7–8 in a Swedish municipality. The cohort was followed longitudinally, and this study included all individuals (n = 475) with NSSI data from three waves: T1 (when they were 13–15 years old); T2 (one year later); and T3 (ten years later). RepNSSI was operationalized as self-reports of at least 5 instances of NSSI during the past six/twelve months. Results The two pathways that involved stable repNSSI were observed significantly more often than expected by chance, with the strongest overrepresentation for the Prolonged RepNSSI pathway. Still, most adolescents who engaged in stable repNSSI stopped this before reaching young adulthood. Those who stopped did not, however, show a significantly better psychological adjustment in young adulthood than those who continued. Compared to participants with no repNSSI, participants who had stopped still reported significantly more stress, anxiety, and emotional dysregulation. As to the prediction of late onset NSSI, the findings were less robust, but sporadic NSSI at T1 and poor sleep at T2 were significant predictors, whereas depressive symptoms fell just short of significance at both timepoints. Conclusions The present results indicate that among adolescents who engage in stable adolescent repNSSI (1) significantly more individuals than expected by chance still engage in repNSSI ten years later, and (2) those who stop engaging in repNSSI do not show significantly better psychological adjustment than those who still engage in it. The present findings also indicate that late onset of repNSSI as reported in young adulthood to some extent is predictable from symptom measures ten years earlier.

Abstract Background Food protein-induced enterocolitis syndrome (FPIES) is a delayed, non-IgE-mediated food allergy. This syndrome was once thought to be rare, but emerging literature suggests an increasing incidence along with more foods being implicated. Also, with the introduction of guidelines on early peanut introduction, peanut-induced FPIES seems to be increasing in Australia and USA. Although most patients are diagnosed with FPIES within the first year of life, most commonly with food triggers to cow’s milk or soy, other phenotypes exist in comparison to this classic presentation. In this case report, we present a patient with late onset of acute FPIES at age 3 to walnut. Case Presentation We describe a case of FPIES in a 12-year-old boy who had recurrent episodes of repetitive emesis, that began at age 3, each time after consuming walnuts. Mom does not give a history of intentional feeding (or avoidance) of walnut and/ or pecans. She also described possible reactions with pine nuts and macadamia. He was assessed with an oral food challenge to walnut, which triggered an episode of acute FPIES. He developed vomiting with onset 2 h post-ingestion, pallor, lethargy, and required an emergency department visit for anti-emetic medications and oral rehydration therapy. He improved on the therapy and now avoids cashew, pistachio, hazelnuts, walnuts, pecans, pine nuts, and macadamia nuts. Conclusions This case report adds to the limited literature that exists on culprit food allergens in FPIES. We present an acute FPIES triggered by the ingestion of walnuts. The diagnosis, common food triggers, and natural history of FPIES are described. There remains a lack of information on the natural history of FPIES, especially towards uncommon food triggers and on FPIES that present beyond infancy.

Objectives: We performed a clinical study comparing early-onset and late-onset conventional colorectal adenomas (CCRAs) since little is known about the differences in their characteristics. Methods: Pearson's chi-square test and the Kruskal‒Wallis test were used to compare basic information. MCAR tests and multiple imputation were performed to complete missing values. Multivariate logistic analysis and propensity score matching were used to identify the risk factors for recurrence. Results: We included 2793 patients (688 with early-onset CCRAs and 2105 with late-onset CCRAs) from January 2017 to December 2021. Patients with early-onset CCRAs had higher levels of Hb, ALB, and triglycerides but lower HDL levels and N/L ratios. Moreover, we found that more early-onset CCRAs were in the left colon than late-onset CCRAs, and the size of early-onset CCRAs was larger. Early-onset CCRAs tended to lack pedicles compared to late-onset CCRAs. Additionally, the ratio of EMR and APC in early-onset CCRAs was higher than that in late-onset CCRAs, and the ratio of ESD and surgery for late-onset CCRAs was higher. We found that age ≥ 50 years, abnormal vessels, drinking alcohol, and DB and ALB levels may be risk factors for recurrence, while the LDL level may be a protective factor. Finally, analysis of cumulative recurrence rates after PSM showed that patients with late-onset CCRAs exhibited higher recurrence rates (P < 0.05). Conclusion: Compared with late-onset CCRAs, early-onset CCRAs were associated with higher triglyceride levels, lower HDL levels, and larger tumor volumes. Age ≥ 50 years, abnormal vessels, alcohol consumption, and DB and ALB levels were independent risk factors for recurrence of CCRAs. [ABSTRACT FROM AUTHOR]

Background: Much longitudinal research has been carried out on non-suicidal self-injury (NSSI) during the last decades, but there still is a lack of studies of the individual developmental pathways of NSSI from adolescence into young adulthood. The aim of the present study was to investigate individual developmental pathways of repetitive non-suicidal self-injury (repNSSI) from adolescence into young adulthood, including adolescent predictors and psychological outcomes in young adulthood. Three developmental pathways were targeted: stable adolescence-limited repNSSI; repNSSI prolonged into young adulthood; and late-onset repNSSI; with no repNSSI as comparison. Methods: Data were taken from a cohort of compulsory school students (N = 1064) in grades 7–8 in a Swedish municipality. The cohort was followed longitudinally, and this study included all individuals (n = 475) with NSSI data from three waves: T1 (when they were 13–15 years old); T2 (one year later); and T3 (ten years later). RepNSSI was operationalized as self-reports of at least 5 instances of NSSI during the past six/twelve months. Results: The two pathways that involved stable repNSSI were observed significantly more often than expected by chance, with the strongest overrepresentation for the Prolonged RepNSSI pathway. Still, most adolescents who engaged in stable repNSSI stopped this before reaching young adulthood. Those who stopped did not, however, show a significantly better psychological adjustment in young adulthood than those who continued. Compared to participants with no repNSSI, participants who had stopped still reported significantly more stress, anxiety, and emotional dysregulation. As to the prediction of late onset NSSI, the findings were less robust, but sporadic NSSI at T1 and poor sleep at T2 were significant predictors, whereas depressive symptoms fell just short of significance at both timepoints. Conclusions: The present results indicate that among adolescents who engage in stable adolescent repNSSI (1) significantly more individuals than expected by chance still engage in repNSSI ten years later, and (2) those who stop engaging in repNSSI do not show significantly better psychological adjustment than those who still engage in it. The present findings also indicate that late onset of repNSSI as reported in young adulthood to some extent is predictable from symptom measures ten years earlier. [ABSTRACT FROM AUTHOR]

A 35‐year‐old woman experienced left back pain after a 2‐h flight. She reported coughing and left back pain 1 day later when she presented to our hospital. Chest computed tomography showed pneumothorax of the left lung, bronchiectasis, thickening of the bronchial wall, nodules, and cavity lesions in both lungs. A pulmonary function test revealed obstructive ventilation disorder with normal lung diffusing capacity. She had a history of haematopoietic stem cell transplantation (HSCT) at 2 years and 3 months of age during the second disease remission of acute myeloid leukaemia. She was diagnosed with chronic graft‐versus‐host disease (cGVHD) presenting with bronchiolitis obliterans (BO) and pleuroparenchymal fibroelastosis (PPFE). To our knowledge, this is the first reported case of BO and PPFE diagnosed more than 30 years after HSCT. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is a life-threatening pregnancy complication for the mother and fetus. High concentrations of human chorionic gonadotrophin (hCG) and soluble fms-like tyrosine kinase-1 (sFLt-1) during pregnancy may have a role in the pathophysiology of PE. Swimming Exercise (SE) is one of the physical activities recommended for pregnant women and carries a minimal risk. This study is aimed at analyzing the interaction between the conditions of rats (normal and PE), the onset of PE (early onset and late onset), and the time of SE (SE 0 minutes; SE 5 minutes; SE 10 minutes) on the concentrations of B-CG and sFlt-1 in the Rattus norvegicus (R. norvegicus) model of PE. 72 R. norvegicus were included in this study and divided into 12 experimental groups (each group n = 6 individuals). R. norvegicus PE was prepared by inducing L-Nitro-Arginine-Methyl Ester (L-NAME) at a 75 mg/kg BW/day dose. The determination of PE was supported by the observation of differences in the values of urine protein (PU), urine glucose (GU), and urine leukocytes (LU) in R. norvegicus before and after injection of L-NAME. The three-factorial statistical test showed a significant interaction between the concentration of B-CG and the condition of R. norvegicus, the onset of PE, and the time of SE, with a p-value

Early-onset Alzheimer’s disease (EOAD), defined as Alzheimer’s disease onset before 65 years of age, has been significantly less studied than the “classic” late-onset form (LOAD), although EOAD often presents with a more aggressive disease course, caused by variants in the APP, PSEN1, and PSEN2 genes. EOAD has significant differences from LOAD, including encompassing diverse phenotypic manifestations, increased genetic predisposition, and variations in neuropathological burden and distribution. Phenotypically, EOAD can be manifested with non-amnestic variants, sparing the hippocampi with increased tau burden. The aim of this article is to review the different genetic bases, risk factors, pathological mechanisms, and diagnostic approaches between EOAD and LOAD and to suggest steps to further our understanding. The comprehension of the monogenic form of the disease can provide valuable insights that may serve as a roadmap for understanding the common form of the disease.

Objective: To compare derangement of cerebrospinal fluid markers in neonates with early and late-onset sepsis managed at the Neonatal Intensive Care Unit. Study Design: Comparative cross-sectional study. Setting and Duration of Study: Neonatology Department, Pak Emirates Military Hospital, Rawalpindi Pakistan, from Jul 2021 to Jun 2022. Methodology: This study was conducted on neonates managed at our Neonatal Intensive Care Unit for late or early-onset sepsis. A consultant neonatologist diagnosed neonatal sepsis based on clinical and laboratory findings. The cerebrospinal fluid routine examination was performed on all the study participants, and the derangement of various markers was compared in neonates with early and late-onset sepsis. Results: A total of 348 neonates admitted to the neonatal intensive care unit with sepsis were included in the final analysis. The mean age of the newborns included in the study was 5.38±4.53 days. Out of all the neonates in the study, 194(55.7%) had early-onset sepsis, while 154(44.3%) neonates had late-onset sepsis. All the cerebrospinal fluid markers were statistically significantly deranged in patients with late-onset sepsis (p-value

Abstract A 35‐year‐old woman experienced left back pain after a 2‐h flight. She reported coughing and left back pain 1 day later when she presented to our hospital. Chest computed tomography showed pneumothorax of the left lung, bronchiectasis, thickening of the bronchial wall, nodules, and cavity lesions in both lungs. A pulmonary function test revealed obstructive ventilation disorder with normal lung diffusing capacity. She had a history of haematopoietic stem cell transplantation (HSCT) at 2 years and 3 months of age during the second disease remission of acute myeloid leukaemia. She was diagnosed with chronic graft‐versus‐host disease (cGVHD) presenting with bronchiolitis obliterans (BO) and pleuroparenchymal fibroelastosis (PPFE). To our knowledge, this is the first reported case of BO and PPFE diagnosed more than 30 years after HSCT.

Background: Ocular myasthenia gravis (OMG) is an autoimmune disease which causes ptosis, diplopia, or both. It can be categorized as early or late onset, with differing presenting characteristics and prognoses. Currently, there is limited information available to compare characteristics and outcomes in onset groups in Thailand. Objective: To describe and compare baseline characteristics and outcomes in OMG patients classified by onset groups and to investigate the factors associated with the disease, especially in terms of treatment responses classified according to the MGFA Post-Intervention Status (MGFA-PIS). Methods: OMG patients diagnosed between January 2014 and March 2021 at Rajavithi Hospital, Thailand, were categorized into 2 groups based on age of onset, and baseline characteristics were analyzed and compared. The treatment responses of each group in terms of time to achievement of minimal manifestations (MM) were analyzed. Results: Eighty-one patients (38 with early and 43 with late onset) were included, and the mean (SD) follow-up time was 35.85 months (17.25). There was no significant difference between the baseline characteristics of the two groups. A low dose of pyridostigmine was more commonly used in the early-onset group (p = 0.01), while the mean dose of corticosteroids was significantly lower in the late-onset patients (p < 0.001). We found that seropositivity of acetylcholine receptor antibody decreased the odds ratio of achievement of MM (OR 0.185, 95% CI 0.043–0.789, p = 0.023) and receiving a high dose of pyridostigmine (≥ 120 mg/day) increased the odds ratio of achieving it (OR 8.296, 95% CI 2.136–32.226, p = 0.002). Conclusions: A higher dose of pyridostigmine may be necessary for achievement of favorable treatment response. AChRAb seropositivity is a predictor for unfavorable treatment response in Thai populations. [ABSTRACT FROM AUTHOR]

Background: Food protein-induced enterocolitis syndrome (FPIES) is a delayed, non-IgE-mediated food allergy. This syndrome was once thought to be rare, but emerging literature suggests an increasing incidence along with more foods being implicated. Also, with the introduction of guidelines on early peanut introduction, peanut-induced FPIES seems to be increasing in Australia and USA. Although most patients are diagnosed with FPIES within the first year of life, most commonly with food triggers to cow's milk or soy, other phenotypes exist in comparison to this classic presentation. In this case report, we present a patient with late onset of acute FPIES at age 3 to walnut. Case Presentation: We describe a case of FPIES in a 12-year-old boy who had recurrent episodes of repetitive emesis, that began at age 3, each time after consuming walnuts. Mom does not give a history of intentional feeding (or avoidance) of walnut and/ or pecans. She also described possible reactions with pine nuts and macadamia. He was assessed with an oral food challenge to walnut, which triggered an episode of acute FPIES. He developed vomiting with onset 2 h post-ingestion, pallor, lethargy, and required an emergency department visit for anti-emetic medications and oral rehydration therapy. He improved on the therapy and now avoids cashew, pistachio, hazelnuts, walnuts, pecans, pine nuts, and macadamia nuts. Conclusions: This case report adds to the limited literature that exists on culprit food allergens in FPIES. We present an acute FPIES triggered by the ingestion of walnuts. The diagnosis, common food triggers, and natural history of FPIES are described. There remains a lack of information on the natural history of FPIES, especially towards uncommon food triggers and on FPIES that present beyond infancy. [ABSTRACT FROM AUTHOR]

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There is little research on personality disorder (PD) onset in older age. Many studies have shown that normative personality traits change across the life span, even into later life. This study aimed to investigate the onset of PDs in later adulthood (>age 55), and the possible influence of major life events on predicting this late onset. The current analysis was conducted with data from the St. Louis Personality and Aging Network (SPAN). Structured diagnostic interviews were administered three times over five years. Logistic regressions were conducted predicting late onset PD from baseline to FU5 and from FU5 to FU10 as a function of each major life event. 75 PD onsets occurred from baseline to FU5, and 39 PD onsets occurred from FU5 to FU10. Personal illness predicted the onset of PDs from FU5 to FU10. [ABSTRACT FROM AUTHOR]

Darier disease is an autosomal dominant inherited skin disorder with complete penetrance and variable expressivity due to mutation in the ATP 2A2 gene. It usually develops from childhood and persists through adolescence. Late onset of this genodermatosis has been infrequently reported and found to have minimal findings compared to the classical cases. Classical disease presents with greasy keratotic yellowish-brown papules over the seborrheic areas with palmar pits and nail changes. We hereby report a case of late onset comedonal darier disease with extensive hypopigmented lesions, involvement of palms and nails which is rarely reported in this setting. A thorough review of literature was done and a compendium prepared of late onset darier and no other case report was found to have such extensive involvement as the case reported. It will be interesting to compare more such late onset cases to see if they have a common pattern which can suggest them to be a separate entity from the classical darier.

Abstract Background The prevalence of rheumatoid arthritis (RA) in persons 60 years or older is estimated to be 2%. Late-onset rheumatoid arthritis (LORA) is traditionally defined as the onset of RA after the age of 60 years. Compared to younger-onset rheumatoid arthritis (YORA) which occurs before the age of 60 years, LORA has unique characteristics and disease manifestations. To date, few reports have addressed LORA and the prognosis of LORA patients remains unclear. We compared the clinical characteristics, time to remission and treatment regimen at remission between LORA and YORA patients. Methods This prospective cohort study used a registry database in Ontario, Canada from 2008 to 2020. Patients were included if they had active rheumatoid arthritis (RA) disease (≥1 swollen joint) and were enrolled within 1 year of diagnosis. LORA was defined as a diagnosis of RA in persons 60 years and older and YORA as a diagnosis of RA in persons under the age of 60. Remission was defined by Disease Activity Score 28 (DAS28) ≤2.6. A multivariable Cox proportional hazards model was used to estimate time to remission. Results The study included 354 LORA patients and 518 YORA patients. The mean (standard deviation) baseline DAS28 score was 5.0 (1.3) and 4.8 (1.2) in LORA and YORA patients, respectively (p=0.0946). Compared to YORA patients, the hazard ratio for remission in LORA patients was 1.10 (95% confidence interval 0.90 to 1.34 p=0.36) after adjusting for other prognostic factors. For patients who reached remission, LORA patients were less likely to be on a biologic or Janus kinase (JAK) inhibitor (16% vs. 27%) and more likely to be on a single conventional synthetic disease-modifying anti-rheumatic drugs (csDMARD) (34% vs. 27%) than YORA patients (p=0.0039). Conclusion LORA and YORA patients had similar prognosis in terms of time to remission. At remission, LORA patients were more likely to be on a single csDMARD without a biologic or JAK inhibitor.

Background: Inflammatory bowel disease (IBD) is a chronic condition and children are affected by the disease's burden and therapeutic interventions for much longer than adults. Children of various ages can be diagnosed with IBD. Methods: The research was carried out at the Pediatric Gastroenterology Clinic at Cairo University's Faculty of Medicine's Children's Hospital. From January 2013 to December 2017, this single-center observational cross-sectional study included 197 children aged 14 years and compared the clinical phenotypes of very-early-onset IBD (VEO-IBD) in patients aged six years and late-onset IBD (LO-IBD) in patients aged six to 14 years. Results: Children with IBD at less than six years of age have a more colonic phenotype than children diagnosed later in life, who are more likely to have ileocolonic diseases (p = 0.002). In VEO-disease Crohn's (VEO-CD), growth failure/poor weight gain was 14%, while in LO-CD, it was 31%. Children with VEO-IBD do not always present with more severe disease than older children. Most clinical features in children with VEO-ulcerative colitis (VEO-UC) and LO-UC were similar at the first presentation, with the exception of abdominal pain, which was significantly less common in the VEO-UC group (p = 0.001) and hematochezia, which was significantly more common in the LO-UC group (p = 0.048). Children with VEO-disease Crohn's (VEO-CD) had a higher risk of bloody stools, diarrhea and fever (p = 0.013, p = 0.001 and p = 0.008, respectively), but a lower risk of abdominal pain (p = 0.000). Conclusions: Growth failure/poor weight gain occurred in 14% of VEO-CD patients and 31% of LO-CD patients. In LO-UC, abdominal pain and hematochezia were significantly more common. In LO-CD, hematochezia, diarrhea and fever were significantly more common. In LO-IBD-U, abdominal pain and diarrhea were significantly more common. [ABSTRACT FROM AUTHOR]

Warfarin-induced skin necrosis is a rare complication of warfarin therapy and is associated with high mortality. Here, we present a case of warfarin-induced skin necrosis, that was fatal in a 53-year-old female patient who was started on warfarin treatment 5.5 years ago due to atrial fibrillation and previous mitral valve surgery. Patients using warfarin should be evaluated for warfarin-induced skin necrosis when they present with skin lesions. Early diagnosis, early discontinuation of the drug, early initiation of supportive treatment can be life-saving.

Nevus comedonicus is an uncommon hamartoma of the pilosebaceous unit characterized by keratin filled pits simulating open comedones. It may present at birth but is more commonly seen during childhood or adolescence. The most commonly affected sites are the face, neck, trunk, and arms with a few reported cases on palms, genitalia, and scalp. We report a case of a 19-year old woman with nevus comedonicus of the scalp that appeared in adolescence. This case has been presented for its sheer rarity, atypical site, and classic appearance.

Abstract Background Late-onset depression is different from early-onset depression in its sociodemographic and clinical characteristics and risk factors. This study aimed to demonstrate the differences in sociodemographic characteristics as well as clinical presentation between late-onset depression (after the age of 60 years) and early-onset depression (before the age of 45 years) and to determine the sociodemographic risk factors for late onset depression. Fifty-five patients between 18 and 45 years of age (group 1) and 55 patients aged 60 years and above (group 2) diagnosed for the first time with major depressive disorder were compared regarding sociodemographic and clinical characteristics. They were recruited from the psychiatric clinic at Sohag University Hospital. All participants were subjected to a Structured Clinical Interview for DSM-IV (SCID-IV), sociodemographic data form, Beck Depression Inventory-Second Edition (BDI-II), and Apathy Evaluation Scale (AES). Results The patients in group 2 were more commonly single (29%), employed (74.54%), living in rural areas (56.36%), and had high school education (41.81%). While the patients in group 2 were more commonly widows (18.18%), unemployed (61.81%), had less than high school education (47.27%), and had chronic diseases (78.81%). Significant risk factors for late onset depression are being widow, unemployed, having low socioeconomic status, and having a chronic medical disease. Patients with late-onset depression were more commonly presented with apathy, cognitive impairment, and somatic symptoms, as well as sleep disturbance (mean±SD 57±6, 70.9%, 61.81%, and 81.81%, respectively) than early-onset depression (mean±SD 49± 4, 47.27%, 36.36%, and 70.9%, respectively). Conclusions Cases with late onset depression are featured by being unemployed, widow, having low socioeconomic status and low educational level, suffering from a chronic medical condition and living in an urban area. In late onset depression, somatic symptoms, apathy, sleep disturbances, as well as cognitive impairment are prevalent presenting symptoms.

Background: Wilson's disease (WD) is usually diagnosed in children and young adults; limited data exist on late‐onset forms. Objective: The aim was to characterize the clinical and paraclinical presentations, therapeutic management, and outcomes in patients with late‐onset WD. Methods: Patients diagnosed with WD after age 40 years were identified from the French Wilson's Disease Registry (FWDR). Clinical, laboratory, and imaging findings and treatment were reported at diagnosis and last follow‐up. Results: Forty‐five patients were identified (median age: 49, range: 40–64) and placed in three groups according to their clinical presentation: neurological (n = 20, median diagnostic delay: 20 months), hepatic (n = 13, diagnostic delay: 12 months), and family screening (n = 12), all confirmed genetically. Six neurological patients had an atypical presentation (1 torticollis, 2 writer's cramps, 2 functional movement disorders, and 1 isolated dysarthria), without T2/fluid‐attenuated inversion recovery brain magnetic resonance imaging (MRI) hyperintensities; 5 of 6 had no Kayser–Fleischer ring (KFR); 5 of 6 had liver involvement. In the neurological group, 84% of patients improved clinically, and 1 developed copper deficiency. In the hepatic group, 77% had cirrhosis; 6 patients required liver transplantation. In the screened group, 43% had mild liver involvement; 3 were not treated and remained stable; 24‐h urinary copper excretion was normal in 33% of patients at diagnosis. Conclusions: In the FWDR, late‐onset forms of WD affect 8% of patients, mostly with neurological presentations. Thirty percent of the neurological forms were atypical (isolated long‐lasting symptoms, inconspicuous brain MRI, no KFR). With personalized treatment, prognosis was good. This study emphasized that WD should be suspected at any age and even in cases of atypical presentation. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

In recent years, there has been a significant increase in the diagnosis of asymptomatic Late-Onset Pompe Disease (LOPD) patients, who are detected via family screening or Newborn Screening (NBS). The dilemma is when to start Enzyme Replacement Therapy (ERT) in patients without any clinical sign of the disease, considering its important benefits in terms of loss of muscle but also its very high cost, risk of side effects, and long-term immunogenicity. Muscle Magnetic Resonance Imaging (MRI) is accessible, radiation-free, and reproducible; therefore, it is an important instrument for the diagnosis and follow-up of patients with LOPD, especially in asymptomatic cases. European guidelines suggest monitoring in asymptomatic LOPD cases with minimal MRI findings, although other guidelines consider starting ERT in apparently asymptomatic cases with initial muscle involvement (e.g., paraspinal muscles). We describe three siblings affected by LOPD who present compound heterozygosis and wide phenotypic variability. The three cases differ in age at presentation, symptoms, urinary tetrasaccharide levels, and MRI findings, confirming the significant phenotypic variability of LOPD and the difficulty in deciding when to start therapy. [ABSTRACT FROM AUTHOR]

More frequent among adults, phenocopies may be caused by somatic mutations or anti-cytokine autoantibodies, mimicking the phenotypes of primary immunodeficiencies. A fourteen-year-old girl was referred for a two-year history of weight loss and multiple recurrent abscesses, complicated recurrent pneumonia, pyelonephritis, osteomyelitis, and septic shock, without fever. She had started with nausea, hyporexia, and weight loss, then with abscesses in her hands, knee, ankle, and spleen. She also developed a rib fracture and left thoracic herpes zoster. The patient was cachectic, with normal vital signs, bilateral crackles on chest auscultation, tumefaction of the knee joint, and poorly healed wounds in hands and chest, oozing a yellowish fluid. Chest computed tomography revealed multiple bilateral bronchiectases. Laboratory workup reported chronic anemia, leukocytosis, neutrophilia, mild lymphopenia, thrombocytosis, pan-hypergammaglobulinemia, and elevated acute serum reactants. Lymphocyte subsets were low but present. Mycobacterium tuberculosis was detected via polymerase chain reaction in a bone biopsy specimen from ankle osteomyelitis. Whole-exome sequencing failed to identify a monogenic defect. Interleukin-12 was found markedly elevated in the serum of the patient. Phosphorylation of STAT4, induced by increasing doses of IL-12, was neutralized by patient serum, confirming the presence of anti-IL12 autoantibodies. IL-12 and IL-23 are crucial cytokines in the defense against intracellular microorganisms, the induction of interferon-gamma production by lymphocytes, and other inflammatory functions. Patients who develop neutralizing serum autoantibodies against IL12 manifest late in life with weight loss, multiple recurrent abscesses, poor wound healing, and fistulae. Treatment with anti-CD20 monoclonal antibodies was effective. • A 12-year-old girl developed weight loss, poor wound healing, and multiple abscesses, caused by anti-cytokine autoantibodies. • The patient had a spectacular improvement after treatment with rituximab and has not relapsed. • Patients with neutralizing anti-IL12p40 autoantibodies might manifest late in life with weight loss, multiple recurrent abscesses, poor wound healing, and fistulae. • IL-12 and IL-23 are crucial cytokines in the defense against intracellular microorganisms, via the induction of interferon-gamma by lymphocytes. [ABSTRACT FROM AUTHOR]

We report the case of a 19-month-old girl with late-onset ornithine transcarbamylase (OTC) deficiency initially referred to gastroenterology for intermittent vomiting lasting a year and abnormal liver enzymes (AST 730 U/L [reference range 26–55 U/L]; ALT 1213 U/L [reference range 11–30 U/L]) without hepatomegaly. While the patient was hospitalized for liver biopsy, intermittent tremors of the upper extremities with varying severity were noted. The patient was presumed to have hyperammonemia secondary to acute liver failure and was discharged after 5 days; follow-up monitoring led to readmission 7 days later. A brain MRI showed nonspecific bilateral pericallosal and bifrontal white matter FLAIR hyperintensities. These findings raised suspicion for a metabolic disease and prompted a genetics consultation. After inconclusive biochemical testing and worsening clinical status, rapid whole genome sequencing results were obtained identifying a novel, de novo, likely pathogenic, variant c.608C > T (p.Ser203Phe) in the OTC gene. The patient was promptly started on an oral nitrogen scavenger, citrulline supplementation, and protein restriction. Ammonia and glutamine levels normalized within 1 month of treatment and have stayed within the goal ranges with continued tailoring of treatment. Her parents noted resolution of vomiting and improved mood stability. Liver enzymes normalized after 2 months of treatment. The tremor, identified as asterixis, improved and a repeat brain MRI 3 months after the initial imaging showed near-complete resolution of previous white matter hyperintensities.

We report on a family with ornithine transcarbamylase (OTC) deficiency, an X-linked urea cycle disorder, with variable disease severity and tailored management strategies based on each family member's biochemical profile and clinical presentation. Our primary patient is a female monozygotic twin who presented to medical care at 10 months of age with acute liver failure, gastrointestinal symptoms, altered mental status, hypoglycemia, and hyperammonemia. The patient's older brother, known to have hemizygous OTC deficiency, died at 8 months of age from cardiac arrest after complications secondary to his diagnosis. Despite her family history, manifestation of symptoms of heterozygous (partial) OTC deficiency went unrecognized by multiple providers based on misconceptions regarding a female's risk for X-linked disease. Despite barriers related to the family's low socioeconomic status, follow-up care by a multidisciplinary metabolic care team, including moderate protein restriction and nitrogen scavenger therapy, led to positive outcomes for the patient. Her twin sister and mother are also heterozygous for variants in OTC and remain controlled on moderate protein restriction. This case illustrates the importance of genotyping all individuals with genetic risk factors for OTC deficiency and the variability in disease manifestation that necessitates tailored treatment approaches for individuals with partial OTC deficiency.

We report the case of a medically complex African American adult female with ornithine transcarbamylase (OTC) deficiency diagnosed after lifelong protein aversion and new onset of chronic vomiting and abdominal pain with intermittent lethargy and confusion. Symptomatology was crucial to diagnosis as genetic testing did not identify any pathogenic variants in OTC; however, the patient's diagnosis was delayed despite her having longstanding symptoms of a urea cycle disorder (UCD). Her symptoms improved after treatment with a modified protein-restricted diet, long-term nitrogen-scavenger therapy, and supplemental L-citrulline. Adherence to her UCD management regimen remained a challenge due to her underlying frailty and other medical conditions, which included primary renal impairment (further exasperated by type 2 diabetes mellitus) and decreased left-ventricular function. She passed away 3 years after her OTC deficiency diagnosis due to complications of congestive heart failure. Her OTC deficiency did not have a major impact on her final illness, and appropriate OTC deficiency management was provided until the decision was made to withdraw medical care.

Urea cycle disorders (UCDs) are a group of rare inherited metabolic conditions caused by enzyme deficiency within the hepatic ammonia detoxification pathway. Ornithine transcarbamylase (OTC) deficiency, the most frequently occurring UCD, is an X-linked condition known to yield a vastly heterogeneous phenotype, with variable onset and presentation across the lifespan. Here, we introduce a series of 4 original cases, published as part of this special supplement, that illustrate learnings for the care of heterozygous females with OTC deficiency, including challenges with diagnosis, potential triggers of hyperammonemia, cognitive effects, and approaches to disease management, including peripartum care.

Introduction: Intradiploic pseudomeningoceles, also called intradiploic cerebrospinal fluid (CSF) fistulas, are abnormal CSF collections between the two bony tables of the calvaria resulting from postsurgical CSF leakage. To date, only six cases of intradiploic pseudomeningocele have been reported, all occurring in the occipital area. In this paper, we report the seventh case of late-onset occipital intradiploic pseudomeningocele (OIP) occurring in a young female patient who underwent surgery for the removal of a cerebellar pilocytic astrocytoma. In this regard, we also review the literature on the few recognized cases of OIP. Case Presentation: The case of an 18-year-old female patient known to our institute for an operation 12 years earlier to remove a pilocytic astrocytoma is illustrated. At admission, the patient complained only of occasional orthostatic headache. Brain imaging demonstrated a pseudomeningocele extended intradiploically from the occipital squama to the condylar and clivus regions, thinning both occipital bone tables and dilating the CSF-filled diploe. Watertight duroplasty and cranioplasty were effectively performed. Conclusion: Pediatric patients undergoing posterior cranial fossa craniotomy/craniectomy may postoperatively develop OIP. In this setting, treatment of any dural CSF fistula should be considered because of the risk of progressive extension and bone erosion. [ABSTRACT FROM AUTHOR]

Behçet's disease (BD) is a systemic vasculitis of unknown etiology causing recurrent mucocutaneous lesions, ocular involvement, central nervous system involvement, and vascular involvement. The disease is characterized by exacerbations and spontaneous remissions. Prognosis is poor in young men when the vessels are involved. The course is more active and severe in the first years of the disease. One of the most interesting features of BD is that the disease changes to a state of low activity and remission over time. Although the association between aging and lower disease activity is well established, there is limited literature data and research investigating the cause. Similarly, there are not many studies on the late onset of BD and its characteristics. In this regard, understanding the cause of the decline in disease activity over time may open new avenues for pathogenesis and treatment research. In this review, we focus on the immunosenescence caused by chronic inflammation and aging in BD. Based on the effect of testosterone on innate immune cells, we also briefly discussed the potential effects of this hormone on vascular involvement. [ABSTRACT FROM AUTHOR]

Background: Group B Streptococcus (GBS) significantly contributes to neonatal sepsis and meningitis, with varying disease rates reported globally and limited population-based data. We estimated infant GBS disease burden in Ontario, Canada and assessed the association of maternal GBS screening (35-37 weeks' gestation) and intrapartum antibiotic prophylaxis (IAP) provision with infant disease rates., Methods: Our population-based cohort study included pregnant individuals and their offspring from April 2012 to March 2018, utilising the provincial birth registry linked to health administrative data. GBS cases were ascertained through culture results and diagnostic codes. We calculated incidence rates for early-onset disease (EOD: 0-6 days), late-onset disease (LOD: 7-89 days), and ultra-LOD (ULOD: 90-365 days). Adjusted incidence rate ratios (aIRR) were derived via log-binomial regression to compare infant GBS rates according to screening and IAP-receipt., Findings: Among 776,148 liveborn infants, we identified 803 with GBS, with multiples exhibiting a threefold incidence increase. Incidence rates of EOD, LOD and ULOD were 0.49, 0.46 and 0.07 per 1000 livebirths, respectively. Of eligible pregnancies, 94% were screened; 23% screened positive, and 81% of them received IAP. Nearly 12% of term EOD infants had mothers who missed IAP despite screening positive. Maternal screening was associated with lower rates of any infant GBS disease (aIRR: 0.60; 95% CI: 0.45, 0.80). Among screen-positive births, IAP-receipt was associated with reduced rates of EOD (aIRR: 0.72, 95% CI: 0.48, 1.29) and LOD/ULOD (aIRR: 0.69; 95% CI: 0.46, 1.05), but confidence intervals included 1.0., Interpretation: Our study, the largest Canadian investigation into infant GBS disease, highlights both widespread adoption and ongoing challenges of the current prevention strategy., Funding: Canadian Institutes of Health Research., Competing Interests: MS has been an investigator on projects funded by Pfizer, Merck, Moderna, Sanofi Pasteur, and GlaxoSmithKline (all unrelated to study). All funds have been paid to his institute, and he has not received any personal payments. KW is the CEO of CANImmunize Inc and served as a member of the independent data safety monitoring committee for the Medicago COVD-19 vaccine trial. When this project was funded and initiated, DBF was employed by the University of Ottawa and had an academic appointment at the Children’s Hospital of Eastern Ontario Research Institute; she is now employed by Pfizer and works on an unrelated topic. DEC has been an investigator on projects funded by Moderna and Pfizer. All funds have been paid to her institute, and she has not received any personal payments. AM has received research funds to her institution from Pfizer and Sanofi Pasteur and received personal fees for advisory boards and DSMBs from Astra-Zeneca, GlaxoSmithKline, Medicago, Merck, Moderna, Pfizer, Roche and Sanofi Pasteur. SB is the director of the Centre for Vaccine Preventable Diseases at the University of Toronto, which has received support from Merck, Sanofi and Pfizer. All funds are paid to the institute and are subject to the University of Toronto’s governance policies., (© 2024 The Author(s).)

Background: Colorectal cancer (CRC) remains a major burden worldwide, ranking third and second in incidence and mortality respectively. Detection of biomarkers including KRAS mutations can help predict prognosis and response to therapy in CRC, thus this study evaluated the frequency of KRAS mutations among Indonesian patients and their associations with clinicopathologic characteristics., Methods: Fifty-three CRC samples were collected from January to September 2022 in the Department of Surgery, Dr. Hasan Sadikin General Hospital, Bandung, Indonesia. KRAS mutations were analyzed using PCR followed by Sanger sequencing. Associations between KRAS mutations were evaluated using binary logistic regression analysis., Result: KRAS mutations were detected in 52.8% of patients (n=28), of which 3.6% were p.Gly12Ser (n=1), 32.1% were p.Gly12Asp (n=9), 7.1% were p.Gly13Asp (n=2), 3.6% were p.Gln61His (n=1), 3.6% were p.Asp126His (n=1), and 3.6% were p.Lys169Glu (n=1). The p.Asp73= polymorphism was detected in 57.1% of the samples (n=16). KRAS mutation status did not differ significantly between the groups based on the age of onset, sex, tumor location, tumor histology, stage, and family history., Conclusion: KRAS mutations are present in high frequency in this cohort of CRC patients in a tertiary hospital in West Java, Indonesia. However, KRAS mutation status is not associated with the age of onset, sex, tumor location, tumor histology, stage, and family history.