Historically, the intestinal lymphatics were considered passive conduits for fluids, immune cells, dietary lipids, lipid soluble vitamins, and lipophilic drugs. Studies of intestinal lymphatic drug delivery in the late 20th century focused primarily on the drugs’ physicochemical properties, especially high lipophilicity, that resulted in intestinal lymphatic transport. More recent discoveries have changed our traditional view by demonstrating that the lymphatics are active, plastic, and tissue-specific players in a range of biological and pathological processes, including within the intestine. These findings have, in turn, inspired exploration of lymph-specific therapies for a range of diseases, as well as the development of more sophisticated strategies to actively deliver drugs or vaccines to the intestinal lymph, including a range of nanotechnologies, lipid prodrugs, and lipid-conjugated materials that "hitchhike" onto lymphatic transport pathways. With the increasing development of novel therapeutics such as biologics, there has been interest in whether these therapeutics are absorbed and transported through intestinal lymph after oral administration. Here we review the current state of understanding of the anatomy and physiology of the gastrointestinal lymphatic system in health and disease, with a focus on aspects relevant to drug delivery. We summarize the current state-of-the-art approaches to deliver drugs and quantify their uptake into the intestinal lymphatic system. Finally, and excitingly, we discuss recent examples of significant pharmacokinetic and therapeutic benefits achieved via intestinal lymphatic drug delivery. We also propose approaches to advance the development and clinical application of intestinal lymphatic delivery strategies in the future.

Over 4 decades of research support the link between Alzheimer disease (AD) and somatostatin [somatotropin-releasing inhibitory factor (SRIF)]. SRIF and SRIF-expressing neurons play an essential role in brain function, modulating hippocampal activity and memory formation. Loss of SRIF and SRIF-expressing neurons in the brain rests at the center of a series of interdependent pathological events driven by amyloid-β peptide (Aβ), culminating in cognitive decline and dementia. The connection between the SRIF and AD further extends to the neuropsychiatric symptoms, seizure activity, and inflammation, whereas preclinical AD investigations show SRIF or SRIF receptor agonist administration capable of enhancing cognition. SRIF receptor subtype-4 activation in particular presents unique attributes, with the potential to mitigate learning and memory decline, reduce comorbid symptoms, and enhance enzymatic degradation of Aβ in the brain. Here, we review the links between SRIF and AD along with the therapeutic implications.

α-Synuclein (α-Syn) aggregation in Lewy bodies and Lewy neurites has emerged as a key pathogenetic feature in Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Various factors, including posttranslational modifications (PTMs), can influence the propensity of α-Syn to misfold and aggregate. PTMs are biochemical modifications of a protein that occur during or after translation and are typically mediated by enzymes. PTMs modulate several characteristics of proteins including their structure, activity, localization, and stability. α-Syn undergoes various posttranslational modifications, including phosphorylation, ubiquitination, SUMOylation, acetylation, glycation, O-GlcNAcylation, nitration, oxidation, polyamination, arginylation, and truncation. Different PTMs of a protein can physically interact with one another or work together to influence a particular physiological or pathological feature in a process known as PTMs crosstalk. The development of detection techniques for the cooccurrence of PTMs in recent years has uncovered previously unappreciated mechanisms of their crosstalk. This has led to the emergence of evidence supporting an association between α-Syn PTMs crosstalk and synucleinopathies. In this review, we provide a comprehensive evaluation of α-Syn PTMs, their impact on misfolding and pathogenicity, the pharmacological means of targeting them, and their potential as biomarkers of disease. We also highlight the importance of the crosstalk between these PTMs in α-Syn function and aggregation. Insight into these PTMS and the complexities of their crosstalk can improve our understanding of the pathogenesis of synucleinopathies and identify novel targets of therapeutic potential.

Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites, and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, type-2 diabetes, and inflammatory bowel diseases. Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders.

This review explores the concept of synergy in pharmacology, emphasizing its importance in optimizing treatment outcomes through the combination of drugs with different mechanisms of action. Synergy, defined as an effect greater than the expected additive effect elicited by individual agents according to specific predictive models, offers a promising approach to enhance therapeutic efficacy while minimizing adverse events. The historical evolution of synergy research, from ancient civilizations to modern pharmacology, highlights the ongoing quest to understand and harness synergistic interactions. Key concepts, such as concentration-response curves, additive effects, and predictive models, are discussed in detail, emphasizing the need for accurate assessment methods throughout translational drug development. Although various mathematical models exist for synergy analysis, selecting the appropriate model and software tools remains a challenge, necessitating careful consideration of experimental design and data interpretation. Furthermore, this review addresses practical considerations in synergy assessment, including preclinical and clinical approaches, mechanism of action, and statistical analysis. Optimizing synergy requires attention to concentration/dose ratios, target site localization, and timing of drug administration, ensuring that the benefits of combination therapy detected bench-side are translatable into clinical practice. Overall, the review advocates for a systematic approach to synergy assessment, incorporating robust statistical analysis, effective and simplified predictive models, and collaborative efforts across pivotal sectors, such as academic institutions, pharmaceutical companies, and regulatory agencies. By overcoming critical challenges and maximizing therapeutic potential, effective synergy assessment in drug development holds promise for advancing patient care.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS), with a putative autoimmune origin and complex pathogenesis. Modification of the natural history of MS by reducing relapses and slowing disability accumulation was first attained in the 1990 s with the development of the first-generation disease-modifying therapies. Glatiramer acetate (GA), a copolymer of L-alanine, L-lysine, L-glutamic acid, and L-tyrosine, was discovered due to its ability to suppress the animal model of MS, experimental autoimmune encephalomyelitis. Extensive clinical trials and long-term assessments established the efficacy and the safety of GA. Furthermore, studies of the therapeutic processes induced by GA in animal models and in MS patients indicate that GA affects various levels of the innate and the adaptive immune response, generating deviation from proinflammatory to anti-inflammatory pathways. This includes competition for binding to antigen presenting cells; driving dendritic cells, monocytes, and B-cells toward anti-inflammatory responses; and stimulating T-helper 2 and T-regulatory cells. The immune cells stimulated by GA reach the CNS and secrete in situ anti-inflammatory cytokines alleviating the pathological processes. Furthermore, cumulative findings reveal that in addition to its immunomodulatory effect, GA promotes neuroprotective repair processes such as neurotrophic factors secretion, remyelination, and neurogenesis. This review aims to provide an overview of MS pathology diagnosis and treatment as well as the diverse mechanism of action of GA.

Our knowledge of the roles of individual cytochrome P450 (P450) enzymes in drug metabolism has developed considerably in the past 30 years, and this base has been of considerable use in avoiding serious issues with drug interactions and issues due to variations. Some newer approaches are being considered for "phenotyping" metabolism reactions with new drug candidates. Endogenous biomarkers are being used for noninvasive estimation of levels of individual P450 enzymes. There is also the matter of some remaining "orphan" P450s, which have yet to be assigned reactions. Practical problems that continue in drug development include predicting drug-drug interactions, predicting the effects of polymorphic and other P450 variations, and evaluating interspecies differences in drug metabolism, particularly in the context of "metabolism in safety testing" regulatory issues ["disproportionate (human) metabolites"].

Both preclinical and clinical studies implicate functional impairments of several neuroactive metabolites of the kynurenine pathway (KP), the major degradative cascade of the essential amino acid tryptophan in mammals, in the pathophysiology of neurologic and psychiatric diseases. A number of KP enzymes, such as tryptophan 2,3-dioxygenase (TDO2), indoleamine 2,3-dioxygenases (IDO1 and IDO2), kynurenine aminotransferases (KATs), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilic acid oxygenase (3-HAO), and quinolinic acid phosphoribosyltransferase (QPRT), control brain KP metabolism in health and disease and are therefore increasingly considered to be promising targets for the treatment of disorders of the nervous system. Understanding the distribution, cellular expression, and regulation of KP enzymes and KP metabolites in the brain is therefore critical for the conceptualization and implementation of successful therapeutic strategies.

BACKGROUND AND PURPOSE:

Low-field 64 mT portable brain MRI has recently shown diagnostic promise for MS. This study aimed to evaluate the utility of portable MRI (pMRI) in assessing dissemination in space (DIS) in patients presenting with optic neuritis and determine whether deploying pMRI in the MS clinic can shorten the time from symptom onset to MRI.

BACKGROUND AND PURPOSE:

Percutaneous cement augmentation has been reported as an effective salvage procedure for frail patients with spinal instrumentation failure, such as screw loosening, hardware breakage, cage subsidence, and fractures within or adjacent to stabilized segments. Favorable results were reported during a median follow-up period of 16 months in a retrospective analysis of 31 consecutive procedures performed in 29 patients. In the present study, the long-term effectiveness of this treatment in avoiding or postponing revision surgery is reported.

BACKGROUND AND PURPOSE:

Patients with brain tumors have high intersubject variation in putative language regions, which may limit the utility of straightforward application of healthy subject brain atlases in clinical scenarios. The purpose of this study was to develop a probabilistic functional brain atlas that consolidates language functional activations of sentence completion and Silent Word Generation language paradigms using a large sample of patients with brain tumors.

BACKGROUND AND PURPOSE:

Neuronal ceroid lipofuscinoses are a group of neurodegenerative disorders. Recently, enzyme replacement therapy (ERT) was approved for neuronal ceroid lipofuscinosis type 2 (CLN2), a subtype of neuronal ceroid lipofuscinoses. The aim of this study was to quantify brain volume loss in CLN2 disease in patients on ERT in comparison with a natural history cohort using MRI.

BACKGROUND AND PURPOSE:

World Health Organization (WHO) grade 2 and 3 diffuse gliomas account for approximately 5% of primary brain tumors. They are invasive and infiltrative tumors and have considerable morbidity, causing progressive neurologic deterioration. The mean survival time is <10 years from diagnosis. Surgical debulking represents first-line management. The extent of resection is associated with progression-free and overall survival. Radiologic assessment of the extent of resection is challenging. This can be underestimated on early postoperative MRI, meaning that accurate assessment may be achieved only on delayed follow-up imaging. We hypothesized that DWI may help facilitate more reliable estimates of the extent of resection on early postoperative MRI. This study aimed to assess the utility of DWI in early postoperative MRI to evaluate the extent of resection.

BACKGROUND AND PURPOSE:

Gadolinium-based contrast agents are widely used for meningioma imaging; however, concerns exist regarding their side effects, cost, and environmental impact. At the standard gadolinium dose, most meningiomas show avid contrast enhancement, suggesting that administering a smaller dose may be feasible. The purpose of this study was to evaluate the impact of a lower gadolinium dose on the differentiation between meningiomas and adjacent intracranial tissues.

BACKGROUND AND PURPOSE:

Previous studies have reported metal accumulation and microstructure changes in deep gray nuclei (DGN) in Wilson disease (WD). However, there are limited studies that investigate whether there is metal accumulation and microstructure changes in DGN of patients with WD with normal-appearing routine MRI. This study aimed to evaluate multiparametric changes in DGN of WD and whether the findings correlate with clinical severity in patients with WD.

BACKGROUND AND PURPOSE:

Brain atrophy occurs in the late stage of dementia, yet structural MRI is widely used in the work-up. Atrophy patterns can suggest a diagnosis of Alzheimer disease (AD) or frontotemporal dementia (FTD) but are difficult to assess visually. We hypothesized that the availability of a quantitative volumetric brain MRI report would increase neuroradiologists’ accuracy in diagnosing AD, FTD, or healthy controls compared with visual assessment.

BACKGROUND AND PURPOSE:

Overuse of CT-based cerebrovascular imaging in the emergency department and inpatient settings, notably CTA of the head and neck for minor and nonfocal neurologic presentations, stresses imaging services and exposes patients to radiation and contrast. Furthermore, such CT-based imaging is often insufficient for definitive diagnosis, necessitating additional MR imaging. Recent advances in fast MRI may allow timely assessment and a reduced need for head and neck CTA in select populations.

BACKGROUND AND PURPOSE:

Angioplasty and stent placement have been described as a bailout technique in individuals with failed thrombectomy. We aimed to investigate Stent retriever AssIsted Lysis (SAIL) with tirofiban before angioplasty and stent placement.

BACKGROUND AND PURPOSE:

Prediction of aneurysm instability is crucial to guide treatment decisions and to select appropriate patients with unruptured intracranial aneurysms (IAs) for preventive treatment. High-resolution 4D MR flow imaging and 3D quantification of aneurysm morphology could offer insights and new imaging markers for aneurysm instability. In this cross-sectional study, we aim to identify 4D MR flow imaging markers for aneurysm instability by relating hemodynamics in the aneurysm sac to 3D morphologic proxy parameters for aneurysm instability.

BACKGROUND AND PURPOSE:

Intracranial vessel wall imaging is technically challenging to implement, given the simultaneous requirements of high spatial resolution, excellent blood and CSF signal suppression, and clinically acceptable gradient times. Herein, we present our preliminary findings on the evaluation of a deep learning–optimized sequence using T1-weighted imaging.

SUMMARY:

The 2021 World Health Organization Classification of Tumors of the Central Nervous System (CNS5), introduced significant changes, impacting tumors ranging from glial to ependymal neoplasms. Ependymal tumors were previously classified and graded based on histopathology, which had limited clinical and prognostic utility. The updated CNS5 classification now divides ependymomas into 10 subgroups based on anatomic location (supratentorial, posterior fossa, and spinal compartment) and genomic markers. Supratentorial tumors are defined by zinc finger translocation associated (ZFTA) (formerly v-rel avian reticuloendotheliosis viral oncogene [RELA]), or yes-associated protein 1 (YAP1) fusion; posterior fossa tumors are classified into groups A (PFA) and B (PFB), spinal ependymomas are defined by MYCN amplification. Subependymomas are present across all these anatomic compartments. The new classification kept an open category of "not elsewhere classified" or "not otherwise specified" if no pathogenic gene fusion is identified or if the molecular diagnosis is not feasible. Although there is significant overlap in the imaging findings of these tumors, a neuroradiologist needs to be familiar with updated CNS5 classification to understand tumor behavior, for example, the higher tendency for tumor recurrence along the dural flap for ZFTA fusion-positive ependymomas. On imaging, supratentorial ZFTA-fused ependymomas are preferentially located in the cerebral cortex, carrying predominant cystic components. YAP1-MAMLD1-fused ependymomas are intra- or periventricular with prominent multinodular solid components and have significantly better prognosis than ZFTA-fused counterparts. PFA ependymomas are aggressive paramedian masses with frequent calcification, seen in young children, originating from the lateral part of the fourth ventricular roof. PFB ependymomas are usually midline, noncalcified solid-cystic masses seen in adolescents and young adults arising from the fourth ventricular floor. PFA has a poorer prognosis, higher recurrence, and higher metastatic rate than PFB. Myxopapillary spinal ependymomas are now considered grade II due to high recurrence rates. Spinal-MYCN ependymomas are aggressive tumors with frequent leptomeningeal spread, relapse, and poor prognosis. Subependymomas are noninvasive, intraventricular, slow-growing benign tumors with an excellent prognosis. Currently, the molecular classification does not enhance the clinicopathologic understanding of subependymoma and myxopapillary categories. However, given the molecular advancements, this will likely change in the future. This review provides an updated molecular classification of ependymoma, discusses the individual imaging characteristics, and briefly outlines the latest targeted molecular therapies.

Dihydropyrimidinase (DHP) deficiency is an autosomal recessive metabolic disorder caused by biallelic pathogenic variants of DPYS. Patients with DHP deficiency exhibit a broad spectrum of phenotypes, ranging from severe neurological and gastrointestinal involvement to cases with no apparent symptoms. The biochemical diagnosis of DHP deficiency is based on the detection of a significant amount of dihydropyrimidines in urine, plasma, and cerebrospinal fluid samples. Molecular genetic testing, specifically the identification of biallelic pathogenic variants in DPYS, has proven instrumental in confirming the diagnosis and facilitating family studies. This case study documents the diagnostic journey of an 18-yr-old patient with DHP deficiency, highlighting features at the severe end of the clinical spectrum. Notably, our patient exhibited previously unreported skeletal features that positively responded to bisphosphonate treatment, contributing valuable insights to the clinical characterization of DHP deficiency. Additionally, a novel DPYS variant was identified and confirmed pathogenicity through metabolic testing, further expanding the variant spectrum of the gene. Our case emphasizes the importance of a comprehensive diagnostic approach using genetic sequencing and metabolic testing for accurate diagnosis.

We present a unique case of a single patient presenting with two mutationally distinct, PD-L1⁺ diffuse large B-cell lymphomas (DLBCLs). One of these DLBCLs demonstrated exceptionally high mutational burden (eight disease-associated variants and 41 variants of undetermined significance) with microsatellite instability (MSI) and an acquired PMS2 mutation with loss of PMS2 protein expression, detected postchemotherapy. This report, while highlighting the extent of possible tumor heterogeneity across separate clonal expansions as well as possible syndromic B-cell neoplasia, supports the notion that, although rare, PD-L1 expression and associated states permissive of high mutational burden (such as mismatch repair gene loss of function/MSI) should be more routinely considered in DLBCLs. Appropriate testing may be predictive of outcome and inform the utility of targeted therapy in these genetically diverse and historically treatment-refractory malignancies.

Rare genetic conditions are challenging for the primary care provider to manage without proper guidelines. This clinical review is designed to assist the pediatrician, family physician, or internist in the primary care setting to manage the complexities of 16p11.2 deletion syndrome. A multidisciplinary medical home with the primary care provider leading the care and armed with up-to-date guidelines will prove most helpful to the rare genetic patient population. A special focus on technology to fill gaps in deficits, review of case studies on novel medical treatments, and involvement with the educational system for advocacy with an emphasis on celebrating diversity will serve the rare genetic syndrome population well.

The diagnosis of maturity-onset diabetes of the young (MODY), a monogenic form of diabetes mellitus caused by a mutation in a single gene, is often uncertain until genetic testing is performed. We report a 13-yr-old Korean boy who was initially diagnosed with type 2 diabetes (T2DM). MODY was suspected because of his nonobese body habitus and family history of multiple affected members. Targeted panel sequencing of all MODY-related genes was performed using the NextSeq 550Dx platform (Illumina). Sanger sequencing was performed using blood samples from the parents, siblings, and other relatives. A frameshift variant in the 3' region of the last exon of PDX1 was detected in the patient and his family members with diabetes. PP1_Moderate criterion was applied and this variant was confirmed to be the genetic cause of diabetes in the family and classified as likely pathogenic. The study highlights the importance of genetic testing for nonobese, early-onset diabetic patients with multiple affected family members. Increased awareness and aggressive genetic testing for MODY are needed.

Inositol 1,4,5-triphosphate receptor type 1 (ITPR1) is an endoplasmic reticulum–bound intracellular inositol triphosphate receptor involved in the regulation of intracellular calcium. Pathogenic variants in ITPR1 are associated with spinocerebellar ataxia (SCA) types 15/16 and 29 and have recently been implicated in a facial microsomia syndrome. In this report, we present a family with three affected individuals found to have a heterozygous missense c.800C > T (predicted p.Thr267Met) who present clinically with a SCA29-like syndrome. All three individuals presented with varying degrees of ataxia, developmental delay, and apparent intellectual disability, as well as craniofacial involvement—an uncommon finding in patients with SCA29. The variant was identified using clinical exome sequencing and validated with Sanger sequencing. It is presumed to be inherited via parental germline mosaicism. We present our findings to provide additional evidence for germline mosaic inheritance of SCA29, as well as to expand the clinical phenotype of the syndrome.

Electron transport chain (ETC) disorders are a group of rare, multisystem diseases caused by impaired oxidative phosphorylation and energy production. Deficiencies in complex III (CIII), also known as ubiquinol–cytochrome c reductase, are particularly rare in humans. Ubiquinol–cytochrome c reductase core protein 2 (UQCRC2) encodes a subunit of CIII that plays a crucial role in dimerization. Several pathogenic UQCRC2 variants have been identified in patients presenting with metabolic abnormalities that include lactic acidosis, hyperammonemia, hypoglycemia, and organic aciduria. Almost all previously reported UQCRC2-deficient patients exhibited neurodevelopmental involvement, including developmental delays and structural brain anomalies. Here, we describe a girl who presented at 3 yr of age with lactic acidosis, hyperammonemia, and hypoglycemia but has not shown any evidence of neurodevelopmental dysfunction by age 15. Whole-exome sequencing revealed compound heterozygosity for two novel variants in UQCRC2: c.1189G>A; p.Gly397Arg and c.437T>C; p.Phe146Ser. Here, we discuss the patient's clinical presentation and the likely pathogenicity of these two missense variants.

Anorectal malformations (ARMs) constitute a group of congenital defects of the gastrointestinal and urogenital systems. They affect males and females, with an estimated worldwide prevalence of 1 in 5000 live births. These malformations are clinically heterogeneous and can be part of a syndromic presentation (syndromic ARM) or as a nonsyndromic entity (nonsyndromic ARM). Despite the well-recognized heritability of nonsyndromic ARM, the genetic etiology in most patients is unknown. In this study, we describe three siblings with diverse congenital anomalies of the genitourinary system, anemia, delayed milestones, and skeletal anomalies. Genome sequencing identified a novel, paternally inherited heterozygous Caudal type Homeobox 2 (CDX2) variant (c.722A > G (p.Glu241Gly)), that was present in all three affected siblings. The variant identified in this family is absent from population databases and predicted to be damaging by most in silico pathogenicity tools. So far, only two other reports implicate variants in CDX2 with ARMs. Remarkably, the individuals described in these studies had similar clinical phenotypes and genetic alterations in CDX2. CDX2 encodes a transcription factor and is considered the master regulator of gastrointestinal development. This variant maps to the homeobox domain of the encoded protein, which is critical for interaction with DNA targets. Our finding provides a potential molecular diagnosis for this family's condition and supports the role of CDX2 in anorectal anomalies. It also highlights the clinical heterogeneity and variable penetrance of ARM predisposition variants, another well-documented phenomenon. Finally, it underscores the diagnostic utility of genomic profiling of ARMs to identify the genetic etiology of these defects.

We identified a de novo heterozygous transient receptor potential cation channel subfamily M (melastatin) member 3 (TRPM3) missense variant, p.(Asn1126Asp), in a patient with developmental delay and manifestations of cerebral palsy (CP) using phenotype-driven prioritization analysis of whole-genome sequencing data with Exomiser. The variant is localized in the functionally important ion transport domain of the TRPM3 protein and predicted to impact the protein structure. Our report adds TRPM3 to the list of Mendelian disease–associated genes that can be associated with CP and provides further evidence for the pathogenicity of the variant p.(Asn1126Asp).

Alveolar capillary dysplasia (ACD) is a fatal disorder that typically presents in the neonatal period with refractory hypoxemia and pulmonary hypertension. Lung biopsy is traditionally required to establish the diagnosis. We report a 22-mo-old male who presented with anemia, severe pulmonary hypertension, and right heart failure. He had a complicated hospital course resulting in cardiac arrest and requirement for extracorporeal membrane oxygenation. Computed tomography of the chest showed a heterogenous pattern of interlobular septal thickening and pulmonary edema. The etiology of his condition was unknown, lung biopsy was contraindicated because of his medical fragility, and discussions were held to move to palliative care. Rapid whole-genome sequencing (rWGS) was performed. In 2 d it resulted, revealing a novel FOXF1 gene pathogenic variant that led to the presumptive diagnosis of atypical ACD. Cases of atypical ACD have been reported with survival in patients using medical therapy or lung transplantation. Based on the rWGS diagnosis and more favorable potential of atypical ACD, aggressive medical treatment was pursued. The patient was discharged home after 67 d in the hospital; he is currently doing well more than 30 mo after his initial presentation with only one subsequent hospitalization and no requirement for lung transplantation. Our case reveals the potential for use of rWGS in a critically ill child in which the diagnosis is unknown. rWGS and other advanced genetic tests can guide clinical management and expand our understanding of atypical ACD and other conditions.

T-lymphoblastic lymphoma (T-LLy) is the most common lymphoblastic lymphoma in children and often presents with a mediastinal mass. Lymphomatous suprarenal masses are possible but rare. Here, we discuss the case of a previously healthy 3-yr-old male who presented with mediastinal T-LLy with bilateral suprarenal masses. Following initial treatment, surgical biopsy of persisting adrenal masses revealed bilateral neuroblastoma (NBL). A clinical genetics panel for germline cancer predisposition did not identify any pathogenic variants. Combination large panel (864 genes) profiling analysis in the context of a precision oncology study revealed two novel likely pathogenic heterozygous variants: SMARCA4 c.1420-1G > T p.? and EZH2 c.1943G > C p.(Ile631Phefs*44). Somatic analysis revealed potential second hits/somatic variants in EZH2 (in the T-LLy) and a segmental loss in Chromosome 19p encompassing SMARCA4 (in the NBL). Synchronous cancers, especially at a young age, warrant genetic evaluation for cancer predisposition; enrollment in a precision oncology program assessing germline and tumor DNA can fulfill that purpose, particularly when standard first-line genetic testing is negative and in the setting of tumors that are not classic for common cancer predisposition syndromes.

Pilocytic astrocytomas are the most common pediatric brain tumors, typically presenting as low-grade neoplasms. We report two cases of pilocytic astrocytoma with atypical tumor progression. Case 1 involves a 12-yr-old boy with an unresectable suprasellar tumor, negative for BRAF rearrangement but harboring a BRAF p.V600E mutation. He experienced tumor size reduction and stable disease following dabrafenib treatment. Case 2 describes a 6-yr-old boy with a thalamic tumor that underwent multiple resections, with no actionable driver detected using targeted next-generation sequencing. Whole-genome and RNA-seq analysis identified an internal tandem duplication in FGFR1 and RAS pathway activation. Future management options include FGFR1 inhibitors. These cases demonstrate the importance of escalating molecular diagnostics for pediatric brain cancer, advocating for early reflexing to integrative whole-genome sequencing and transcriptomic profiling when targeted panels are uninformative. Identifying molecular drivers can significantly impact treatment decisions and improve patient outcomes.

BackgroundLong-term health conditions are major challenges for care systems. Social prescribing link workers have been introduced via primary care networks (PCNs) across England since 2019 to address the wider determinants of health by connecting individuals to activities, groups, or services within their local community.AimTo assess whether the rollout of social prescribing link workers was in areas with the highest need.Design and settingA retrospective study of social prescribing link workers in England from 2019 to 2023.MethodWorkforce, population, survey, and area-level data at the PCN-level from April 2020 to October 2023 were combined. Population need before the rollout of link workers was measured using reported lack of support from local services in the 2019 General Practice Patient Survey. To assess if rollout reflected need, linear regression was used to relate provision of link workers (measured by full-time equivalent [FTE] per 10 000 patients) in each quarter to population need for support.ResultsPopulations in urban, more deprived areas and with higher proportions of people from minority ethnic groups had the highest reported lack of support. Geographically these were in the North West and London. Initially, there was no association between need and provision; then from July 2022, this became negative and significant. By October 2023, a 10-percentage point higher need for support was associated with a 0.035 (95% confidence interval = −0.634 to −0.066) lower FTE per 10 000 patients.ConclusionRollout of link workers has not been sufficiently targeted at areas with the highest need. Future deployments should be targeted at those areas.

BackgroundCOVID-19 pandemic restrictions may have influenced behaviours related to weight.AimTo describe patterns of weight change among adults living in England with type 2 diabetes (T2D) and/or hypertension during the pandemic.Design and settingAn observational cohort study using the routinely collected health data of approximately 40% of adults living in England, accessed through the OpenSAFELY service inside TPP.MethodClinical and sociodemographic characteristics associated with rapid weight gain (>0.5 kg/m2/year) were investigated using multivariable logistic regression.ResultsData were extracted on adults with T2D (n = 1 231 455, 43.9% female, and 76.0% White British) or hypertension (n = 3 558 405, 49.7% female, and 84.3% White British). Adults with T2D lost weight overall (median δ = −0.1 kg/m2/year [interquartile range {IQR} −0.7–0.4]). However, rapid weight gain was common (20.7%) and associated with the following: sex (male versus female: adjusted odds ratio [aOR] 0.78 [95% confidence interval {CI} = 0.77 to 0.79]); age (older age reduced odds, for example, aged 60–69 years versus 18–29 years: aOR 0.66 [95% CI = 0.61 to 0.71]); deprivation (least deprived Index of Multiple Deprivation [IMD] quintile versus most deprived IMD quintile: aOR 0.87 [95% CI = 0.85 to 0.89]); White ethnicity (Black versus White: aOR 0.95 [95% CI = 0.92 to 0.98]); mental health conditions (for example, depression: aOR 1.13 [95% CI = 1.12 to 1.15]); and diabetes treatment (non-insulin treatment versus no pharmacological treatment: aOR 0.68 [95% CI = 0.67 to 0.69]). Adults with hypertension maintained stable weight overall (median δ = 0.0 kg/m2/year [IQR −0.6–0.5]); however, rapid weight gain was common (24.7%) and associated with similar characteristics as in T2D.ConclusionAmong adults living in England with T2D and/or hypertension, rapid pandemic weight gain was more common among females, younger adults, those living in more deprived areas, and those with mental health conditions.

BackgroundOrlistat is recommended as an adjunct to diet and exercise for weight loss in the treatment of type 2 diabetes mellitus (T2DM).AimTo explore associations between patient characteristics and orlistat prescribing, and to determine associations of orlistat with weight loss in T2DM and prediabetes.Design and settingCohort study using anonymised health records from a UK database of general practice.MethodThe UK Clinical Practice Research Datalink (CPRD) Aurum database was searched to compile a cohort of patients aged ≥18 years, first diagnosed with T2DM or prediabetes in 2016 or 2017. Once the data had been collated, multivariable logistic regression models were used to determine associations with starting orlistat and stopping it early (<12 weeks of prescriptions) and orlistat’s associations with weight loss in those who had not been prescribed second-line antidiabetic medications.ResultsOut of 100 552 patients with incident T2DM or prediabetes, 655 (0.8%) patients with T2DM and 128 (0.7%) patients with prediabetes were prescribed orlistat. Younger people, females, those in areas of deprivation, current smokers, those coprescribed metformin, and those recorded as having hypertension were statistically significantly more likely to be prescribed orlistat; higher baseline glycated haemoglobin levels were associated with early stopping. In comparison with patients not on orlistat, those who continued using it for ≥12 weeks were more likely to lose ≥5% weight (adjusted odds ratio [AOR] 1.69, 95% confidence interval [CI] = 1.07 to 2.67) but those who stopped orlistat early were less likely to lose ≥5% weight (AOR 0.56, 95% CI = 0.29 to 1.09).ConclusionOrlistat was significantly associated with weight loss in patients with T2DM and prediabetes when taken for at least 12 weeks; however, it was infrequently prescribed and often taken for <12 weeks. Orlistat may be a useful adjunct to lifestyle modifications for patients with T2DM and prediabetes, but barriers to continued use means it may not be effective for everyone in managing weight loss.

BackgroundMost people with type 2 diabetes receive treatment in primary care by GPs who are not specialised in diabetes. Thus, it is important to uncover the most essential information needs regarding type 2 diabetes in general practice.AimTo identify information needs related to type 2 diabetes for GPs.Design and settingSystematic review focused on literature relating to Western countries.MethodMEDLINE, Embase, PsycInfo and CINAHL were searched from inception to January 2024. Two researchers conducted the selection process, and citation searches were performed to identify any relevant articles missed by the database search. Quality appraisal was conducted with the Mixed Methods Appraisal Tool. Meaning units were coded individually, grouped into categories, and then studies were summarised within the context of these categories using narrative synthesis. An evidence map was created to highlight research gaps.ResultsThirty-nine included studies revealed eight main categories and 36 subcategories of information needs. Categories were organised into a comprehensive hierarchical model of information needs, suggesting ‘Knowledge of guidelines’ and ‘Reasons for referral’ as general information needs alongside more specific needs on ‘Medication’, ‘Management’, ‘Complications’, ‘Diagnosis’, ‘Risk factors’, and ‘Screening for diabetes’. The evidence map provides readers with the opportunity to explore the characteristics of the included studies in detail.ConclusionThis systematic review provides GPs, policymakers, and researchers with a hierarchical model of information and educational needs for GPs, and an evidence map showing gaps in the current literature. Information needs about clinical guidelines and reasons for referral to specialised care overlapped with needs for more specific information.

BackgroundIncident benzodiazepine prescriptions in primary care for anxiety decreased between 2003 and 2018. However, from 2008, incident prescribing of benzodiazepines for anxiety increased among those aged 18–34 years. There are increasing concerns around prescribing of benzodiazepines. Further, although guidelines state benzodiazepines should only be prescribed short term, in 2017, 44% of incident prescriptions were prescribed for longer than the recommended duration of 2–4 weeks.AimTo understand when and why GPs prescribe benzodiazepines for anxiety in young adults.Design and settingA qualitative study was undertaken using in-depth interviews with 17 GPs from 10 general practices in South West England.MethodInterviews were conducted by telephone or videocall. A topic guide was used to ensure consistency across interviews. Interviews were audio-recorded, transcribed verbatim, and data analysed using reflexive thematic analysis.ResultsGPs described caution in prescribing benzodiazepines for anxiety in young adults, but thought they had an important role in acute situations. GPs described caution in prescribing duration, but some thought longer-term prescriptions could be appropriate. In light of these views, some GPs questioned whether primary care needs to revisit how clinicians are using benzodiazepines. GPs perceived that some young adults requested benzodiazepines and suggested this might be because they wanted quick symptom relief. GPs noted that refusing to prescribe felt uncomfortable and that the number of young adults presenting to general practice, already dependent on benzodiazepines, had increased.ConclusionPatient-driven factors for prescribing benzodiazepines suggest there are current unmet treatment needs among young adults with anxiety. Given increases in prescribing in this age group, it may be timely to revisit the role of benzodiazepines in the management of people with anxiety in primary care.

BackgroundBetween 2003 and 2018, incident prescriptions of beta-blockers for anxiety increased substantially, particularly for young adults. National Institute for Health and Care Excellence guidance for anxiety does not recommend beta-blockers, probably due to a lack of evidence to support such use. Recent reports have highlighted the potential risks of beta-blockers.AimTo understand when and why GPs prescribe beta-blockers for people with anxiety.Design and settingIn-depth interviews with 17 GPs in Bristol and the surrounding areas.MethodInterviews were held by telephone or video call. A topic guide was used to ensure consistency across interviews. Interviews were audio-recorded, transcribed verbatim, and analysed thematically.ResultsMany GPs viewed beta-blockers as ‘low risk’, particularly for young adults. Some GPs viewed beta-blockers as an alternative to benzodiazepines, acting quickly and not leading to dependence. GPs reflected that some patients appeared to want an ‘immediate fix’ to their symptoms, which GPs thought beta-blockers could potentially offer. This is salient in light of substantial waiting lists for talking therapies and delays in antidepressants taking effect. GPs described how some patients seemed more willing to try beta-blockers than antidepressants, as patients did not perceive them as ‘mental health drugs’ and therefore viewed them as potentially more acceptable and less stigmatising. Further, GPs viewed beta-blockers as ‘patient-led’, with patients managing their own dose and frequency, without GP input.ConclusionMany GPs believe that beta-blockers have a role to play in the management of anxiety. Given recent increases in the prescribing of these drugs in primary care, there is a need to assess their safety and effectiveness as a treatment for people with anxiety disorders.

BackgroundThere has been significant investment in pharmacists working in UK general practice to improve the effective and safe use of medicines. However, evidence of how to optimise collaboration between GPs and pharmacists in the context of polypharmacy (multiple medication) is lacking.AimTo explore GP and pharmacist views and experiences of in-person, interprofessional collaborative discussions (IPCDs) as part of a complex intervention to optimise medication use for patients with polypharmacy in general practice.Design and settingA mixed-method process evaluation embedded within the Improving Medicines use in People with Polypharmacy in Primary Care (IMPPP) trial conducted in Bristol and the West Midlands, between February 2021 and September 2023.MethodAudio-recordings of IPCDs between GPs and pharmacists, along with individual semi-structured interviews to explore their reflections on these discussions, were used. All recordings were transcribed verbatim and analysed thematically.ResultsA total of 14 practices took part in the process evaluation from February 2022 to September 2023; 17 IPCD meetings were audio-recorded, discussing 30 patients (range 1–6 patients per meeting). In all, six GPs and 13 pharmacists were interviewed. The IPCD was highly valued by GPs and pharmacists who described benefits, including: strengthening their working relationship; gaining in confidence to manage more complex patients; and learning from each other. It was often challenging, however, to find time for the IPCDs.ConclusionThe model of IPCD used in this study provided protected time for GPs and pharmacists to work together to deliver whole-patient care, with both professions finding this beneficial. Protected time for interprofessional liaison and collaboration, and structured interventions may facilitate improved patient care.