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IMPORTANCE: Nearly half of the older adult population has diabetes or a high-risk intermediate glycemic category, but we still lack trial evidence for effective type 2 diabetes prevention interventions in most of the current high-risk glycemic categories. OBJECTIVE: To determine whether a group-based lifestyle intervention (with or without trained volunteers with type 2 diabetes) reduced the risk of progression to type 2 diabetes in populations with a high-risk glycemic category. DESIGN, SETTING, AND PARTICIPANTS: The Norfolk Diabetes Prevention Study was a parallel, 3-arm, group-based, randomized clinical trial conducted with up to 46 months of follow-up from August 2011 to January 2019 at 135 primary care practices and 8 intervention sites in the East of England. We identified 141 973 people at increased risk of type 2 diabetes, screened 12 778 (9.0%), and randomized those with a high-risk glycemic category, which was either an elevated fasting plasma glucose level alone (≥110 and <126 mg/dL [to convert to millimoles per liter, multiply by 0.0555]) or an elevated glycated hemoglobin level (≥6.0% to <6.5%; nondiabetic hyperglycemia) with an elevated fasting plasma glucose level (≥100 to <110 mg/dL). INTERVENTIONS: A control arm receiving usual care (CON), a theory-based lifestyle intervention arm of 6 core and up to 15 maintenance sessions (INT), or the same intervention with support from diabetes prevention mentors, trained volunteers with type 2 diabetes (INT-DPM). MAIN OUTCOMES AND MEASURES: Type 2 diabetes incidence between arms RESULTS: In this study, 1028 participants were randomized (INT, 424 [41.2%] [166 women (39.2%)]; INT-DPM, 426 [41.4%] [147 women (34.5%)]; CON, 178 [17.3%] [70 women (%39.3)]) between January 1, 2011, and February 24, 2017. The mean (SD) age was 65.3 (10.0) years, mean (SD) body mass index 31.2 (5) (calculated as weight in kilograms divided by height in meters squared), and mean (SD) follow-up 24.7 (13.4) months. A total of 156 participants progressed to type 2 diabetes, which comprised 39 of 171 receiving CON (22.8%), 55 of 403 receiving INT (13.7%), and 62 of 414 receiving INT-DPM (15.0%). There was no significant difference between the intervention arms in the primary outcome (odds ratio [OR], 1.14; 95% CI, 0.77-1.7; P = .51), but each intervention arm had significantly lower odds of type 2 diabetes (INT: OR, 0.54; 95% CI, 0.34-0.85; P = .01; INT-DPM: OR, 0.61; 95% CI, 0.39-0.96; P = .033; combined: OR, 0.57; 95% CI, 0.38-0.87; P = .01). The effect size was similar in all glycemic, age, and social deprivation groups, and intervention costs per participant were low at $153 (£122). CONCLUSIONS AND RELEVANCE: The Norfolk Diabetes Prevention lifestyle intervention reduced the risk of type 2 diabetes in current high-risk glycemic categories. Enhancing the intervention with DPM did not further reduce diabetes risk. These translatable results are relevant for current diabetes prevention efforts. TRIAL REGISTRATION: ISRCTN Registry Identifier: ISRCTN34805606

Phosphaturic mesenchymal tumours are a heterogeneous set of bone and soft tissue neoplasms that can cause a number of paraneoplastic syndromes such as tumour induced osteomalacia. The term phosphaturic comes from the common finding that these tumours secrete high levels of fibroblast growth factor 23 which causes renal phosphate wasting leading to hypophosphatemia. Phosphaturic mesenchymal tumours are rare and diagnosis is difficult. A very active 68year old male presented with bone pain and muscle weakness. He was hypophosphataemic and total alkaline phosphatase was markedly elevated. The patient was placed on vitamin D supplementation but his condition progressed. In the fifth year of presentation the patient required the use of a wheelchair and described “explosive” bone pain on physical contact. Serum 1,25 dihydroxyvitamin D was low and serum fibroblast growth factor 23 was significantly elevated, raising suspicion of a phosphaturic mesenchymal tumour. A lesion was detected in his left femoral head and the patient underwent a total hip replacement. The patient displayed a rapid improvement to his condition and during a three year follow up period he returned to an active lifestyle. As molecular testing may help provide a robust diagnosis and is particularly useful in rare diseases we took a next generation sequencing approach to identify a differential expression of small RNAs in the resected tumour. Small RNAs are non-coding RNA molecules that play a key role in regulation of gene expression and can be used as specific biomarkers. We found an upregulation of miR-197. We also found a downregulation of miR-20b, miR-144 and miR-335 which is a small RNA profile typical of osteosarcoma. MiR-21, the most frequently upregulated microRNA in cancer, was downregulated. We conclude that the specific small RNA profile is typical of osteosarcoma except for the downregulation of oncogenic miR-21. Transcriptional plasticity of miR-197, which is computationally predicted to target fibroblast growth factor 23 messenger RNA, may be upregulated in a cellular effort to correct the ectopic expression of the protein.

Pregnant women with type 1 diabetes are a high-risk population who are recommended to strive for optimal glucose control, but neonatal outcomes attributed to maternal hyperglycaemia remain suboptimal. Our aim was to examine the effectiveness of continuous glucose monitoring (CGM) on maternal glucose control and obstetric and neonatal health outcomes.

Hypercalcaemia is most commonly caused by primary hyperparathyroidism (PHPT) or malignancy. PHPT is common, affects women more than men, and is usually caused by a solitary parathyroid adenoma. The most common presentation is an asymptomatic incidental finding on blood tests performed for another indication. The only curative treatment is parathyroidectomy. In 2014, the Fourth International Workshop on the management of asymptomatic PHPT updated its guidance on the management of asymptomatic PHPT. It recommended surgery in: all symptomatic patients; asymptomatic patients with hypercalcaemia >0.25 mmol/litre above the upper limit of the reference range, evidence of end-organ damage, including impaired renal function, reduced bone mineral density, established vertebral fractures and hypercalciuria; and patients <50 years old. In other patients with PHPT, conservative management with regular monitoring is an acceptable management strategy. Defining ‘asymptomatic’ is not always easy, and there is growing awareness of the prevalence of reduced quality-of-life scores among patients with ‘asymptomatic’ PHPT; however, there is a lack of definitive evidence showing benefit in these domains following parathyroidectomy. Therefore, careful clinical decision-making is required in this group of patients.

Despite currently available therapies, most patients diagnosed with acute myeloid leukemia (AML) die of their disease. Tumor-host interactions are critical for the survival and proliferation of cancer cells; accordingly, we hypothesize that specific targeting of the tumor microenvironment may constitute an alternative or additional strategy to conventional tumor-directed chemotherapy. Because adipocytes have been shown to promote breast and prostate cancer proliferation, and because the bone marrow adipose tissue accounts for up to 70% of bone marrow volume in adult humans, we examined the adipocyte-leukemia cell interactions to determine if they are essential for the growth and survival of AML. Using in vivo and in vitro models of AML, we show that bone marrow adipocytes from the tumor microenvironment support the survival and proliferation of malignant cells from patients with AML. We show that AML blasts alter metabolic processes in adipocytes to induce phosphorylation of hormone-sensitive lipase and consequently activate lipolysis, which then enables the transfer of fatty acids from adipocytes to AML blasts. In addition, we report that fatty acid binding protein-4 (FABP4) messenger RNA is upregulated in adipocytes and AML when in coculture. FABP4 inhibition using FABP4 short hairpin RNA knockdown or a small molecule inhibitor prevents AML proliferation on adipocytes. Moreover, knockdown of FABP4 increases survival in Hoxa9/Meis1-driven AML model. Finally, knockdown of carnitine palmitoyltransferase IA in an AML patient-derived xenograft model improves survival. Here, we report the first description of AML programming bone marrow adipocytes to generate a protumoral microenvironment.

Despite currently available therapies, most patients diagnosed with acute myeloid leukemia (AML) die of their disease. Tumor-host interactions are critical for the survival and proliferation of cancer cells; accordingly, we hypothesize that specific targeting of the tumor microenvironment may constitute an alternative or additional strategy to conventional tumor-directed chemotherapy. Because adipocytes have been shown to promote breast and prostate cancer proliferation, and because the bone marrow adipose tissue accounts for up to 70% of bone marrow volume in adult humans, we examined the adipocyte-leukemia cell interactions to determine if they are essential for the growth and survival of AML. Using in vivo and in vitro models of AML, we show that bone marrow adipocytes from the tumor microenvironment support the survival and proliferation of malignant cells from patients with AML. We show that AML blasts alter metabolic processes in adipocytes to induce phosphorylation of hormone-sensitive lipase and consequently activate lipolysis, which then enables the transfer of fatty acids from adipocytes to AML blasts. In addition, we report that fatty acid binding protein-4 (FABP4) messenger RNA is upregulated in adipocytes and AML when in coculture. FABP4 inhibition using FABP4 short hairpin RNA knockdown or a small molecule inhibitor prevents AML proliferation on adipocytes. Moreover, knockdown of FABP4 increases survival in Hoxa9/Meis1-driven AML model. Finally, knockdown of carnitine palmitoyltransferase IA in an AML patient-derived xenograft model improves survival. Here, we report the first description of AML programming bone marrow adipocytes to generate a protumoral microenvironment.

AbstractThis article describes the implementation and artistic evaluation of an abstract, believable virtual agent known as Qiezli. Possessing the ability to create aesthetic output by itself, Qiezli functions as an automated performance artist in Second Life (SL). Seemingly pre-occupied with its own daydreaming imagination, Qiezli is visually inspired by Josephine Anstey’s narrative-embedded zoomorphic agent, ‘The thing growing’ (2000). Qiezli uses aesthetic abstraction, Non-Verbal Communication (NVC) and combinatorial creativity to interact with SL-avatar participants beyond the confines of a goal-oriented narrative. This research catalyses methods for simulating alien ontologies and stereotypically western (i.e. Enlightenment and Romantic-era) artistic behaviours in user-generated virtual worlds. Qiezli appears alien not only via its abstract appearance but also through its idiosyncratic usage of expressing itself non-verbally by wearing video-textures in response to avatar interactions. Whereas character-traits such as self-absorption or aloofness are not usually seen as a benefit to interactivity; Qiezli’s insistence on focusing on its solitary daydreaming state mirrors a stereotypical characteristic among Romantic artists who chose to transcend society by detaching from it. This article contributes to the metaverse art-discourse by showing the perceptual and technical limitations of designing an agent in SL – especially one that is meant to be visually and behaviourally distinct from a human-controlled avatar. The main limitations are due to SL’s proprietary Linden Scripting Language (LSL) and its design that structures agent ­behaviour around a finite-state architecture comprised of event-activated gestural loops. Based on the observation results from representatives from SL’s artistic community; the authors now suggest that Qiezli or an equivalent agent be produced using a more robust cognitive architecture. Therefore, Qiezli would appear less reactive by managing external memory-storage and engage in genuine deliberation of states and ­operators.

Hypercalcaemia is most commonly caused by primary hyperparathyroidism (PHPT) or malignancy. PHPT is common, affects more women than men, and is usually due to a solitary parathyroid adenoma. Nowadays, the most common presentation is an incidental finding on blood testing. The only curative treatment is parathyroidectomy. In 2009 the Third International Workshop on the management of asymptomatic primary hyperparathyroidism updated their guidance on management of asymptomatic PHPT. They recommend surgery in: all symptomatic patients; asymptomatic patients with hypercalcaemia above the upper limit of the reference range by more than 0.25 mmol/litre, evidence of end-organ damage, including impaired renal function, and reduced bone mineral density; and patients under 50 years old. In other patients, conservative management with regular monitoring is an acceptable management strategy. Defining ‘asymptomatic’ is not always easy and there is growing awareness of the prevalence of reduced quality-of-life scores among patients with ‘asymptomatic’ PHPT, but there is a lack of definitive evidence showing benefit in these domains following parathyroidectomy. Therefore, careful clinical decision-making is required in this group of patients.

Presbyacusis, one of the most common ailments of the elderly, is often treated with hearing aids, which serve to reintroduce some or all of those sounds lost to peripheral hearing loss. However, little is known about the underlying changes to the ear and brain as a result of such experience with sound late in life. The present study attempts to model this process by rearing aged CBA mice in an augmented acoustic environment (AAE).

Hypercalcaemia is most commonly caused by primary hyperparathyroidism (PHPT) or malignancy. PHPT is common, affects more females than males, and is usually due to a solitary parathyroid adenoma. The usual presentation now is asymptomatic and incidentally picked up on blood testing. The only curative treatment is parathyroidectomy. In 2009 the Third International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism updated their guidance on management of asymptomatic PHPT. They recommend surgery in: all symptomatic patients; asymptomatic patients with hypercalcaemia greater than 0.25 mmol/litre above the upper limit of reference range, evidence of end-organ damage, including impaired renal function, and reduced bone mineral density; and patients under 50 years old in whom disease is more likely to progress. In other patients, conservative management is an acceptable management strategy so long as they can be monitored regularly. However, defining ‘asymptomatic’ is not always clear and there is growing awareness of the prevalence of reduced quality-of-life scores among patients with asymptomatic PHPT. Therefore, careful clinical decision-making is required in this group of patients. Medical management of PHPT is generally unsatisfactory although there is some evidence that alendronate may increase bone mineral density in PHPT and there are preliminary data supporting a possible role for the calcimimetic, cinacalcet.

The tumour suppressor gene causing multiple endocrine neoplasia type 1 (MEN1) encodes a 610 amino acid protein, menin. In order to identify menin-interacting proteins we used a yeast two-hybrid assay to screen a 12.5-dpc mouse embryo library with partial menin encompassing amino acids 278 to 476. This identified a homeobox containing protein encoded by a placenta and embryonic expression gene, referred to as Pem. GST-pull-down and coimmunoprecipitation experiments confirmed the interaction. Both proteins colocalised predominantly in the nucleus but were occasionally also found in the cytoplasm. Furthermore, in situ hybridisation studies revealed similarities in their expression patterns in mouse embryos and adult tissues. In adult mice both Men1 and Pem yielded strong signals in testis, Sertoli cells and particularly in seminiferous tubules. Thus, our study has identified that menin interacts with Pem, and the high expression of these proteins in the testis suggests a role in spermatogenesis.

We have identified a novel human zinc finger protein, hFOG-2, which is related to but distinct from the murine transcription factor Friend-of-GATA-1 (mFOG-1). The hFOG-2 gene was initially detected in K562 cells using a polymerase chain reaction approach with degenerate primers corresponding to zinc finger regions of mFOG-1. A murine homologue of hFOG-2 was also identified in the mouse expressed sequence tag data banks, indicating that a family of FOG genes exists in mammals. hFOG-2 appears to be widely expressed, while mFOG-1 is expressed primarily in erythroid and megakaryocytic cells and plays a fundamental role in the development of these lineages. Sequencing of the full-length hFOG-2 cDNA indicates that the interaction domains for transcription factors GATA-1 and mCtBP2 are both conserved and we have shown that this new FOG protein also physically interacts with these factors. We have demonstrated that hFOG-2, like mFOG-1, can act in concert with GATA-1 to activate gene expression from the p45 NF-E2 promoter region, but that it can also act to repress GATA-mediated activation of additional reporter constructs. Finally, we have identified a repression domain in hFOG-2 and show that repression is dependent upon the integrity of the mCtBP2 interaction motif Pro-Ile-Asp-Leu-Ser.

The effects of exposure to an augmented acoustic environment (AAE) on auditory function were evaluated in mouse strains that exhibit high-frequency hearing loss beginning during young adulthood (the C57BL/6J strain [C57]) or around the time of weaning/adolescence (the DBA/2J strain [DBA]). Beginning at age 25 days, mice were exposed 12 h every night to a 70 dB SPL broad-band noise AAE. The AAE was maintained until age 14 months in C57 mice and 9 months in DBA mice. Control mice were age-matched and maintained under normal vivarium acoustic conditions. The auditory brainstem response (ABR), acoustic startle response amplitude, and prepulse inhibition (PPI) were used to assess the auditory system. Exposure to the AAE resulted in improved auditory performance in both strains (better PPI, lower ABR thresholds, bigger startle amplitudes).

The safety and immunogenicity profile of COVID-19 vaccines when administered concomitantly with seasonal influenza vaccines have not yet been reported. We therefore aimed to report the results of a substudy within a phase 3 UK trial, by evaluating the safety, immunogenicity, and efficacy of NVX-CoV2373 when co-administered with licensed seasonal influenza vaccines.

Hypercalcaemia is most commonly caused by primary hyperparathyroidism (PHPT) or malignancy. PHPT is common, affects women more than men, and is usually caused by a solitary parathyroid adenoma. The most common presentation is an asymptomatic incidental finding on blood tests performed for another indication. The only curative treatment is parathyroidectomy. In 2019, National Institute for Health and Care Excellence guidelines were published regarding the management of PHPT. These recommended a surgical referral for confirmed PHPT, particularly if patients display symptoms of hypercalcaemia or show end-organ disease, or if albumin-adjusted calcium concentrations are >2.85 mmol/litre. In patients who have had unsuccessful surgery, multidisciplinary team discussions are recommended to consider reoperation. Clear guidelines on the usage of calcimimetics and bisphosphonates, as well as the routine monitoring of patients in this group, have been given. Other emerging aspects of the field that are discussed in this article include the role of genetic testing in PHPT and the diagnosis and management of normocalcaemic PHPT.

As an enthusiastic physics teacher, I love reading Physics Worldand sharing the latest research with my pupils. Many times, I have read articles that I can recommend as accessible for A-level students.

No relevant conflicts of interest to declare.

Introduction

Metabolically unhealthy obesity is associated with insulin resistance. Dysfunctional adipose tissue remodelling might explain features of this disorder, such as chronic white adipose tissue inflammation, adipocyte hypertrophy, and ectopic lipid deposition. Metalloproteinases and their tissue inhibitors (TIMPs) have been implicated in human adipose tissue remodelling. In a cross-sectional study, we investigated the association of adipose metalloproteinase and TIMP expression with whole-body lipid distribution and insulin resistance.

Metabolically unhealthy obesity is associated with adipose tissue inflammation and increased risk of type 2 diabetes. Dysfunctional adipose tissue remodelling has been implicated in development of metabolically unhealthy obesity, but the pathogenesis remains poorly characterised. We hypothesised that in health, tissue inhibitor of metalloproteinases 3 (TIMP3) modulates adipose tissue remodelling by regulating extracellular matrix turnover and shedding of the adipogenic regulator DLK1, but that in adipose tissue inflammation it might drive development of metabolically unhealthy obesity.

The article presents several recipes for oyster and squid including Oyster Shots, Oyster Natural, Tempura Oysters, Chili Salt Squid, and Tomato Chili Jam.