Advancing the social return on investment framework to capture the social value of public health interventions: semistructured interviews and a review of scoping reviews.

OBJECTIVES: Investment in public health has far-reaching impacts, not only on physical health but also on communities, economies and the environment. There is increasing demand to account for the wider impact of public health and the social value that can be created, which can be captured through the use of the social return on investment (SROI) framework. This study aims to explore the application of SROI and identify areas of advancement for its use in public health. STUDY DESIGN AND METHODS: Publically available SROI studies of public health interventions previously identified through published systematic scoping reviews were examined through a methodological lens. This was complemented by semistructured interviews with key public health academic experts with experience in the field of SROI. The results were thematically analysed and triangulated. RESULTS: In total, 53 studies and nine interviews were included in the analysis. All interviewees agreed that SROI is a suitable framework to demonstrate the social value of public health interventions. Developmental aspects were also identified through the analysis. This included a more systematic use of SROI principles and methodological developments. Lastly, it was identified that further advancements were needed to promote awareness of SROI and how it can be used to generate investment. CONCLUSION: By identifying key areas for advancement, the results from this study can be used to further refine the SROI framework for use within the speciality to promote investment in services and interventions that demonstrate maximum value to people, communities, economies and the environment.

20-Year trends of hospitalisation among people with dementia: a region-wide retrospective cohort study from Lombardy, Italy.

OBJECTIVES: The aim of this study was to investigate the trends of hospitalisations among people with dementia, linking region-wide hospital and demographic health records. STUDY DESIGN: A retrospective cohort study was conducted using hospitalisation health records from the Lombardy region in Italy. METHODS: The study included people aged ≥65 years with a diagnosis of dementia who were hospitalised between 2002 and 2020 in Lombardy, which is the most populated region in Italy with 10 million inhabitants. Using data on resident population, this study computed rates of hospitalisation by calendar year, age, sex and cause of hospitalisation. RESULTS: In total, 340,144 hospitalised patients with dementia were included in the study. The rate of hospitalisation was 100.6 per 10,000 in 2002 and progressively decreased to 65.1 per 10,000 in 2020. The average age at hospitalisation in 2002 was 78.9 years for men and 81.8 years for women, which increased to 82.0 years and 84.2 years, respectively, in 2020. Respiratory diseases caused 10.4% of all hospitalisations in 2002 and grew steadily to 26.8% in 2020, becoming the leading cause of hospital admissions since 2017. CONCLUSIONS: Hospitalisation patterns for people with dementia have changed over the last 20 years, reflecting evolving epidemiological trends and the impact of healthcare policies. Region-wide administrative health record data analysis should be further utilised to explore the health needs of people with dementia and inform the planning, implementation and monitoring of effective prevention strategies in this population group.

[Endobronchial presentation of an inflammatory myofibroblastic tumor]. / Présentation endobronchique d'une tumeur myofibroblastique inflammatoire.

INTRODUCTION: Inflammatory myofibroblastic tumors are a rare cause of primary lung tumors, most often solitary and in more than 50% of cases detected in individuals under 40 years of age. OBSERVATION: A 17-year-old patient consulted in pneumology for development of hemoptysis over a period of two weeks. Thoracic computed tomography revealed a left lower lobe cavity 24mm in diameter with bronchial fistulation and hydro-aeric level. Bronchial fibroscopy by mini-endoscope highlighted an endobronchial lesion in a subdivision of the sub-segmental posterior aspect of the left lower lobe. Paraclinical assessment highlighted a probable inflammatory myofibroblastic tumour. A surgical intervention was indicated and a lower left lobectomy performed. Histological analysis confirmed the presence of the tumour, which was resected in healthy margins by left lower lobectomy.

Ultraviolet A radiation and COVID-19 deaths in the USA with replication studies in England and Italy.

BACKGROUND: Understanding factors impacting deaths from COVID-19 is of the highest priority. Seasonal variation in environmental meteorological conditions affects the incidence of many infectious diseases and may also affect COVID-19. Ultraviolet (UV) A (UVA) radiation induces release of cutaneous photolabile nitric oxide (NO) impacting the cardiovascular system and metabolic syndrome, both COVID-19 risk factors. NO also inhibits the replication of SARS-CoV2. OBJECTIVES: To investigate the relationship between ambient UVA radiation and COVID-19 deaths. METHODS: COVID-19 deaths at the county level, across the USA, were modelled in a zero-inflated negative-binomial model with a random effect for states adjusting for confounding by demographic, socioeconomic and long-term environmental variables. Only those areas where UVB was too low to induce significant cutaneous vitamin D3 synthesis were modelled. We used satellite-derived estimates of UVA, UVB and temperature and relative humidity. Replication models were undertaken using comparable data for England and Italy. RESULTS: The mortality rate ratio (MRR) in the USA falls by 29% [95% confidence interval (CI) 40% to 15%) per 100 kJ m-2 increase in mean daily UVA. We replicated this in independent studies in Italy and England and estimate a pooled decline in MRR of 32% (95% CI 48% to 12%) per 100 kJ m-2 across the three studies. CONCLUSIONS: Our analysis suggests that higher ambient UVA exposure is associated with lower COVID-19-specific mortality. Further research on the mechanism may indicate novel treatments. Optimized UVA exposure may have population health benefits.

Bone and the regulation of global energy balance.

The skeleton, populated by large numbers of osteoblasts and long-lived osteocytes, requires a constant supply of energy-rich molecules to fuel the synthesis, deposition and mineralization of bone matrix during bone modelling and remodelling. When these energetic demands are not met, bone acquisition is suppressed. Recent findings suggest that key developmental signals emanating from Wnt low-density lipoprotein-related receptor 5 and hypoxia-inducible factor pathways impact osteoblast bioenergetics to accommodate the energy requirements for bone cells to fulfil their function. In vivo studies in several mutant mouse strains have confirmed a link between bone cells and global metabolism, ultimately leading to the identification of hormonal interactions between the skeleton and other tissues. The hormones insulin and leptin affect postnatal bone acquisition, whilst osteocalcin produced by the osteoblast in turn stimulates insulin secretion by the pancreas. These observations have prompted additional questions regarding the nature of the mechanisms of fuel sensing and processing in the osteoblast and their contribution to overall energy utilization and homeostasis. Answers to such questions should advance our understanding of metabolic diseases and may ultimately improve management of affected patients. In this review, we highlight recent studies in this field and offer a perspective on the evolutionary implications of bone as a metabolic endocrine organ.

The role of angiogenesis in a murine tibial model of distraction osteogenesis.

Distraction osteogenesis (DO) is one of the most dramatic in vivo applications of mechanical stimulation as a means of inducing bone regeneration. A simple and reproducible murine model of tibia distraction osteogenesis was developed using a monolateral fixator. Bone formation was assessed histologically over a 35-day time course. The steady state expression of a broad family of angiogenesis-associated genes was assessed by microarray hybridization analyses over the same time course, while the immediate gene response that was induced during each cycle of distraction was assessed at 30 min and 8 h after the first and last rounds of activation of the fixator. Distraction osteogenesis promoted new bone formation primarily through an intramembranous process with maximal osteogenesis during the active distraction period. Histological analysis also showed that dense cortical bone continued to be formed, during the consolidation phase, for 2 weeks after distraction ended. The analysis of steady state mRNA expression levels over the time course of DO showed that VEGF-A and neuropilin, an alternate receptor for VEGF-A, both angiopoietin (Ang) 1 and 2 factors, and the Ang receptor Tie2 were the critical angiogenic factors during DO. A key transcriptional regulator of many of the angiogenic factors, hypoxia-induced factor1alpha (Hif-1a), the FGF binding protein pleiotropin/OSF1, and multiple MMP(s), were also induced during the active distraction period. Examination of the expression of angiogenic factors that were induced after each cycle of activation, demonstrated that Hif-1a, Nrp1, and VEGF-A were all cyclically induced after each increment of distraction. These results suggest that these factors are early mediators that are produced by distraction and contribute toward the processes that promote bone formation. These experiments represent the first step in defining the molecular mechanisms that regulate skeletal regeneration and the functional relationship between angiogenesis and osteogenesis during distraction osteogenesis.

Parathyroid hormone-related protein and its receptors: nuclear functions and roles in the renal and cardiovascular systems, the placental trophoblasts and the pancreatic islets.

The cloning of the so-called 'parathyroid hormone-related protein' (PTHrP) in 1987 was the result of a long quest for the factor which, by mimicking the actions of PTH in bone and kidney, is responsible for the hypercalcemic paraneoplastic syndrome, humoral calcemia of malignancy. PTHrP is distinct from PTH in a number of ways. First, PTHrP is the product of a separate gene. Second, with the exception of a short N-terminal region, the structure of PTHrP is not closely related to that of PTH. Third, in contrast to PTH, PTHrP is a paracrine factor expressed throughout the body. Finally, most of the functions of PTHrP have nothing in common with those of PTH. PTHrP is a poly-hormone which comprises a family of distinct peptide hormones arising from post-translational endoproteolytic cleavage of the initial PTHrP translation products. Mature N-terminal, mid-region and C-terminal secretory forms of PTHrP are thus generated, each of them having their own physiologic functions and probably their own receptors. The type 1 PTHrP receptor, binding both PTH(1-34) and PTHrP(1-36), is the only cloned receptor so far. PTHrP is a PTH-like calciotropic hormone, a myorelaxant, a growth factor and a developmental regulatory molecule. The present review reports recent aspects of PTHrP pharmacology and physiology, including: (a) the identification of new peptides and receptors of the PTH/PTHrP system; (b) the recently discovered nuclear functions of PTHrP and the role of PTHrP as an intracrine regulator of cell growth and cell death; (c) the physiological and developmental actions of PTHrP in the cardiovascular and the renal glomerulo-vascular systems; (d) the role of PTHrP as a regulator of pancreatic beta cell growth and functions, and, (e) the interactions of PTHrP and calcium-sensing receptors for the control of the growth of placental trophoblasts. These new advances have contributed to a better understanding of the pathophysiological role of PTHrP, and will help to identify its therapeutic potential in a number of diseases.

Selected Contribution: Osteocytes upregulate HIF-1alpha in response to acute disuse and oxygen deprivation.

Loss of mechanical loading, or disuse, rapidly precipitates locally mediated bone resorption. However, the pathway by which this process is initiated and mediated is poorly understood. In this study, we used a complementary in vivo and in vitro approach to determine whether disuse-induced osteocyte hypoxia resulted in upregulation of the hypoxia-dependent transcription factor HIF-1alpha. We found that acute disuse (1-5 days) resulted in a significant increase in the percentage of osteocytes staining positive for HIF-1alpha vs. normal bone (30.9 +/- 6.1 vs. 14.1 +/- 3.8%) and that this response was uniform around the cortex. In addition, we found that acute oxygen deprivation (4-12 h of 2% O2) resulted in a 2.1- to 3.7-fold upregulation of HIF-1alpha protein expression in MLO-Y4 osteocyte-like cells compared with cells cultured in parallel under normal oxygen conditions. Given known HIF-1alpha targets genes, we suggest that osteocyte hypoxia and subsequent upregulation of hypoxia-dependent pathways may serve to initiate and mediate disuse-induced bone resorption.

Hypoxia induces vascular endothelial growth factor gene transcription in human osteoblast-like cells through the hypoxia-inducible factor-2alpha.

VEGF is produced by osteoblasts and has been postulated to function as an angiogenic stimulus during normal skeletal development and in fracture repair. In this study, we characterized the molecular mechanisms by which experimental hypoxia increases VEGF mRNA in human MG63 osteoblast-like cells. Exposure of MG63 cells to 1% O(2) for 24 h resulted in a four-fold increase in VEGF mRNA. Immunoblotting of nuclear extracts demonstrated a time-dependent increase in the level of the Hif-2alpha protein, which preceded the rise in VEGF mRNA. To determine the effect of hypoxia on VEGF gene transcription, MG63 cells were transiently transfected with a segment of the VEGF promoter construct fused to luciferase and then exposed to 1% O(2). Hypoxia induced VEGF promoter activity five-fold by 24 h. Forced expression of Hif-2alpha, but not Hif-1alpha, increased both basal and hypoxia induced VEGF promoter activity. By contrast, the ability of the VEGF reporter to respond to hypoxia or recombinant Hif-2alpha was abolished in cells transfected with a VEGF promoter construct containing a mutation in the hypoxia response element. In summary, exposure of osteoblast-like cells to hypoxia induces VEGF expression via induction of Hif-2alpha and transcriptional activation of the VEGF promoter.

Parathyroid hormone-related protein induces G1 phase growth arrest of vascular smooth muscle cells.

In this study, we investigated the mechanisms responsible for the growth-inhibitory action of parathyroid hormone-related protein (PTHRP) in A10 vascular smooth muscle cells (VSMC). Fluorescence-activated cell sorting analysis of serum-stimulated VSMC treated with PTHRP or dibutyryl-cAMP (DBcAMP) demonstrated an enrichment of cells in G1 and a reduction in the S phase. Measurement of DNA synthesis in platelet-derived growth factor-stimulated VSMC treated with DBcAMP revealed that cells became refractory to growth inhibition by 12-16 h, consistent with blockade in mid-G1. cAMP treatment blunted the serum-induced rise in cyclin D1 during cell cycle progression without altering levels of the cyclin-dependent kinase cdk4 or cyclin E and its associated kinase, cdk2. Exposure of cells to PTHRP or cAMP resulted in a reduction in retinoblastoma gene product (Rb) phosphorylation. Immunoblotting of extracts from cAMP-treated cells with antibodies to cdk inhibitors revealed a striking increase in p27(kip1) abundance coincident with the G1 block. Immunoprecipitation with an anti-cyclin D1 antibody of cell lysates prepared from cAMP-treated cells followed by immunoblotting with antisera to p27(kip1) disclosed a threefold increase in p27(kip1) associated with cyclin D1 compared with lysates treated with serum alone. We conclude that PTHRP, by increasing intracellular cAMP, induces VSMC cycle arrest in mid-G1. This occurs secondary to a suppression in cyclin D1 and induction of p27(kip1) expression, which in turn inhibits Rb phosphorylation.

Targeted overexpression of insulin-like growth factor I to osteoblasts of transgenic mice: increased trabecular bone volume without increased osteoblast proliferation.

Insulin-like growth factor I (IGF-I) is an important growth factor for bone, yet the mechanisms that mediate its anabolic activity in the skeleton are poorly understood. To examine the effects of locally produced IGF-I in bone in vivo, we targeted expression IGF-I to osteoblasts of transgenic mice using a human osteocalcin promoter. The IGF-I transgene was expressed in bone osteoblasts in OC-IGF-I transgenic mice at high levels in the absence of any change in serum IGF-I levels, or of total body growth. Bone formation rate at the distal femur in 3-week-old OC-IGF-I transgenic mice was approximately twice that of controls. By 6 weeks, bone mineral density as measured by dual energy x-ray, and quantitative computed tomography was significantly greater in OC-IGF-I transgenic mice compared with controls. Histomorphometric measurements revealed a marked (30%) increase femoral cancellous bone volume in the OC-IGF-I transgenic mice, but no change in the total number of osteoblasts or osteoclasts. Transgenic mice also demonstrated an increase in the osteocyte lacunea occupancy, suggesting that IGF-I may extend the osteocyte life span. We conclude that IGF-I produced locally in bone osteoblasts exerts its anabolic effect primarily by increasing the activity of resident osteoblasts.

Vasorelaxant properties of parathyroid hormone-related protein in the mouse: evidence for endothelium involvement independent of nitric oxide formation.

PTH-related peptide is produced in vascular smooth muscle and is believed to participate in the local control of vascular tone. The recent identification of mid-region PTHrP peptides, as well as the discovery of multiple receptors in blood vessels, raises new questions concerning the mechanisms by which PTHrP relaxes the vasculature. In this study, we examined these mechanisms in two vascular beds of the mouse. PTHrP-(1-34) and PTH-(1-34), but not PTHrP-(38-64) or PTHrP-(38-94), caused concentration-dependent relaxation of pre-contracted aortas and reduced the spontaneous phasic activity of the portal vein. PTHrP and PTH-induced aortic relaxations were largely endothelium dependent, whereas an intact endothelium was not necessary for maximal portal vein relaxation. The endothelium-dependent component of PTHrP and PTH-induced aortic relaxations were unaffected by pretreatment with either L-NNA or indomethacin but were abolished by pretreatment with tetrabutyl ammonium. These results demonstrate that the N-terminal portions of PTHrP and PTH are required for their vasorelaxant activity in the mouse. In addition, maximal relaxant activity of PTHrP and PTH in murine aorta is dependent on the endothelium, which appears to involve the generation of an endothelium-derived hyperpolarizing factor.

Targeted overexpression of parathyroid hormone-related protein (PTHrP) to vascular smooth muscle in transgenic mice lowers blood pressure and alters vascular contractility.

PTH-related protein (PTHrP) and its receptor are expressed in vascular smooth muscle cells and are believed to participate in the local regulation of vascular tone. To explore the function of locally produced PTHrP in vascular smooth muscle in vivo, we developed transgenic mice that overexpress PTHrP in smooth muscle using a smooth muscle alpha-actin promoter to direct expression of the transgene. In the PTHrP-overexpressing mice, messenger RNA expression was mainly restricted to smooth muscle-containing tissues. Several founders also expressed the transgene in bone and heart and exhibited striking abnormalities in the development of these tissues. In PTHrP-overexpressing mice, blood pressure was significantly lower than that in wild-type controls (121 +/- 3 vs. 135 +/- 2 mm Hg; P < 0.01). Moreover, the magnitude of the vasorelaxant response to iv infusions of PTHrP-(1-34)NH2 was significantly attenuated in the transgenic animals. A similar desensitization to PTHrP was observed in aortic ring and portal vein preparations. Surprisingly, PTHrP-overexpressing mice were also significantly less responsive to the hypotensive action of infused acetylcholine in vivo and to the relaxant actions of acetylcholine on aortic vessel preparations in vitro. In summary, we have successfully targeted overexpression of PTHrP to the smooth muscle of transgenic mice. When expressed in its normal autocrine/paracrine setting, PTHrP lowers systemic blood pressure and decreases vascular responsiveness to further relaxation by PTHrP and other endothelium-dependent vasorelaxants such as acetylcholine. We postulate that the heterologous desensitization to acetylcholine-induced relaxation in PTHrP-overexpressing blood vessels involves desensitization of second messenger/effector signaling pathways common to PTHrP and acetylcholine.

Reduced blood pressure and increased sensitivity of the vasculature to parathyroid hormone-related protein (PTHrP) in transgenic mice overexpressing the PTH/PTHrP receptor in vascular smooth muscle.

PTH-related protein (PTHrP) is produced in vascular smooth muscle, where it is postulated to exert vasorelaxant properties by activation of the PTH/PTHrP type 1 receptor. As a model for studying the actions of locally produced PTHrP in vascular smooth muscle in vivo, we developed transgenic mice that overexpress the PTH/PTHrP receptor (PTHrP-R) in smooth muscle. Oocyte injection with a SMP8-PTHrP-R fusion construct yielded six founder mice. F1 offspring were viable and demonstrated selective overexpression of the SMP8-PTHP-R messenger RNA in smooth muscle-rich tissues. Baseline blood pressure measured in conscious mice by tail sphygmomanometry was significantly lower in the receptor-overexpressing mice than that in controls (117 +/- 4 vs. 133 +/- 3 mm Hg; P < 0.05). In anesthetized animals, iv infusion of PTHrP-(1-34)NH2 caused a significantly greater reduction in blood pressure and total peripheral resistance in transgenic mice than in control animals. Vascular contractility was studied in paired, isometrically mounted aortas from 9-week-old transgenic and wild-type mice. The force of contraction in response to phenlyephrine was not significantly different between transgenic and wild-type mice. However, PTHrP-(1-34) NH2 relaxed aortic vessel preparations from transgenic mice to a greater extent than in controls (77.1 +/- 3% vs. 38.4 +/- 4%; P < 0.001). To determine the impact of overexpression of PTH/PTHrP type 1 receptor and its ligand on the development of the cardiovascular system, double transgenic mice were created by crossing SMP8-PTHrP-R transgenic mice with mice overexpressing PTHrP (SMP8-PTHrP). Double transgenic mice died around day E9 with abnormalities in the developing heart. In conclusion, overexpression of PTH/PTHrP type 1 receptor in vascular smooth muscle of transgenic mice reduces blood pressure, probably through sustained activation of the receptor by endogenous ligand. The cardiovascular defects observed in mice overexpressing both PTHrP and its receptor suggest that PTHrP may play a role in the normal development of the cardiovascular system.

Parathyroid hormone-related protein expression in vascular smooth muscle of spontaneously hypertensive rats: evidence for lack of response to angiotensin II.

OBJECTIVE: We studied the expression of parathyroid hormone (PTH)-related protein in vascular smooth muscle cells of spontaneously hypertensive rats (SHR) using Wistar-Kyoto (WKY) and Sprague-Dawley rats as normotensive controls. METHODS: Aortae from 4- and 18-week-old SHR versus age-matched WKY and Sprague-Dawley rats were excised to obtain total RNA or smooth muscle cells. The cells were subcultured in Dulbecco's Modified Eagle's Medium containing 10% fetal calf serum, then serum-deprived for 72 h and stimulated with 0.1 micromol/I angiotensin II. PTH-related protein, c-myc and angiotensin II type qa receptor (AT1aR) messenger (m)RNA levels were measured by Northern blot, using total RNA extracted by phenol/chloroform. The effects of PTH-related protein(1-34)NH2 intravenous injections on arterial blood pressure and the heart rate were studied in anesthetized SHR and WKY rats. RESULTS: The Northern blots showed a significantly higher abundance of PTH-related protein mRNA in aortae of SHR versus WKY rats in the prehypertensive state but no significant difference in adult animals. In cultured aortic smooth muscle cells, angiotensin II induced a four- to sixfold increase in PTH-related protein mRNA levels in smooth muscle cells from normotensive animals, but failed to elicit a significant response in smooth muscle cells derived from SHR in either the prehypertensive or the hypertensive state. This lack of response to angiotensin II in SHR smooth muscle cells was not due to decreased expression or responsiveness of the AT1aR, since SHR smooth muscle cells had more AT1aR mRNA than Sprague-Dawley smooth muscle cells, and angiotensin II-induced activation of c-myc was faster and greater in smooth muscle cells derived from 4- or 18-week-old SHR than in Sprague-Dawley smooth muscle cells. In contrast, PTH-related protein(1-34)NH2 induced a long-lasting dose-dependent hypotensive and tachycardic response in both SHR and WKY rats, indicating that SHR retained responsiveness to the vasodilator. CONCLUSIONS: PTH-related protein gene expression in response to angiotensin II is impaired in SHR arteries. A deficiency in this potent local vasodilator may contribute to the development and/or maintenance of arterial hypertension in this model.

Risedronate, a highly effective oral agent in the treatment of patients with severe Paget's disease.

Thirteen patients with severe Paget's disease of bone [mean serum alkaline phosphatase (SAP) level 17 times the upper limit of normal] were treated with 30 mg oral risedronate daily for 8 weeks. Patients were followed for 16 weeks without treatment. The change from baseline SAP was the primary end point. Those patients whose SAP levels did not reach the normal range were retreated with 30 mg for another 8 weeks. There was a mean percent decrease in SAP of 77% after the first course of risedronate treatment and 87% after the second course of treatment. All patients who completed the study had a decrease in SAP of at least 77% from the baseline. The urinary hydroxyproline/creatinine level was decreased by 64% and 79%, respectively, during the first and second treatment courses. There were transient asymptomatic decreases in serum calcium and phosphorus levels. The urinary calcium/creatinine ratio also decreased in these patients. Serum intact PTH and 1,25-dihydroxyvitamin D levels increased transiently during risedronate treatment. Oral risedronate was well tolerated by the patients. Only one patient discontinued treatment because of an adverse event (diarrhea) thought to be related to risedronate therapy.