In several malignancies, only a limited number of patients respond to immune checkpoint inhibitors. Predicting and monitoring responses to these inhibitors represent an unmet clinical need. Here, we developed a PET/CT probe targeting granzyme B, [⁶⁸Ga]Ga-NOTA-Gly-Gly-Gly-Ile-Glu-Pro-Asp-CHO (GSI), and aimed to investigate whether it can be used to monitor the effects of immune checkpoint inhibitors early in the course of therapy. Methods: Seventy-two patients with gastric cancer (stages III–IV) were recruited for [⁶⁸Ga]Ga-NOTA-GSI PET/CT imaging after 2 or 3 cycles of the immunotherapy, and 40 patients were included in the final analysis. The SUV_max of primary tumors (SUV_max-t), SUV_max of metastatic lymph nodes (SUV_max-LN), and SUV_max of normal tissues (liver and blood pool) were measured, and their target-to-liver background ratio (TLR) and target-to-blood background ratio (TBR) were denoted for primary tumors as TLR_tumor and TBR_tumor and for metastatic lymph nodes as TLR_LN and TBR_LN, respectively. The treatment responses were assessed within 1 wk after full-course treatment according to RECIST version 1.1. Wilcoxon rank-sum tests were used to compare the PET/CT parameters between responders and nonresponders. Receiver operating characteristic curve analysis was used to assess the diagnostic efficacy of [⁶⁸Ga]Ga-NOTA-GSI PET/CT parameters in identifying responders. Two-tailed P value of less than 0.05 was considered statistically significant. Results: We found that SUV_max-t, TLR_tumor, TBR_tumor, SUV_max-LN, and TBR_LN were higher in responders than in nonresponders (2.49 ± 0.58 vs. 1.55 ± 0.48, P = 0.000; 2.24 ± 0.48 vs. 1.74 ± 0.67, P = 0.007; 1.38 ± 0.43 vs. 0.90 ± 0.23, P = 0.000; 2.24 ± 0.99 vs. 1.42 ± 0.55, P = 0.003; and 1.28 ± 0.68 vs. 0.83 ± 0.32, P = 0.012, respectively). According to receiver operating characteristic curve analysis, the area under the curve for SUV_max-t, TBR_tumor, TLR_tumor, SUV_max-LN, TLR_LN, and TBR_LN was 0.886, 0.866, 0.746, 0.772, 0.648, and 0.731, respectively. The threshold of SUV_max-t was 2.05, and its sensitivity and specificity were 81.0% and 84.2%, respectively. In addition, multivariate logistic regression indicated that TBR_tumor was an independent predictor of treatment response (P = 0.03). Conclusion: Our results indicated that [⁶⁸Ga]Ga-NOTA-GSI PET/CT is a promising tool for predicting early response to combined immunotherapy in gastric cancer patients.

The clinical impact of 16α-¹⁸F-fluoro-17β-estradiol (¹⁸F-FES) PET/CT on patient management has not been well investigated. The aim of this study was to assess the clinical impact of ¹⁸F-FES PET/CT on the management of patients with recurrent or metastatic breast cancer. Methods: Study subjects were identified retrospectively from a database of a prospective trial for postmarketing surveillance of ¹⁸F-FES between 2021 and 2023. Patients who were suspected or known to have recurrent or metastatic estrogen receptor–positive breast cancer based on a routine standard workup were included. Planned management before and actual management after ¹⁸F-FES PET/CT were assessed by 2 experienced medical oncologists via medical chart review. A 5-point questionnaire was provided to evaluate the value of ¹⁸F-FES PET/CT for management planning. The rate of intention-to-treat and interdisciplinary changes, and the impact of ¹⁸F-FES PET/CT according to PET/CT result or clinical indication, were examined. Results: Of the 344 included patients, 120 (35%) experienced a change in management after ¹⁸F-FES PET/CT. In 139 (40%) patients,¹⁸F-FES PET/CT supported the existing management decision without a change in management. Intention-to-treat and interdisciplinary changes accounted for 64% (77/120) and 68% (82/120) of all changes, respectively. A higher rate of change was observed when lesions were ¹⁸F-FES–negative (44% [36/81]) than ¹⁸F-FES–positive (30% [51/172]) or mixed ¹⁸F-FES–positive/negative (36% [33/91]). Regarding clinical indications, the highest rate of change was shown when evaluating the origins of metastasis of double primary cancers (64% [9/14]). Conclusion: ¹⁸F-FES PET/CT modified the management of recurrent or metastatic breast cancer, serving as an impactful imaging modality in clinical practice.

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.

Karolinska Institutet is a medical university encompassing 21 departments distributed across three departmental or campus groups. Pharmacological research has a long and successful tradition at the institute with a multitude of seminal findings in the areas of neuronal control of vasodilatation, cardiovascular pharmacology, neuropsychopharmacology, receptor pharmacology, and pharmacogenomics that resulted in, among many other recognitions, two Nobel prizes in Physiology and Medicine, one in 1970 to Ulf von Euler for his discovery of the processes involved in storage, release, and inactivation of neurotransmitters and the other in 1982 to Sune Bergström and Bengt Samuelsson for their work on prostaglandins and the discovery of leukotrienes. Pharmacology at Karolinska Institutet has over the last decade been ranked globally among the top 10 according to the QS World University Ranking. With the Department of Physiology and Pharmacology now celebrating its 75-year anniversary, we wanted to take this as an opportunity to showcase recent research achievements and how they paved the way for current activities at the department. We emphasize examples from preclinical and clinical research where the dpartment's integrative environment and robust infrastructure have successfully facilitated the translation of findings into clinical applications and patient benefits. The close collaboration between preclinical scientists and clinical researchers across various disciplines, along with a strong network of partnerships within the department and beyond, positions us to continue leading world-class pharmacological research at the Department of Physiology and Pharmacology for decades to come.

Hearing disorders pose significant challenges to individuals experiencing them and their overall quality of life, emphasizing the critical need for advanced pharmacological approaches to address these conditions. Current treatment options often focus on amplification devices, cochlear implants, or other rehabilitative therapies, leaving a substantial gap regarding effective pharmacological interventions. Advancements in our understanding of the molecular and cellular mechanisms involved in hearing disorders induced by noise, aging, and ototoxicity have opened new avenues for drug development, some of which have led to numerous clinical trials, with promising results. The development of optimal drug delivery solutions in animals and humans can also enhance the targeted delivery of medications to the ear. Moreover, large genome studies contributing to a genetic understanding of hearing loss in humans combined with advanced molecular technologies in animal studies have shown a great potential to increase our understanding of the etiologies of hearing loss. The auditory system exhibits circadian rhythms and temporal variations in its physiology, its vulnerability to auditory insults, and its responsiveness to drug treatments. The cochlear clock rhythms are under the control of the glucocorticoid system, and preclinical evidence suggests that the risk/benefit profile of hearing disorder treatments using chronopharmacological approaches would be beneficial. If translatable to the bedside, such approaches may improve the outcome of clinical trials. Ongoing research into the molecular and genetic basis of auditory disorders, coupled with advancements in drug formulation and delivery as well as optimized timing of drug administration, holds great promise of more effective treatments.

Nitric oxide (NO) from endothelial NO synthase importantly contributes to vascular homeostasis. Reduced NO production or increased scavenging during disease conditions with oxidative stress contribute to endothelial dysfunction and NO deficiency. In addition to the classical enzymatic NO synthases (NOS) system, NO can also be generated via the nitrate-nitrite-NO pathway. Dietary and pharmacological approaches aimed at increasing NO bioactivity, especially in the cardiovascular system, have been the focus of much research since the discovery of this small gaseous signaling molecule. Despite wide appreciation of the biological role of NOS/NO signaling, questions still remain about the chemical nature of NOS-derived bioactivity. Recent studies show that NO-like bioactivity can be efficiently transduced by mobile NO-ferroheme species, which can transfer between proteins, partition into a hydrophobic phase, and directly activate the soluble guanylyl cyclase-cGMP-protein kinase G pathway without intermediacy of free NO. Moreover, interaction between red blood cells and the endothelium in the regulation of vascular NO homeostasis have gained much attention, especially in conditions with cardiometabolic disease. In this review we discuss both classical and nonclassical pathways for NO generation in the cardiovascular system and how these can be modulated for therapeutic purposes.

The class F of G protein-coupled receptors (GPCRs) consists of 10 Frizzleds (FZD_1–10) and Smoothened (SMO). FZDs bind and are activated by secreted lipoglycoproteins of the Wingless/Int-1 (WNT) family, and SMO is indirectly activated by the Hedgehog (Hh) family of morphogens acting on the transmembrane protein Patched. The advance of our understanding of FZDs and SMO as dynamic transmembrane receptors and molecular machines, which emerged during the past 14 years since the first-class F GPCR IUPHAR nomenclature report, justifies an update. This article focuses on the advances in molecular pharmacology and structural biology providing new mechanistic insight into ligand recognition, receptor activation mechanisms, signal initiation, and signal specification. Furthermore, class F GPCRs continue to develop as drug targets, and novel technologies and tools such as genetically encoded biosensors and CRISP/Cas9 edited cell systems have contributed to refined functional analysis of these receptors. Also, advances in crystal structure analysis and cryogenic electron microscopy contribute to the rapid development of our knowledge about structure-function relationships, providing a great starting point for drug development. Despite the progress, questions and challenges remain to fully understand the complexity of the WNT/FZD and Hh/SMO signaling systems.

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:

Hemangioblastoma is a rare vascular tumor that occurs within the central nervous system in children. Differentiating hemangioblastoma from other posterior fossa tumors can be challenging on imaging, and preoperative diagnosis can change the neurosurgical approach. We hypothesize that a "lightbulb sign" on the arterial spin-labeling (ASL) sequence (diffuse homogeneous intense hyperperfusion within the solid component of the tumor) will provide additional imaging finding to differentiate hemangioblastoma from other posterior fossa tumors.

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:

Preoperative assessment of meningioma consistency is beneficial for optimizing surgical strategy and prognosis of patients. We aim to develop a noninvasive prediction model for meningioma consistency utilizing MR elastography and DTI.

BACKGROUND AND PURPOSE:

Periprocedural intracranial hemorrhage is one of common complications after stent placement for symptomatic intracranial atherosclerotic stenosis. This study was conducted to demonstrate predictors and long-term outcomes of periprocedural intracranial hemorrhage after stent placement for symptomatic intracranial atherosclerotic stenosis.

BACKGROUND AND PURPOSE:

Mechanical thrombectomy is a fundamental intervention for acute ischemic stroke treatment. While conventional techniques are effective, cyclic aspiration (CyA) shows potential for better recanalization rates. We aim to investigate factors affecting CyA and compare them with static aspiration (StA).

SUMMARY:

Vascular inflammation is widely recognized as an important factor in the atherosclerotic process, particularly in terms of plaque development and progression. Conventional tests, such as measuring circulating inflammatory biomarkers, lack the precision to identify specific areas of vascular inflammation. In this context, noninvasive imaging modalities can detect perivascular fat changes, serving as a marker of vascular inflammation. This review aims to provide a comprehensive overview of the key concepts related to perivascular carotid fat and its pathophysiology. Additionally, we examine the existing literature on the association of pericarotid fat with features of plaque vulnerability and cerebrovascular events. Finally, we scrutinize the advantages and limitations of the noninvasive assessment of pericarotid fat.

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.

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.

Although the progressive histologic steps leading to endometrial cancer (EndoCA), the most common female reproductive tract malignancy, from endometrial hyperplasia are well-established, the molecular changes accompanying this malignant transformation in a single patient have never been described. We had the unique opportunity to investigate the paired histologic and molecular features associated with the 12-yr development of EndoCA in a postmenopausal female who could not undergo hysterectomy and instead underwent progesterone treatment. Using a specially designed 58-gene next-generation sequencing panel, we analyzed a total of 10 sequential biopsy samples collected over this time frame. A total of eight pathogenic/likely pathogenic mutations in seven genes, APC, ARID1A, CTNNB1, CDKN2A, KRAS, PTEN, and TP53, were identified. A PTEN nonsense mutation p.W111* was present in all samples analyzed except histologically normal endometrium. Apart from this PTEN mutation, the only other recurrent mutation was KRAS G12D, which was present in six biopsy samplings, including histologically normal tissue obtained at the patient's first visit but not detectable in the cancer. The PTEN p.W111* mutant allele fractions were lowest in benign, inactive endometrial glands (0.7%), highest in adenocarcinoma (36.9%), and, notably, were always markedly reduced following progesterone treatment. To our knowledge, this report provides the first molecular characterization of EndoCA development in a single patient. A single PTEN mutation was present throughout the 12 years of cancer development. Importantly, and with potential significance toward medical and nonsurgical management of EndoCA, progesterone treatments were consistently noted to markedly decrease PTEN mutant allele fractions to precancerous levels.

Here, we highlight the case of a 31-yr-old man who had clinical features of primary hypertrophic osteoarthropathy (PHOAR) and harbored a homozygous variant (c.38C > A, p.Ala13Glu) in the HPGD gene, as indicated by whole-exome sequencing (WES). This variant has been previously classified by our laboratory as a variant of uncertain significance (VUS). However, another patient with the same phenotype and the same homozygous variant in HPGD was subsequently reported. In reassessing the variant, the absence of this variant in the gnomAD population database, supporting computational predictions, observation in homozygosity in two probands, and specificity of the phenotype for HPGD, all provide sufficient evidence to reclassify the HPGD c.38C > A, p.Ala13Glu variant as likely pathogenic.

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.

The usual challenges of conducting primary care research, including randomized trials, have been exacerbated, and new ones identified, during the COVID-19 pandemic. HOMER (Home versus Office for Medication Enhanced Recovery; subsequently, Comparing Home, Office, and Telehealth Induction for Medication Enhanced Recovery) is a pragmatic, comparative-effectiveness research trial that aims to answer a key question from patients and clinicians: What is the best setting in which to start treatment with buprenorphine for opioid use disorder for this patient at this time? In this article, we describe the difficult journey to find the answer. The HOMER study began as a randomized trial comparing treatment outcomes in patients starting treatment with buprenorphine via induction at home (unobserved) vs in the office (observed, synchronous). The study aimed to enroll 1,000 participants from 100 diverse primary care practices associated with the State Networks of Colorado Ambulatory Practices and Partners and the American Academy of Family Physicians National Research Network. The research team faced unexpected challenges related to the COVID-19 pandemic and dramatic changes in the opioid epidemic. These challenges required changes to the study design, protocol, recruitment intensity, and funding conversations, as well as patience. As this is a participatory research study, we sought, documented, and responded to practice and patient requests for adaptations. Changes included adding a third study arm using telehealth induction (observed via telephone or video, synchronous) and switching to a comprehensive cohort design to answer meaningful patient-centered research questions. Using a narrative approach based on the Greek myth of Homer, we describe here the challenges and adaptations that have provided the opportunity for HOMER to thrive and find the way home. These clinical trial strategies may apply to other studies faced with similar cultural and extreme circumstances.

Patient expectations of receiving antibiotics for common symptoms can trigger unnecessary use. We conducted a survey (n = 564) between January 2020 to June 2021 in public and private primary care clinics in Texas to study the prevalence and predictors of patients’ antibiotic expectations for common symptoms/illnesses. We surveyed Black patients (33%) and Hispanic/Latine patients (47%), and over 93% expected to receive an antibiotic for at least 1 of the 5 pre-defined symptoms/illnesses. Public clinic patients were nearly twice as likely to expect antibiotics for sore throat, diarrhea, and cold/flu than private clinic patients. Lack of knowledge of potential risks of antibiotic use was associated with increased antibiotic expectations for diarrhea (odds ratio [OR] = 1.6; 95% CI, 1.1-2.4) and cold/flu symptoms (OR = 2.9; 95% CI, 2.0-4.4). Lower education and inadequate health literacy were predictors of antibiotic expectations for diarrhea. Future antibiotic stewardship interventions should tailor patient education materials to include information on antibiotic risks and guidance on appropriate antibiotic indications.

PURPOSE

The impact of digital health on medically underserved patients is unclear. This study aimed to determine the early impact of a digital innovation to grow quality care through an interprofessional care team (DIG IT) on the blood pressure (BP) and 10-year atherosclerotic cardiovascular disease (ASCVD) risk score of medically underserved patients.

BACKGROUND

For many patients with post–COVID-19 condition (long COVID), primary care is the first point of interaction with the health care system. In principle, primary care is well situated to manage long COVID. Beyond expressions of disempowerment, however, the patient’s perspective regarding the quality of long COVID care is lacking. Therefore, this study aimed to analyze the expectations and experiences of primary care patients seeking treatment for long COVID.

The strength of reproductive isolation (RI) between two or more lineages during the process of speciation can vary by the ecological conditions. However, most speciation research has been limited to studying how ecologically dependent RI varies among a handful of broadly categorized environments. Very few studies consider the variability of RI and its effects on speciation at finer scales—that is, within each environment due to spatial or temporal environmental heterogeneity. Such variation in RI across time and/or space may inhibit speciation through leaky reproductive barriers or promote speciation by facilitating reinforcement. To investigate this overlooked aspect of speciation research, we conducted a literature review of existing studies of variation in RI in the field and then conducted individual-based simulations to examine how variation in hybrid fitness across time and space affects the degree of gene flow. Our simulations indicate that the presence of variation in hybrid fitness across space and time often leads to an increase in gene flow compared to scenarios where hybrid fitness remains static. This observation can be attributed to the convex relationship between the degree of gene flow and the strength of selection on hybrids. Our simulations also show that the effect of variation in RI on facilitating gene flow is most pronounced when RI, on average, is relatively low. This finding suggests that it could serve as an important mechanism to explain why the completion of speciation is often challenging. While direct empirical evidence documenting variation in extrinsic RI is limited, we contend that it is a prevalent yet underexplored phenomenon. We support this argument by proposing common scenarios in which RI is likely to exhibit variability and thus influence the process of speciation.

Surprisingly little attention has been given to the impact of selfing on speciation, even though selfing reduces gene flow between populations and affects other key population genetics parameters. Here we review recent theoretical work and compile empirical data from crossing experiments and genomic and phylogenetic studies to assess the effect of mating systems on the speciation process. In accordance with theoretical predictions, we find that accumulation of hybrid incompatibilities seems to be accelerated in selfers, but there is so far limited empirical support for a predicted bias toward underdominant loci. Phylogenetic evidence is scarce and contradictory, including studies suggesting that selfing either promotes or hampers speciation rate. Further studies are therefore required, which in addition to measures of reproductive barrier strength and selfing rate should routinely include estimates of demographic history and genetic divergence as a proxy for divergence time.

α-Synuclein (AS) is a small presynaptic protein that is genetically, biochemically, and neuropathologically linked to Parkinson's disease (PD) and related synucleinopathies. We present here a review of the topic of this relationship, focusing on more recent knowledge. In particular, we review the genetic evidence linking AS to familial and sporadic PD, including a number of recently identified point mutations in the SNCA gene. We briefly go over the relevant neuropathological findings, stressing the evidence indicating a correlation between aberrant AS deposition and nervous system dysfunction. We analyze the structural characteristics of the protein, in relation to both its physiologic and pathological conformations, with particular emphasis on posttranslational modifications, aggregation properties, and secreted forms. We review the interrelationship of AS with various cellular compartments and functions, with particular focus on the synapse and protein degradation systems. We finally go over the recent exciting data indicating that AS can provide the basis for novel robust biomarkers in the field of synucleinopathies, while at the same time results from the first clinical trials specifically targeting AS are being reported.

Approximately 8.5%–16.2% of childhood cancers are associated with a pathogenic/likely pathogenic germline variant—a prevalence that is likely to rise with improvements in phenotype recognition, sequencing, and variant validation. One highly informative, classical hereditary cancer predisposition syndrome is Li–Fraumeni syndrome (LFS), associated with germline variants in the TP53 tumor suppressor gene, and a >90% cumulative lifetime cancer risk. In seeking to improve outcomes for young LFS patients, we must improve the specificity and sensitivity of existing cancer surveillance programs and explore how to complement early detection strategies with pharmacology-based risk-reduction interventions. Here, we describe novel precision screening technologies and clinical strategies for cancer risk reduction. In particular, we summarize the biomarkers for early diagnosis and risk stratification of LFS patients from birth, noninvasive and machine learning–based cancer screening, and drugs that have shown the potential to be repurposed for cancer prevention.

Most childhood cancers possess distinct clinicopathological profiles from those seen in adulthood, reflecting their divergent mechanisms of carcinogenesis. Rather than depending on the decades-long, stepwise accumulation of changes within a mature cell that defines adult carcinomas, many pediatric malignancies emerge rapidly as the consequence of random errors during development. These errors—whether they be genetic, epigenetic, or microenvironmental—characteristically block maturation, resulting in phenotypically primitive neoplasms. Only an event that falls within a narrow set of spatiotemporal parameters will forge a malignant clone; if it occurs too soon then the event might be lethal, or negatively selected against, while if it is too late or in an incorrectly primed precursor cell then the necessary intracellular conditions for transformation will not be met. The precise characterization of these changes, through the study of normal tissues and tumors from patients and model systems, will be essential if we are to develop new strategies to diagnose, treat, and perhaps even prevent childhood cancer.

Redox reactions control fundamental biochemical processes, including energy production, metabolism, respiration, detoxification, and signal transduction. Cancer cells, due to their generally active metabolism for sustained proliferation, produce high levels of reactive oxygen species (ROS) compared to normal cells and are equipped with antioxidant defense systems to counteract the detrimental effects of ROS to maintain redox homeostasis. The KEAP1-NRF2 system plays a major role in sensing and regulating endogenous antioxidant defenses in both normal and cancer cells, creating a bivalent contribution of NRF2 to cancer prevention and therapy. Cancer cells hijack the NRF2-dependent antioxidant program and exploit a very unique metabolism as a trade-off for enhanced antioxidant capacity. This work provides an overview of redox metabolism in cancer cells, highlighting the role of the KEAP1-NRF2 system, selenoproteins, sulfur metabolism, heme/iron metabolism, and antioxidants. Finally, we describe therapeutic approaches that can be leveraged to target redox metabolism in cancer.

The broad application of noninvasive imaging has transformed preclinical cancer research, providing a powerful means to measure dynamic processes in living animals. While imaging technologies are routinely used to monitor tumor growth in model systems, their greatest potential lies in their ability to answer fundamental biological questions. Here we present the broad range of potential imaging applications according to the needs of a cancer biologist with a focus on some of the common biological processes that can be used to visualize and measure. Topics include imaging metastasis; biophysical properties such as perfusion, diffusion, oxygenation, and stiffness; imaging the immune system and tumor microenvironment; and imaging tumor metabolism. We also discuss the general ability of each approach and the level of training needed to both acquire and analyze images. The overall goal is to provide a practical guide for cancer biologists interested in answering biological questions with preclinical imaging technologies.

Vision is initiated by capturing photons in highly specialized sensory cilia known as the photoreceptor outer segment. Because of its lipid and protein composition, the outer segments are prone to photo-oxidation, requiring photoreceptors to have robust antioxidant defenses and high metabolic synthesis rates to regenerate the outer segments every 10 days. Both processes required high levels of glucose uptake and utilization. Retinitis pigmentosa is a prevalent form of inherited retinal degeneration characterized by initial loss of low-light vision caused by the death of rod photoreceptors. In this disease, rods die as a direct effect of an inherited mutation. Following the loss of rods, cones eventually degenerate, resulting in complete blindness. The progression of vision loss in retinitis pigmentosa suggested that rod photoreceptors were necessary to maintain healthy cones. We identified a protein secreted by rods that functions to promote cone survival, and we named it rod-derived cone viability factor (RdCVF). RdCVF is encoded by an alternative splice product of the nucleoredoxin-like 1 (NXNL1) gene, and RdCVF was found to accelerate the uptake of glucose by cones. Without RdCVF, cones eventually die because of compromised glucose uptake and utilization. The NXNL1 gene also encodes for the thioredoxin RdCVFL, which reduces cysteines in photoreceptor proteins that are oxidized, providing a defense against radical oxygen species. We will review here the main steps of discovering this novel intercellular signaling currently under translation as a broad-spectrum treatment for retinitis pigmentosa.