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Aims: To estimate healthcare resource utilization (HCRU) and healthcare costs by body mass index (BMI) in a UK cohort and to explore how this varied by defined BMI strata., Materials and Methods: This retrospective open cohort study used Discover, a linked primary and secondary electronic health records database covering 2.7 million individuals. Adults were stratified by BMI as: overweight (25-<30 kg/m 2 ); obesity class I (30-<35 kg/m 2 ); obesity class II (35-<40 kg/m 2 ); or obesity class III (≥40 kg/m 2 ). Cost data, comprising primary care, secondary care (inpatient admissions, outpatient appointments and emergency room visits) and prescriptions, were reported for 2015-2019., Results: Overall, 1 008 101 individuals were overweight, 278 782 had obesity class I; 80 621 had obesity class II, and 42 642 had obesity class III. Healthcare costs and HCRU events per person per year increased over time (2015: £851-£1321 and 10.6-13.4 events; 2019: £1143-£1871 and 11.4-14.9 events), and were higher for each successive BMI group. Groups with chronic kidney disease or cardiovascular disease incurred particularly high costs. In 270 493 individuals with obesity in 2019, more than 72% of total healthcare costs were incurred by the highest cost quintile, which had a higher mean age and more obesity-related complications (ORCs) than lower cost quintiles., Conclusions: The economic impact of obesity could be alleviated by weight management support based on unmet need, to limit the effects of BMI progression and ORC development., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: To assess the prevalence of individual obesity-related complications (ORCs) and multimorbidity (≥ 1, ≥ 2 and ≥ 3 ORCs), and multimorbidity-associated healthcare costs, over 10 years., Methods: This retrospective open cohort study used Discover, a UK database of linked primary and secondary electronic health records. Adults were stratified by body mass index (BMI; overweight: 25-< 30 kg/m 2 ; obesity class I: 30-< 35 kg/m 2 ; obesity class II: 35-< 40 kg/m 2 ; obesity class III: ≥ 40 kg/m 2 ). Outcomes by year since baseline were assessed for serial cross sections across the study period (1 January 2004 to 31 December 2019; the index date was the date of first eligible BMI measurement)., Results: Across 1 410 146 individuals (overweight: 1 008 101; obesity class I: 278 782; obesity class II: 80 621; obesity class III: 42 642), ORC prevalence was higher in successive BMI groups, and increases over time were generally greater for obesity relative to overweight. In those with ORC multimorbidity, both higher BMI and the presence of more ORCs were associated with higher annual per-person healthcare costs. Costs increased over time in those individuals with obesity and one or more ORC, as well as in those with obesity and two or more ORCs., Conclusions: Higher BMI was associated with higher baseline ORC prevalence and a greater increase in ORC prevalence over time, and with higher healthcare costs in those with multimorbidity. To reduce the burden of overweight and obesity on patients and healthcare systems, the presence, number and type of ORCs should be considered in developing effective, targeted prevention and management care pathways., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: We investigated the impact of intentional weight loss on health care resource utilization (HCRU) and costs among people with obesity., Materials and Methods: This retrospective, observational cohort study used data from the Clinical Practice Research Datalink (CPRD) GOLD database. Adults >18 years at index date [first recorded body mass index (BMI) of 30-50 kg/m 2 between 2006 and 2015 with a further BMI record 4 years later] were assigned to an intentional weight loss cohort (-25% to -10% BMI change) or a stable weight cohort (-3% to +3%), based on their BMI change during a 4-year baseline period from index date. Evidence of intention to lose weight during the baseline period was required. Linked Hospital Episode Statistics datasets captured HCRU and costs over an 8-year follow-up period. Mixed effects models adjusted for demographics, total costs during baseline and baseline comorbidities were used., Results: Baseline characteristics were similar between cohorts with weight loss (n = 8676) and stable weight (n = 44 519). Over follow-up, the weight loss cohort experienced a significantly lower mean annual increase in total costs [2.1% (95% confidence interval: 1.3-2.8)] than the stable weight cohort [4.3% (95% confidence interval: 4.0-4.6); p < .0001]. Weight loss was associated with a lower mean annual increase in multiple HCRU and cost components compared with maintaining a stable high weight., Conclusions: Our findings suggest that intentional weight loss of 10-25% is associated with lower HCRU and costs in the long term among individuals living with obesity, relative to stable weight., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Obesity-related complications (ORCs) are associated with high costs for healthcare systems. We assessed the relationship between comorbidity burden, represented by both number and type of 14 specific ORCs, and total healthcare costs over time in people with obesity in the USA., Methods: Adults (≥ 18 years old) identified from linked electronic medical records and administrative claims databases, with a body mass index measurement of 30-< 70 kg/m 2 between 1 January 2007 and 31 March 2012 (earliest measurement: index date), and with continuous enrolment for ≥ 1 year pre index (baseline year) and ≥ 8 years post index, were included. Individuals were grouped by type and number of ORCs during the pre-index baseline year. The primary outcome was annual total adjusted direct per-person healthcare costs., Results: Of 28,583 included individuals, 12,686 had no ORCs, 7242 had one ORC, 4180 had two ORCs and 4475 had three or more ORCs in the baseline year. Annual adjusted direct healthcare costs increased with the number of ORCs and over the 8-year follow-up. Outpatient costs were the greatest contributor to baseline annual direct costs, irrespective of the number of ORCs. For specific ORCs, costs generally increased gradually over the follow-up; the largest percentage increases from year 1 to year 8 were observed for chronic kidney disease (+ 78.8%) and type 2 diabetes (+ 47.8%)., Conclusions: In a US real-world setting, the number of ORCs appears to be a cost driver in people with obesity, from the time of initial obesity classification and for at least the following 8 years., (© 2023. The Author(s).)

The evolution of microorganisms often involves changes of unclear relevance, such as transient phenotypes and sequential development of multiple adaptive mutations in hotspot genes. Previously, we showed that ageing colonies of an E. coli mutant unable to produce cAMP when grown on maltose, accumulated mutations in the crp gene (encoding a global transcription factor) and in genes involved in pyrimidine metabolism such as cmk; combined mutations in both crp and cmk enabled fermentation of maltose (which usually requires cAMP-mediated Crp activation for catabolic pathway expression). Here, we study the sequential generation of hotspot mutations in those genes, and uncover a regulatory role of pyrimidine nucleosides in carbon catabolism. Cytidine binds to the cytidine regulator CytR, modifies the expression of sigma factor 32 (RpoH), and thereby impacts global gene expression. In addition, cytidine binds and activates a Crp mutant directly, thus modulating catabolic pathway expression, and could be the catabolite modulating factor whose existence was suggested by Jacques Monod and colleagues in 1976. Therefore, transcription factor Crp appears to work in concert with CytR and RpoH, serving a dual role in sensing both carbon availability and metabolic flux towards DNA and RNA. Our findings show how certain alterations in metabolite concentrations (associated with colony ageing and/or due to mutations in metabolic or regulatory genes) can drive the evolution in non-growing cells., (© 2021. The Author(s).)

: The aim of this study was to conduct 3 literature reviews to examine the impact of atopic dermatitis (AD) and chronic hand eczema (CHE) on health-related quality of life (HRQoL) compared with other chronic conditions by comparing reported utility scores of 4 commonly used generic HRQoL instruments. A systematic search was performed using PubMed, ScienceDirect, MEDLINE, EMBASE, Health Technology Assessment database, and ScHARRHUD. Inclusion criteria included, but were not limited to, patients of any age, studies from any location, publications reporting utility data based on EuroQoL 5 dimensions, the EuroQoL 5-dimension Visual Analog Scale, the Short-Form Health Survey, and the Short-Form 6 Dimensions in the English language. Inclusion criteria were met by 16 articles for AD, 25 articles for chronic conditions, and 9 articles for CHE. The findings of this review highlight that the disutility and loss in HRQoL of patients with AD and CHE are similar to or higher than other chronic conditions, such as cancer or hepatitis.

The aim of this work was to start collecting information on rational combination of antibody (Ab) and T cell vaccines into single regimens. Two promising candidate HIV-1 vaccine strategies, sequential isolates of CH505 virus Envs developed for initiation of broadly neutralizing antibody lineages and conserved-mosaic tHIVconsvX immunogens aiming to induce effective cross-clade T cell responses, were combined to assess vaccine interactions. These immunogens were delivered in heterologous vector/modality regimens consisting of non-replicating simian (chimpanzee) adenovirus ChAdOx1 (C), non-replicating poxvirus MVA (M), and adjuvanted protein (P). Outbred CD1-SWISS mice were vaccinated intramuscularly using either parallel CM8M (tHIVconsvX)/CPPP (CH505) or sequential CM16M (tHIVconsvX)/CPPP (CH505) protocols, the latter of which delivered T cell CM prior to the CH505 Env. CM8M (tHIVconsvX) and CPPP or CMMP (CH505) vaccinations alone were included as comparators. The vaccine-elicited HIV-1-specific trimer-binding and neutralizing Abs and CD8 + /CD4 + T cell responses induced by the combined and comparator regimens were not statistically separable among regimens. The Ab-lineage immunogen strategy was particularly suited for combined regimens for its likely less potent induction of Env-specific T cell responses relative to homologous epitope-based vaccine strategies. These results inform design of the first rationally combined Ab and T cell vaccine regimens in human volunteers.

Rabbits and monkeys immunized with HIV type 1 (HIV-1) native-like BG505 SOSIP.664 (BG505s) glycoprotein trimers are known to induce antibodies that can neutralize the autologous tier-2 virus. Here, we assessed the induction of HIV-1 trimer binding and neutralizing antibody (nAb) titres when BG505s trimers were also delivered by non-replicating simian (chimpanzee) adenovirus and non-replicating poxvirus modified vaccinia virus Ankara (MVA) vaccine vectors. First, we showed that approximately two-thirds and one-third of the trimers secreted from the ChAdOx1.BG505s (C) and MVA.BG505s (M) vaccine-infected cells, respectively, were cleaved and in a native-like conformation. Rabbits were immunized intramuscularly with these vaccine vectors and in some cases boosted with ISCOMATRIX™-adjuvanted BG505s protein trimer (P), using CCC, MMM, PPP, CPP, MPP and CMP vaccine regimens. We found that the peak trimer-binding antibody and tier-1A and autologous tier-2 nAb responses induced by the CC, CM, PPP, CPP, MPP and CMP regimens were comparable, although only PPP induced autologous tier-2 nAbs in all the immunized animals. Three animals developed weak heterologous tier-2 nAbs. These results demonstrate that ChAdOx1 and MVA vectors are useful delivery modalities for not only T-cell, but also antibody vaccine development.

Background: Durability of vaccine-elicited immune responses is one of the key determinants for vaccine success. Our aim is to develop a vaccination strategy against the human immunodeficiency virus type 1 (HIV-1), which induces protective and durable CD8+ T-cell responses. The central theorem of our approach is to focus T cells on highly conserved regions of the HIV-1 proteome and this is achieved through the use of the first-generation conserved vaccine immunogen HIVconsv. This immunogen vectored by plasmid DNA, simian adenovirus and poxvirus MVA was tested in healthy, HIV-1-negative adults in UK and induced high magnitudes of HIVconsv-specific plurifunctional CD8+ T cells capable of in vitro HIV-1 inhibition. Here, we assessed the durability of these responses., Methods: Vaccine recipients in trial HIV-CORE 002 were invited to provide a blood sample at 1 and 2 years after vaccination. Their PBMCs were tested in IFN-γ ELISPOT, 25-analyte Luminex, CFSE proliferation and intracellular cytokine staining assays, the last enhanced by HLA-peptide dextramer analysis., Results: 12/12 (1 year) and 8/8 (2 years) returning subjects had median (range) of 990 (150-2495) and 763 (70-1745) IFN-γ SFU/106 PBMC specific for HIVconsv, respectively, and recognized 5 (1-6) out of 6 peptide pools at 2 years. Over one-half of the HIVconsv-specific cells expressed at least 3 functions IFN-γ, TNF-α and CD107a, and were capable of proliferation. Among dextramer-reactive cells, naïve, transitional, effector and terminally differentiated memory subsets were similarly represented., Conclusions: First generation HIVconsv vaccine induced human T cells, which were plurifunctional and persisted for at least 2 years., Trial Registration: ClinicalTrials.gov NCT01151319.

Background: In this study we confirmed the ability of a Gonadotropin Releasing Hormone (GnRH) agonist, leuprorelin acetate (LA), to counteract or even suppress the 5alpha-dihydrotestosterone (DHT)-stimulated growth of androgen-sensitive prostate cancer cells (LNCaP). Since the cellular mechanisms mediating this effect are not well defined, we investigated the activity of LA, also in combination with DHT or with cyproterone acetate (CA), on the expression of genes (bcl-2, bax, c-myc) which may contribute to the proliferative behaviour of LNCaP cells. In addition, experiments aimed to evaluate the action of the analogue on apoptosis were performed., Materials and Methods: Gene expression was evaluated by RT-PCR and Western blotting on cells treated with LA (10(-11) or 10(-6) M), alone or combined with 10(-9) M DHT or 10(-7) M CA. The occurrence of apoptosis following treatment with LA (10(-11), 10(-6) or 10(-5) M), alone or combined with 10(-9) M DHT, was assessed by DNA fragmentation analysis., Results: Both the mRNA and protein of the anti-apoptotic gene bcl-2 were induced (30-125%) by DHT after 24-144 h. LA decreased bcl-2 mRNA (10-40%), while it did not unequivocally affect protein expression. The analogue always reduced (13-74%) both mRNA and protein levels obtained under DHT treatment. The mRNA and protein of the pro-apoptotic gene bax were down-regulated by DHT (15-40%), while LA generally induced bax protein but not its mRNA. LA counteracted DHT activity, even increasing bax protein levels over the controls. c-myc mRNA and protein were enhanced by DHT (15-45%) but down-regulated by LA (10-40%). Once more, the androgen effect was antagonized by LA, sometimes reducing c-myc content below the controls. CA produced the most similar effects to those triggered by DHT. The hormonal treatment did not induce any DNA fragmentation., Conclusion: In spite of gene modulation, apoptosis was not observed under LA treatment, in agreement with the lack of a cell growth effect when the analogue was used alone. Nevertheless, the observed changes in gene expression may be directly or indirectly involved in the antiproliferative effect of LA on androgen-stimulated cells.