Specific Syndromes Research Articles

NEONATAL OUTCOMES IN INFANTS OF DIABETIC MOTHERS: FOCUS ON HYPOGLYCEMIA, RESPIRATORY DISTRESS SYNDROME AND MACROSOMIA

Background: Infants of diabetic mothers (IDMs) face heightened risks of various neonatal complications. This study evaluates the incidence of specific complications-macrosomia, hypoglycaemia, and neonatal respiratory distress syndrome (NRDS)-in this population. Methods: A cross-sectional observational study was conducted over 1.5 years at a tertiary hospital in Mumbai. We reviewed the medical records of infants born to mothers with diabetes (both pregestational and gestational). Data on the incidence of macrosomia (birth weight >4000 grams), hypoglycaemia (blood glucose <40 mg/dL), and NRDS (diagnosed based on clinical and radiographic criteria) were collected. Results: Among the 50 infants studied, 8% were diagnosed with macrosomia, 46% experienced hypoglycaemia, and 20% developed NRDS. The frequency of these complications was significantly higher in IDMs compared to the general neonatal population. Conclusion: This study reveals a high incidence of macrosomia, hypoglycaemia, and NRDS in IDMs, emphasizing the need for regular antenatal follow-up and strict glycaemic control throughout pregnancy. Enhanced monitoring and management strategies are essential to mitigate these risks and improve neonatal health outcomes.

Timing Mechanisms for Circadian Seizures

For centuries, epileptic seizures have been noticed to recur with temporal regularity, suggesting that an underlying biological rhythm may play a crucial role in their timing. In this review, we propose to adopt the framework of chronobiology to study the circadian timing of seizures. We first review observations made on seizure timing in patients with epilepsy and animal models of the disorder. We then present the existing chronobiology paradigm to disentangle intertwined circadian and sleep–wake timing mechanisms. In the light of this framework, we review the existing evidence for specific timing mechanisms in specific epilepsy syndromes and highlight that current knowledge is far from sufficient. We propose that individual seizure chronotypes may result from an interplay between independent timing mechanisms. We conclude with a research agenda to help solve the urgency of ticking seizures.

Study of Rates and Factors Associated to Psychosomatic Syndromes Assessed Using the Diagnostic Criteria for Psychosomatic Research across Different Clinical Settings

Introduction: Diagnostic Criteria for Psychosomatic Research (DCPR) serve as an instrument for identifying and classifying specific psychosomatic syndromes that are not adequately encompassed in standard nosography. The present study aimed at measuring the prevalence of DCPR syndromes in different clinical settings and exploring factors associated to such diagnoses. Methods: A cross-sectional and nationwide study recruited 6,647 patients in different clinical settings: 306 were diagnosed with fibromyalgia (FM), 333 with irritable bowel syndrome, 1,109 with migraine, 2,550 with coronary heart disease (CHD), and 2,349 with type 2 diabetes (T2D). Participants underwent DCPR diagnostic interview and were assessed for depression (Patient Health Questionnaire-9), anxiety (Generalized Anxiety Disorder 7-Item Scale), and subjective well-being (World Health Organization-5 Well-Being Index). The PsychoSocial Index was used to evaluate global well-being, stress, and abnormal illness behavior. The prevalence of DCPR diagnoses was calculated, and factors associated to such diagnoses were analyzed by logistic regression. Results: Alexithymia (64.47%), irritable mood (20.55%), and demoralization (15.60%) were the most prevalent psychosomatic syndromes, with demoralization being most common in FM (49.02%). The factors associated to DCPR diagnoses encompassed high anxiety or abnormal illness behavior, and poor well-being. Notably, stress was found to be associated specifically to FM and T2D, with OR of 1.24 (95% CI: 1.06–1.46) and 1.26 (95% CI: 1.18–1.36), respectively. Conclusion: DCPR is a clinically helpful complementary assessment tool in need of being widely implemented in clinical settings in order to have a comprehensive picture of the patients.

Relative exchangeable copper, a high-quality biomarker for differentiation of Traditional Chinese Medicine syndrome in Wilson's disease.

To investigate the value of relative exchangeable copper (REC) in diagnosing Wilson's disease (WD) and to determine its significance in the differentiation of Traditional Chinese Medicine (TCM) syndrome. A total of 78 patients with WD were recruited on the same day of the medical visit, and among them, 32 were suffering from non-WD (N-WD) and 37 were heterozygous ATP7B carriers (HC) enrolled as controls. Molecular genetic testing was performed for diagnosing WD and HC. Additionally, REC levels in different TCM syndromes were investigated. The correlation between REC and serum ceruloplasmin (Cp), serum copper oxidase (CO), and 24-h urinary copper was analyzed using the Global Assessment Scale and Unified Wilson's Disease Rating Scale and the significance of REC in WD diagnosis was investigated. Resting-state functional magnetic resonance imaging was used to assess the clinical symptoms of WD and analyze its severity in different TCM syndromes. REC determination helped in significantly distinguishing patients with N-WD or HC from those with WD with a cut-off of 21.15%. Furthermore, the comparative analysis of REC ratios among different TCM syndromes showed markedly high REC levels in the dampness-heat internal accumulation syndrome group. Additionally, the seed-based functional connectivity value from the putamen to the cerebellum was significantly correlated with TCM syndromes. REC level is a high-quality biomarker for diagnosing WD that effectively reflects disease severity and plays an essential role in deciding on treatment strategies and prognosis. Furthermore, REC levels are closely related to TCM syndromes in WD; thus, it is a potential objective quantitative indicator for distinguishing TCM syndromes in WD.

Biological Markers of Musculoskeletal Pain: A Scoping Review.

Musculoskeletal pain (MSP) is the leading contributor to disability, limiting mobility and dexterity. As research on the determinants of MSP is evolving, biomarkers can probably play a significant role in understanding its causes and improving its clinical management. This scoping review aimed to provide an overview of the associations between biomarkers and MSP. This study followed Arksey and O'Malley and PRISMA-ScR recommendations. Keywords related to biomarkers, association, and MSP were searched on PubMed, Embase, Cochrane, and Web of Science databases from inception to September 28th, 2023. Data were systematically retrieved from the retained articles. A narrative synthesis approach - but no quality assessment - was used to map the core themes of biological markers of MSP that emerged from this work. In total,81 out of 25,165 identified articles were included in this scoping review. These studies were heterogeneous in many aspects. Overall, vitamin D deficiency, dyslipidemia (or hypercholesterolemia), and cytokines (high levels) were the most studied biomarkers with regards to MSP and were most often reported to be associated with non-specific MSP. Cadmium, calcium, C-reactive protein, collagen, creatinine, hormones, omega-3 fatty acids, sodium, tumor necrosis factor-alpha, and vitamin C were also reported to be associated with MSP syndromes, but the evidence on these associations was sketchier. No conclusions could be drawn as to age and sex. Our findings suggest that some biomarkers are associated with specific MSP syndromes, while others would be associated with non-specific syndromes. Among all candidate markers, the evidence seems to be more consistent for vitamin D, cytokines and lipids (total cholesterol, triglycerides, low- and high-density lipoproteins). High-quality studies, stratified by age and sex, are needed to advance our understanding on biomarkers of MSP.

Research Progress on the Syndrome Differentiation and Treatment of Phlegm-Damp Type Polycystic Ovary Syndrome in Traditional Chinese and Western Medicine

Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in women of childbearing age, with complex etiology and classification of traditional Chinese medicine syndromes, among which the phlegm-damp syndrome is the most prevalent. This article provides an overview of the common types and symptomatic characteristics of kidney deficiency type PCOS, the correlation with physicochemical indicators such as glucose and lipid metabolism levels, sex hormone indicators, inflammatory factor levels, as well as syndrome differentiation treatment and integrated traditional and Western medicine approaches, providing a certain scientific basis for clinical diagnosis and treatment.

A Contemporary Review on Heart Failure with Preserved Ejection Fraction: Epidemiology, Diagnosis, and Management

Heart failure with preserved ejection fraction (HFpEF) includes almost half of heart failure cases typified by a specific clinical syndrome. Despite diagnostic and management advances, HFpEF still presents a diagnostic challenge and a paucity of therapies specifically aimed at enhancing survival and improving quality of life is still lacking. This review elucidates the diagnostic complexity of HFpEF, highlighting the use of both subjective and objective criteria within algorithmic frameworks. It also examines the significant impact of comorbidities on the progression of HFpEF. Additionally, we explore the latest evidence on targeting these comorbidities therapeutically, although the benefits to mortality are still limited.

Short-term effectiveness and side effects of ketogenic diet for drug-resistant epilepsy in children with genetic epilepsy syndromes.

Drug-resistant epilepsy (DRE) impacts a significant portion, one-third, of individuals diagnosed with epilepsy. In such cases, exploring non-pharmacological interventions are crucial, with the ketogenic diet (KD) standing out as a valuable option. KD, a high-fat and low-carb dietary approach with roots dating back to the 1920s for managing DRE, triggers the formation of ketone bodies and modifies biochemistry to aid in seizure control. Recent studies have increasingly supported the efficacy of KD in addressing DRE, showcasing positive outcomes. Furthermore, while more research is needed, limited data suggests that KD May also be beneficial for specific genetic epilepsy syndromes (GESs). This study aimed to assess the short-term efficacy of KD among pediatric patients diagnosed with GESs. This is a multi-center retrospective analysis of pediatric patients with GESs diagnosed using next-generation sequencing. The enrolled patients followed the keto-clinic protocol, and the KD efficacy was evaluated at 3, 6, and 12-month intervals based on seizure control and compliance. The collection instrument included demographic, baseline, and prognostic data. The collected data was coded and analyzed promptly. We enrolled a cohort of 77 patients with a mean current age of 7.94 ± 3.83 years. The mean age of seizure onset was 15.5 months. Notably, patients experienced seizures at a younger age tended to have less positive response to diet. Overall, 55 patients responded favorably to the diet (71.4%) while 22 patients (28.6%) showed no improvement. Patients with genetic etiology showed a significantly more favorable responses to the dietary intervention. Patients with Lennox-Gastaut syndrome showed the most significant improvement (14/15) followed by patients with Dravet syndrome (6/8), and West syndrome (3/4). The number of used anti-seizure medications also played a significant role in determining their response to the diet. While some patients experienced mild adverse events, the most common being constipation, these occurrences were not serious enough to necessitate discontinuation of the diet. The study revealed a high improvement rate in seizure control, especially among younger patients and those with later seizure onset. The success of dietary treatment hinges greatly on early intervention and the patient's age. Certain genetic mutations responded favorably to the KD, while efficacy varied among various genetic profiles.

Is SDF better than the SMART (silver modified atraumatic restorative technique) in the management of molar incisor hypomineralisation molars with initial caries?

A prospective, randomized, split-mouth clinical study by thetwo previously trained and calibrated pediatric dentists without blinding operators and patients due to different protocols in both treatment groups. An SDF + potassium iodide (KI) and SDF + KI + glass ionmer cement(GIC) on International Caries Detection and Assessment System (ICDAS) 1/2 molar was received by each patient on either sideof mouth. The local Ethics Committee approved this study. Sample size calculation was not performed due to the lack of published studies on the longevity of SMART sealant on MIH-affected molarsand the absence of research on the apparent difference between the effectiveness of SMART and SDF treatments in preventing further caries and sensitivity. These were children between the ages of 6 years to 13 years, who visited the Pediatric Dentistry Clinic at XX University School of Dentistry for routine exams and treatment between July 2019 to May 2020. They were in good health and had at least two fully erupted permanent first molars with MIH as per the European Academy of Pediatric Dentistry, ICDAS code 1/2. This study recorded 12 months of treatment outcomes on hypomineralised molars of 48 children with a follow-up of three years. Children were excluded with specific syndromes associated with enamel malformation, lack of cooperation, ongoing orthodontic treatment, and teeth with ICDAS 3/4/5/6 lesions, existing restorations, fluorosis, or pulpal symptoms. Mann-Whitney U Test was used to assess differences between independent groups (SDF and SMART) and the Friedman Test between dependent groups at different time points. Kaplan-Meier analysis to evaluate the cumulative survival of SMART sealants and survival of caries-free hypomineralised molars in both groups. Chi-Square test was used to compare the success percentages of the SDF and SMART groups. To assess the changes in success percentages at three different time intervals for the caries preventive effect of SDF and SMART, and to evaluate the retention percentages for the SMART group. McNemar's test with a Bonferroni correction was used for significant differences. Cohen's kappa test indicated that the inter-examiner reliability determining the presence of MIH was 0.87. The intra-examiner reliability for US Public Health Service (USPHS)-Modified criteria was 0.90. The statistical significance level was set at p < 0.05 for all statistical analyses. At 12, 24 and 36 months the caries preventive effect was 100%, 67.9%, and 65.4% for SDF + KI-treated teeth; and 100%, 97.6%, and 94.7% for SMART (SDF + KI + GIC) respectively. During the recall period, there was no substantial difference in hypersensitivity scores between the groups. There was no hypersensitivity in teeth at 18 months and beyond. Compared to the baseline Schiff Cold Air Sensitivity Scale (SCASS) score 26 molar with initial hypersensitivity to hypomineralisation had a massive reduction at evaluation periods. The mean survival probabilities for the caries-preventive effect were considerably lower in SDF + KI-treated teeth (31.01 months) than in SMART-treated teeth (35.61 months) (p < 0.001). Considering the limitation of the study, both SMART (SDF + KI + GIC) sealants and 6-monthly application of SDF + KI, provided similar and substantial levels of desensitisation on the permanent MIHmolars. When used as a sealing material on non-cavitated permanent MIHmolars, the clinical retention rate for SMART was 88.7%, 73.1%, and 66.6% at 1, 2, and 3 years respectively. The caries preventive effect of SMART (SDF + KI + GIC) sealants was superior to SDF + KI application in hypomineralised teeth, however, a long-term monitoring and review is essential due to the gradual decrease in retention of SMART sealants.

Decoding the Gut Microbiome in Companion Animals: Impacts and Innovations.

The changing notion of "companion animals" and their increasing global status as family members underscores the dynamic interaction between gut microbiota and host health. This review provides a comprehensive understanding of the intricate microbial ecology within companion animals required to maintain overall health and prevent disease. Exploration of specific diseases and syndromes linked to gut microbiome alterations (dysbiosis), such as inflammatory bowel disease, obesity, and neurological conditions like epilepsy, are highlighted. In addition, this review provides an analysis of the various factors that impact the abundance of the gut microbiome like age, breed, habitual diet, and microbe-targeted interventions, such as probiotics. Detection methods including PCR-based algorithms, fluorescence in situ hybridisation, and 16S rRNA gene sequencing are reviewed, along with their limitations and the need for future advancements. Prospects for longitudinal investigations, functional dynamics exploration, and accurate identification of microbial signatures associated with specific health problems offer promising directions for future research. In summary, it is an attempt to provide a deeper insight into the orchestration of multiple microbial species shaping the health of companion animals and possible species-specific differences.

Beyond paraneoplastic neurological syndromes: Anti-neuronal antibodies in neuropsychiatric systemic lupus erythematosus.

Anti-neuronal antibodies target antigens produced by tumour cells and cells of nervous system. These antibodies are formed as a result of autoimmune response elicited by the underlying malignancy, when proteins restricted to immune privileged neurons are presented by the tumour. Previous studies have shown presence of anti-neuronal antibodies in systemic lupus erythematosus and neuropsychiatric lupus (NPSLE) but information on individual antibodies and their pathogenic role is lacking. To assess the frequency of anti-neuronal antibodies in our neuropsychiatric lupus cohort and to assess any significant association with specific neurological syndrome and to see if the antibodies were more likely to occur in active rather than inactive neuropsychiatric lupus. This cross-sectional study was conducted in our center from 2019 to 2022. Neuropsychiatric manifestations were defined according to 1999 American College of Rheumatology (ACR) nomenclature and case definitions for neuropsychiatric lupus. Samples were taken from active or inactive NPSLE patients with their informed consent. Testing was done on an anti-neuronal antigen panel which consisted of [Amphiphysin, CV2, GAD 65, PNMA2 (Ma-2/Ta), Ri, Yo, Hu, recoverin, SOX1, titin, Zic, Tr)] by semi-quantitative Line immune assay. Association between the categorical variables and antibody positivity group was established using chi-square/Fisher's exact test as appropriate. 65 patients were recruited, of which 23 (35%) patients had active NPSLE at the time of sample collection. Anti-neuronal antibodies were positive in 13/65 (20%) patients with anti-Gad 65 antibodies having the highest frequency (6.2%) followed by anti CV 2 (3.1%), anti Sox1 (3.1%), anti Amphiphysin (3.1%) anti recoverin (1.5%), anti Yo (1.5%) and anti Zic (1.5%). The panel of anti-neuronal antibodies did not show any specific association with NPSLE features.However, an interesting finding was that, patients with active disease had higher odds of having anti-neuronal antibodies with an OR = 10 (95% CI:2.38 -42) (p < 0.001) than inactive disease. Anti-neuronal antibodies were more likely to be positive in active neuropsychiatric lupus patients, and these antibodies which are commonly used to diagnose paraneoplastic syndromes may have a potential role in the diagnosis of NPSLE.

Differentiation of Post-Polio Syndrome from Prior Poliomyelitis Sequela by Assessing Paraspinal Muscle Involvement in Magnetic Resonance Imaging.

Background/Objectives: Post-polio syndrome (PPS) affects former polio patients, manifesting decades after initial infection with progressive symptoms like pain, fatigue, and muscle weakness. Diagnosis relies on the clinical criteria and exclusion of other probable causes. The purpose of this study is to determine the scope and new diagnostic value of magnetic resonance imaging (MRI) in identifying muscle involvement in PPS and distinguishing it from prior poliomyelitis (PPM). Methods: This study was approved by the Koç University Ethics Committee with Approval No. 2023.409.IRB2.090. Electronic medical archives from two academic institutions were searched for records tagged with ICD code B-91 for poliomyelitis sequalae. The resulting search query of 291 records was manually sorted for PPS and PPM, medical history, clinical examination findings, and lumbar MR images down to 32 patients. Two independent radiologists evaluated the paraspinal musculature in the MRIs using the Mercuri scale. Inter-rater agreement, comparison of the paraspinal musculatures between groups, and their relationship to leg involvement were assessed with the resulting data. Results: Inter-rater agreement was found to be almost perfect across all muscles, except for the multifidus muscle. When clinical examination findings were included for these muscles, quadratus lumborum (QL) degradation was found in both right-side (p = 0.017) and left-side (p = 0.002) leg involvement. Conclusions: QL muscle deterioration may serve as a diagnostic marker for PPS, potentially guiding lumbar pain treatment through rehabilitation.

International consensus definitions for infection-triggered encephalopathy syndromes.

To develop standardized diagnostic criteria for 'infection-triggered encephalopathy syndrome (ITES)' and five specific clinical syndromes of ITES. The draft definitions were based on existing criteria, standardized, and discussed by a panel of international experts using nominal group technique over 18 months to achieve consensus. All criteria use the same format: (1) presence of infection/fever; (2) clinical features including encephalopathy; (3) neuroradiological features on magnetic resonance imaging; (4) exclusion of other causes. We first highlighted differences between ITES and infectious and autoimmune encephalitis, which is the most important differential diagnosis. Consensus was achieved to define five specific ITESs: acute encephalopathy with biphasic seizures and late reduced diffusion; acute necrotizing encephalopathy; mild encephalopathy with a reversible splenial lesion; acute fulminant cerebral oedema; and acute shock with encephalopathy and multiorgan failure. Two further conditions that are currently classified as epilepsy syndromes but have similar features to ITES, namely febrile infection-related epilepsy syndrome and hemiconvulsion-hemiplegia-epilepsy syndrome, are also discussed. The consensus definition is expected to improve awareness of this disease concept, provide diagnostic framework, and facilitate future international research and clinical trials.

Pearls and Pitfalls in the Management of Vascular Anomalies.

Recent advancements in endovascular techniques have transformed the management of vascular malformations, shifting away from traditional surgical resections to less invasive methods like embolization and sclerotherapy. Vascular malformations are congenital anomalies resulting from embryonic angiogenesis failures, often misdiagnosed but manageable through a multidisciplinary approach. These malformations range from high-flow arteriovenous connections to low-flow venous, lymphatic, or mixed lesions, each requiring specific diagnostic and treatment strategies. Specific syndromes like Klippel-Trenaunay and Parkes-Weber require tailored approaches due to their unique presentations. Diagnosis relies on a combination of physical examination and advanced imaging techniques, including ultrasound and MRI. Treatment is focused on symptomatic relief and improving the patient's quality of life. Interventional treatment is indicated when conservative and/or medical management is insufficient. Surgical interventions remain relevant for select cases, often in a multidisciplinary context. Newer therapies, such as sirolimus, are emerging for complex, treatment-resistant cases.

Therapeutic Approach to Autoimmune Neurologic Disorders.

Autoimmune neurologic disorders encompass a broad category of diseases characterized by immune system attack of the central, peripheral, or autonomic nervous systems. This article provides information on both acute and maintenance immunotherapy used to treat autoimmune neurologic disorders as well as a review of symptomatic management and special considerations when caring for patients with these diseases. Over the past 20 years, more than 50 antibodies have been identified and associated with autoimmune neurologic disorders. Although advances in diagnostic testing have allowed for more rapid diagnosis, the therapeutic approach to these disorders has largely continued to rely on expert opinion, case series, and case reports. With US Food and Drug Administration (FDA) approval of biologic agents to treat neuromyelitis optica spectrum disorder (NMOSD) and myasthenia gravis as well as ongoing clinical trials for the treatment of autoimmune encephalitis, the landscape of immunotherapy options continues to expand. Consideration of the unique pathogenesis of individual autoimmune neurologic disorders as well as the mechanism of action of the diverse range of treatment options can help guide treatment decisions today while evidence from clinical trials informs new therapeutics in the future. Recognizing patients who have a clinical history and examination findings concerning for autoimmune neurologic disorders and conducting a thorough and directed imaging and laboratory evaluation aimed at ruling out mimics, identifying specific autoimmune syndromes, and screening for factors that may have an impact on immunotherapy choices early in the clinical course are essential to providing optimal care for these patients. Providers must consider immunotherapy, symptomatic treatment, and a multidisciplinary approach that addresses each patient's unique needs when treating patients with autoimmune neurologic disorders.

Cenobamate add-on therapy for drug-resistant focal epilepsy.

Although most people with epilepsy achieve complete seizure cessation, approximately one-third of those with the condition continue experiencing seizures despite the use of antiseizure medications (ASMs) given as monotherapy or polytherapy. In this review, we summarised the evidence from randomised controlled trials (RCTs) about cenobamate as an add-on treatment for focal epilepsy uncontrolled by one or more concomitant ASMs. To assess the efficacy and tolerability of add-on oral cenobamate for the treatment of drug-resistant focal-onset seizures, defined as seizures persisting despite treatment with one or more ASMs. We searched the Cochrane Register of Studies (CRS Web) and MEDLINE Ovid (September 2022). In addition, we contacted the manufacturer of cenobamate and experts in the field to enquire after any ongoing or unpublished studies. RCTs comparing add-on cenobamate to placebo or another ASM in people with focal epilepsy uncontrolled by one or more concomitant ASMs. Two review authors independently selected trials for inclusion, extracted data, performed risk of bias assessment, and assessed the certainty of the evidence using the GRADE approach. Our primary outcomes were at least a 50% reduction in total seizure frequency, seizure freedom, and the occurrence of adverse events. We used an intention-to-treat approach for our primary analyses. For each outcome we estimated summary risk ratios (RRs) with their 95% confidence intervals (CIs). We summarised the estimates of effects and certainty of the evidence for each outcome in a summary of findings table. We included two studies (659 adult participants, 442 allocated to cenobamate and 217 to placebo). The overall RR for at least a 50% reduction in seizure frequency for add-on cenobamate at any dose compared to placebo was 2.17 (52% versus 24%, 95% CI 1.66 to 2.84; 2 studies, 605 participants; moderate-certainty evidence). The RR for seizure freedom for add-on cenobamate at any dose compared to placebo was 4.45 (16% versus 5%, 95% CI 2.25 to 8.78; 2 studies, 605 participants; moderate-certainty evidence). The RR for the occurrence of adverse events for add-on cenobamate at any dose compared to placebo was 1.14 (77% versus 67%, 95% CI 1.02 to 1.27; 2 studies, 659 participants; moderate-certainty evidence). We judged the two included RCTs as at low or unclear risk of bias. Both studies were sponsored by the drug company that produces cenobamate. Add-on cenobamate is probably better than placebo in reducing the frequency of seizures by at least 50% and in achieving seizure freedom in adults with focal epilepsy uncontrolled by one or more concomitant ASMs (moderate level of certainty). Its use is probably associated with an increased risk of adverse events (moderate level of certainty). Further prospective, controlled trials are required to evaluate the efficacy and tolerability of add-on cenobamate compared to other ASMs. The efficacy and tolerability of cenobamate as adjunctive treatment for focal epilepsy in children should be further investigated. Finally, the long-term efficacy and tolerability of add-on cenobamate treatment in people with other epilepsy types (e.g. generalised epilepsy) or specific epilepsy syndromes, as well as its use as monotherapy, require additional study.

New epilepsy therapies in development.

Epilepsy is a common brain disorder, characterized by spontaneous recurrent seizures, with associated neuropsychiatric and cognitive comorbidities and increased mortality. Although people at risk can often be identified, interventions to prevent the development of the disorder are not available. Moreover, in at least 30% of patients, epilepsy cannot be controlled by current antiseizure medications (ASMs). As a result of considerable progress in epilepsy genetics and the development of novel disease models, drug screening technologies and innovative therapeutic modalities over the past 10 years, more than 200 novel epilepsy therapies are currently in the preclinical or clinical pipeline, including many treatments that act by new mechanisms. Assisted by diagnostic and predictive biomarkers, the treatment of epilepsy is undergoing paradigm shifts from symptom-only ASMs to disease prevention, and from broad trial-and-error treatments for seizures in general to mechanism-based treatments for specific epilepsy syndromes. In this Review, we assess recent progress in ASM development and outline future directions for the development of new therapies for the treatment and prevention of epilepsy.

European society of clinical microbiology and infectious diseases guidelines for antimicrobial stewardship in emergency departments (endorsed by European association of hospital pharmacists)

ScopeThis European Society of Clinical Microbiology and Infectious Diseases guideline provides evidence-based recommendations to support a selection of appropriate antibiotic use practices for patients seen in the emergency department (ED) and guidance for their implementation. The topics addressed in this guideline are (a) Do biomarkers or rapid pathogen tests improve antibiotic prescribing and/or clinical outcomes? (b) Does taking blood cultures in common infectious syndromes improve antibiotic prescribing and/or clinical outcomes? (c) Does watchful waiting without antibacterial therapy or with delayed antibiotic prescribing reduce antibiotic prescribing without worsening clinical outcomes in patients with specific infectious syndromes? (d) Do structured culture follow-up programs in patients discharged from the ED with cultures pending improve antibiotic prescribing? MethodsAn expert panel was convened by European Society of Clinical Microbiology and Infectious Diseases and the guideline chair. The panel selected in consensus the four most relevant antimicrobial stewardship topics according to pre-defined relevance criteria. For each main question for the four topics, a systematic review was performed, including randomized controlled trials and observational studies. Both clinical outcomes and stewardship process outcomes related to antibiotic use were deemed relevant. The literature searches were conducted between May 2021 and March 2022. In April 2022, the panel members were formally asked to suggest additional studies that were not identified in the initial searches. Data were summarized in a meta-analysis if possible or otherwise summarized narratively. The certainty of the evidence was classified according to the Grading of Recommendations Assessment, Development and Evaluation criteria. The guideline panel reviewed the evidence per topic critically appraising the evidence and formulated recommendations through a consensus-based process. The strength of the recommendations was classified as strong or weak. To substantiate the implementation process, implementation trials or observational studies describing facilitators/barriers for implementation were identified from the same searches and were summarized narratively. RecommendationsThe recommendations on the use of biomarkers and rapid pathogen diagnostic tests focus on the initiation of antibiotics in patients admitted through the ED. Their effect on the discontinuation or de-escalation of antibiotics during hospital stay was not reported, neither was their effect on hospital infection prevention and control practices. The recommendations on watchful waiting (i.e. withholding antibiotics with some form of follow-up) focus on specific infectious syndromes for which the primary care literature was also included. The recommendations on blood cultures focus on the indication in three common infectious syndromes in the ED explicitly excluding patients with sepsis or septic shock. Most recommendations are based on very low and low certainty of evidence, leading to weak recommendations or, when no evidence was available, to best practice statements. Implementation of these recommendations needs to be adapted to the specific settings and circumstances of the ED. The scarcity of high-quality studies in the area of antimicrobial stewardship in the ED highlights the need for future research in this field.

The graded multidimensional geometry of phenotypic variation and progression in neurodegenerative syndromes.

Clinical variants of Alzheimer's disease and frontotemporal lobar degeneration display a spectrum of cognitive-behavioural changes varying between individuals and over time. Understanding the landscape of these graded individual-/group-level longitudinal variations is critical for precise phenotyping; however, this remains challenging to model. Addressing this challenge, we leverage the National Alzheimer's Coordinating Center database to derive a unified geometric framework of graded longitudinal phenotypic variation in Alzheimer's disease and frontotemporal lobar degeneration. We included three time-point, cognitive-behavioural and clinical data from 390 typical, atypical and intermediate Alzheimer's disease and frontotemporal lobar degeneration variants (114 typical Alzheimer's disease; 107 behavioural variant frontotemporal dementia; 42 motor variants of frontotemporal lobar degeneration; and 103 primary progressive aphasia patients). On this data, we applied advanced data-science approaches to derive low-dimensional geometric spaces capturing core features underpinning clinical progression of Alzheimer's disease and frontotemporal lobar degeneration syndromes. To do so, we first used principal component analysis to derive six axes of graded longitudinal phenotypic variation capturing patient-specific movement along and across these axes. Then, we distilled these axes into a visualisable 2D manifold of longitudinal phenotypic variation using Uniform Manifold Approximation and Projection. Both geometries together enabled the assimilation and inter-relation of paradigmatic and mixed cases, capturing dynamic individual trajectories, and linking syndromic variability to neuropathology and key clinical end-points such as survival. Through these low-dimensional geometries, we show that (i) specific syndromes (Alzheimer's disease and primary progressive aphasia) converge over time into a de-differentiated pooled phenotype, while others (frontotemporal dementia variants) diverge to look different from this generic phenotype; (ii) phenotypic diversification is predicted by simultaneous progression along multiple axes, varying in a graded manner between individuals and syndromes; and (iii) movement along specific principal axes predicts survival at 36 months in a syndrome-specific manner and in individual pathological groupings. The resultant mapping of dynamics underlying cognitive-behavioural evolution potentially holds paradigm-changing implications to predicting phenotypic diversification and phenotype-neurobiological mapping in Alzheimer's disease and frontotemporal lobar degeneration.

Ineffective esophageal motility: Characterization and outcomes across pediatric neurogastroenterology and motility centers in the United States.

Ineffective esophageal motility (IEM) on high-resolution manometry (HRM) is not consistently associated with specific clinical syndromes or outcomes. We evaluated the prevalence, clinical features, management, and outcomes of pediatric IEM patients across the United States. Clinical and manometric characteristics of children undergoing esophageal HRM during 2021-2022 were collected from 12 pediatric motility centers. Clinical presentation, test results, management strategies, and outcomes were compared between children with IEM and normal HRM. Of 236 children (median age 15 years, 63.6% female, 79.2% Caucasian), 62 (23.6%) patients had IEM, and 174 (73.7%) patients had normal HRM, with similar demographics, medical history, clinical presentation, and median symptom duration. Reflux monitoring was performed more often for IEM patients (25.8% vs. 8.6%, p = 0.002), but other adjunctive testing was similar. Among 101 patients with follow-up, symptomatic cohorts declined in both groups in relation to the initial presentation (p > 0.107 for each comparison) with management targeting symptoms, particularly acid suppression. Though prokinetics were used more often and behavioral therapy less often in IEM (p ≤ 0.015 for each comparison), symptom outcomes were similar between IEM and normal HRM. Despite a higher proportion with residual dysphagia on follow-up in IEM (64.0% vs. 39.1%, p = 0.043), an alternate mechanism for dysphagia was identified more often in IEM (68.8%) compared to normal HRM (27.8%, p = 0.017). IEM is a descriptive manometric pattern rather than a clinical diagnosis requiring specific intervention in children. Management based on clinical presentation provides consistent symptom outcomes.