Return on investment of fracture liaison services: a systematic review and analysis.

Fracture liaison services (FLS) have been proven clinically effective and cost-effective in preventing subsequent fractures among patients with an existing fragility fracture. Little is known about their monetary benefits such as their return on investment (ROI). This systematic review aimed to investigate the ROI of FLS and identify the FLS characteristics with better ROI. Studies on the cost-effectiveness of FLS published between January 2000 and December 2022 were searched from MEDLINE, EMBASE, PubMed, and Cochrane Central. Two independent reviewers conducted study selection and data extraction. ROI was calculated based on the difference between monetary benefits and FLS costs divided by the FLS costs. Subgroup analysis of ROI was performed across FLS types and FLS design details. A total of 23 FLS were included in this review. The majority of them were targeting patients aged over 50 years having fractures without identified sites. The mean ROI of these FLS was 10.49 (with a median ROI of 7.57), and 86.96% of FLS had positive ROI. FLS making treatment recommendations yielded the highest ROI (with a mean ROI of 18.39 and a median of 13.60). Incorporating primary care providers (with a mean ROI of 16.04 and a median of 13.20) or having them as program leaders (with a mean ROI of 12.07 and a median of 12.07) has demonstrated a high ROI. FLS for specific fracture sites had great monetary return. Intensive FLS such as type A and B FLS programs had higher ROI than non-intensive type C and D FLS. This review revealed a 10.49-fold monetary return of FLS. Identified characteristics contributing to greater economic return informed value-for-money FLS designs. Findings highlight the importance of FLS and the feasibility of expanding their contribution in mitigating the economic burden of osteoporotic fracture and are conducive to the promotion of FLS internationally.

MAPK11 (p38ß) is a major determinant of cellular radiosensitivity by controlling ionizing radiation-associated senescence: An in vitro study.

Background and purpose: MAPKs are among the most relevant signalling pathways involved in coordinating cell responses to different stimuli. This group includes p38MAPKs, constituted by 4 different proteins with a high sequence homology: MAPK14 (p38α), MAPK11 (p38ß), MAPK12 (p38γ) and MAPK13 (p38δ). Despite their high similarity, each member shows unique expression patterns and even exclusive functions. Thus, analysing protein-specific functions of MAPK members is necessary to unequivocally uncover the roles of this signalling pathway. Here, we investigate the possible role of MAPK11 in the cell response to ionizing radiation (IR). Materials and methods: We developed MAPK11/14 knockdown through shRNA and CRISPR interference gene perturbation approaches and analysed the downstream effects on cell responses to ionizing radiation in A549, HCT-116 and MCF-7 cancer cell lines. Specifically, we assessed IR toxicity by clonogenic assays; DNA damage response activity by immunocytochemistry; apoptosis and cell cycle by flow cytometry (Annexin V and propidium iodide, respectively); DNA repair by comet assay; and senescence induction by both X-Gal staining and gene expression of senescence-associated genes by RT-qPCR. Results: Our findings demonstrate a critical role of MAPK11 in the cellular response to IR by controlling the associated senescent phenotype, and without observable effects on DNA damage response, apoptosis, cell cycle or DNA damage repair. Conclusion: Our results highlight MAPK11 as a novel mediator of the cellular response to ionizing radiation through the control exerted onto IR-associated senescence.

Microbiology and Climate Change: a Transdisciplinary Imperative.

Climate change is a complex problem involving nonlinearities and feedback that operate across scales. No single discipline or way of thinking can effectively address the climate crisis. Teams of natural scientists, social scientists, engineers, economists, and policymakers must work together to understand, predict, and mitigate the rapidly accelerating impacts of climate change. Transdisciplinary approaches are urgently needed to address the role that microorganisms play in climate change. Here, we demonstrate with case studies how diverse teams and perspectives provide climate-change insight related to the range expansion of emerging fungal pathogens, technological solutions for harmful cyanobacterial blooms, and the prediction of disease-causing microorganisms and their vector populations using massive networks of monitoring stations. To serve as valuable members of a transdisciplinary climate research team, microbiologists must reach beyond the boundaries of their immediate areas of scientific expertise and engage in efforts to build open-minded teams aimed at scalable technologies and adoptable policies.

Patient perspectives on nipple-areola complex micropigmentation during the COVID-19 pandemic.

BACKGROUND: Micropigmentation is a well-recognised option for nipple-areola complex reconstruction, as part of the breast reconstruction pathway for patients following mastectomy. As a part of delayed breast reconstruction, this treatment was put on hold during the COVID-19 pandemic. AIMS: To assess the views of patients regarding micropigmentation in response to the COVID-19 pandemic, and whether their attitudes to seeking out this part of the reconstructive journey had been altered. METHODS: A questionnaire undertaken with 53 patients between August & September 2020 attending the Micropigmentation clinic. FINDINGS: 81.1% of patients reported COVID-19 had not impacted their decision, with a similar proportion happy to proceed with the treatment at the time of questioning. CONCLUSIONS: The results highlight the importance of nipple-areola complex to our patients' reconstructive journey.

Candida Esophagitis Presenting as an Esophageal Pseudotumor.

The typical appearance of Candida esophagitis is white plaque-like membranes within the esophagus. We describe a unique case of Candida esophagitis that presented as a bulky, malignant-appearing, positron emission tomography-computed tomography-avid mass on endoscopy. Esophageal candidiasis persisted despite a standard course of antifungal medications (fluconazole 400 mg daily for 14 days), and eradication was successful only after fluconazole 800 mg daily was administered. Malignancy was excluded based on 2 separate sessions of endoscopy with multiple biopsies and finally with endoscopic full-thickness resection assisted by preresection closure with an over-the-scope clip.

Cerebrovascular autoregulation monitoring and patient-centred outcomes after cardiac surgery: a systematic review.

BACKGROUND: Impaired cerebrovascular autoregulation (CVAR) is observed in up to 20% of cardiac surgical patients. This systematic review aims to evaluate the association between impaired CVAR, measured by current monitoring techniques, and patient-centred outcomes in adults following cardiac surgery. METHODS: MEDLINE, EMBASE, PubMed, MEDLINE In-Process and Cochrane Library were systematically searched through 8 December 2017. Studies were included if they assessed associations between CVAR and patient-centred outcomes in the adult cardiac surgical population. The primary outcome of this systematic review was mortality. Secondary outcomes were stroke, delirium and acute kidney injury. Risk of bias was systematically assessed, and the GRADE methodology was used to evaluate the quality of evidence across outcomes. RESULTS: Eleven observational studies and no randomised controlled trials met the inclusion criteria. Due to methodological heterogeneity, meta-analysis was not possible. There was a high risk of bias within individual studies and low quality of evidence across outcomes. Of the included studies, one assessed mortality, five assessed stroke, four assessed delirium, and three assessed acute kidney injury. No reliable conclusions can be drawn from the one study assessing mortality. Interpretation of studies investigating CVAR and stroke, delirium and acute kidney injury was complicated by the lack of standardisation of monitoring techniques as well as varying definitions of impaired CVAR. CONCLUSIONS: There is a paucity of high quality evidence for CVAR monitoring and its associations with outcome measures in post-cardiac surgical patients, highlighting the need for future studies.

Six challenges in measuring contact networks for use in modelling.

Contact networks are playing an increasingly important role in epidemiology. A contact network represents individuals in a host population as nodes and the interactions among them that may lead to the transmission of infection as edges. New avenues for data collection in recent years have afforded us the opportunity to collect individual- and population-scale information to empirically describe the patterns of contact within host populations. Here, we present some of the current challenges in measuring empirical contact networks. We address fundamental questions such as defining contact; measurement of non-trivial contact properties; practical issues of bounding measurement of contact networks in space, time and scope; exploiting proxy information about contacts; dealing with missing data. Finally, we consider the privacy and ethical issues surrounding the collection of contact network data.

Reliability of intra-abdominal pressure measurements using the modified Kron technique.

OBJECTIVES: Assessment of intra-abdominal pressure (IAP) and the likelihood of abdominal compartment syndrome using valid and reliable measures is an important tool in the assessment of critically ill patients. The current method of relying on a single IAP per measurement period to determine patient clinical status raises the question: is a single intermittent IAP measurement an accurate indicator of clinical status or should more than one measurement be taken per measurement period? METHODS: This study sought to assess the reliability of IAP measurements. Measurements were taken using the modified Kron technique. A total of two transvesical intra-abdominal pressure measurements were undertaken per patient using a standardized protocol. Recordings were taken at intervals of 5 minutes. RESULTS: The majority of participants (58%) were surgical patients. Thirty-two were males and the mean age was 58 years (SD: 16·7 years). The concordance correlation coefficient between the two measurements was 0·95. Both the scatter and Bland-Altman plots demonstrate that the comparisons of two measurements are highly reproducible. CONCLUSION: The findings of this study suggest that conducting two IAP measurements on single patient produce comparable results; therefore, there appears to be no advantage in doing two IAP measurements on a single patient. The measurement of an IAP requires the implementation of a standardized protocol and competent and credentialed assessors trained in the procedure.

The impact of type 2 diabetes and obesity on the long-term outcomes of more than 85 000 liver transplant recipients in the US.

BACKGROUND: Type 2 diabetes is known to negatively impact the outcome of chronic liver disease. AIM: To evaluate the impact of diabetes on the outcomes of liver transplants (LT). METHODS: Study cohort included adults (>18 years) who received LT in the US between 1994 and 2013 (The Scientific Registry of Transplant Recipients). Pre- and post-transplant diabetes was recorded in patients with mortality follow-up. RESULTS: We included 85 194 liver transplant recipients. Of those, 11.2% had history of pre-transplant diabetes. The most common indications for liver transplant were hepatitis C (36.4%), alcohol-related liver disease (20.6%), primary liver malignancy of unspecified aetiology (14.7%), cryptogenic cirrhosis (8.0%), hepatitis B (4.6%) and non-alcoholic steatohepatitis (3.9%). A total of 96.5% transplants were from deceased donors, and 7.9% donors had history of diabetes. During an average 6.5 years of follow-up, 31.3% recipients died and 8.8% had a graft failure. In multivariate survival analysis [at least 5 years of cohort follow-up (N = 35 870)], after adjustment for age, ethnicity, insurance type, history of chronic diseases, HCV infection and noncompliance, independent predictors of recipient mortality included the presence of pre-transplant diabetes [adjusted hazard ratio (95%CI) = 1.21 (1.12-1.30)] and developing diabetes post-transplant [1.06 (1.02-1.11)]. Donor's history of diabetes was also independently associated with higher mortality [1.10 (1.02-1.19)]. Furthermore, donor's history of diabetes was also associated with an increased the risk of liver graft failure [1.35 (1.24-1.47)]. CONCLUSIONS: Presence of type 2 diabetes pre- and post-transplant, as well as presence of type 2 diabetes in the donors, are all associated with an increased risk of adverse post-transplant outcomes.

Retinal vascular biomarkers for early detection and monitoring of Alzheimer's disease.

The earliest detectable change in Alzheimer's disease (AD) is the buildup of amyloid plaque in the brain. Early detection of AD, prior to irreversible neurological damage, is important for the efficacy of current interventions as well as for the development of new treatments. Although PiB-PET imaging and CSF amyloid are the gold standards for early AD diagnosis, there are practical limitations for population screening. AD-related pathology occurs primarily in the brain, but some of the hallmarks of the disease have also been shown to occur in other tissues, including the retina, which is more accessible for imaging. Retinal vascular changes and degeneration have previously been reported in AD using optical coherence tomography and laser Doppler techniques. This report presents results from analysis of retinal photographs from AD and healthy control participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing. This is the first study to investigate retinal blood vessel changes with respect to amyloid plaque burden in the brain. We demonstrate relationships between retinal vascular parameters, neocortical brain amyloid plaque burden and AD. A number of RVPs were found to be different in AD. Two of these RVPs, venular branching asymmetry factor and arteriolar length-to-diameter ratio, were also higher in healthy individuals with high plaque burden (P = 0.01 and P = 0.02 respectively, after false discovery rate adjustment). Retinal photographic analysis shows potential as an adjunct for early detection of AD or monitoring of AD-progression or response to treatments.

Novel setting for addressing tobacco-related disparities: a survey of community welfare organization smoking policies, practices and attitudes.

Research in the United States and Australia acknowledges the potential of non-government social and community service organizations (SCSOs) for reaching socially disadvantaged smokers. This study aimed to describe SCSO smoking policies and practices, and attitudes of senior staff towards smoking and cessation. It also investigated factors associated with positive tobacco control attitudes. In 2009, a cross-sectional telephone survey was undertaken of senior staff in Australian SCSOs, 149 respondents representing 93 organizations completed the survey (response rate=65%; 93/142). Most service clients (60%) remained in programs for 6 months plus, and 77% attended at least weekly. Although 93% of respondents indicated they had an organizational smoking policy, it often did not include the provision of smoking cessation support. Most respondents indicated that client smoking status was not recorded on case notes (78%). Attitudes were mostly positive towards tobacco control in SCSOs, with a mean (standard deviation) score of 8.3 (2.9) of a possible 13. The practice of assessing clients' interest in quitting was the only statistically significant factor associated with high tobacco control attitude scores. The results suggest that SCSOs are appropriate settings for reaching socially disadvantaged smokers with cessation support. Although generally receptive to tobacco control, organizations require further support to integrate smoking cessation support into usual care. In particular, education, training and support for staff to enable them to help their clients quit smoking is important.

Dynamics of extracellular release of Aspergillus fumigatus DNA and galactomannan during growth in blood and serum.

Aspergillus fumigatus is the major cause of invasive aspergillosis (IA), a disease associated with high rates of morbidity and mortality in patients undergoing treatment for haematological malignancies. This study investigated A. fumigatus growth in vitro and in a murine model of IA in order to provide insights into the dynamics of extracellular DNA and galactomannan (GM) release and their relevance to early diagnosis of IA. Following inoculation of whole blood with 20 A. fumigatus conidia ml(-1), DNA that corresponded to the inoculum could be detected by PCR but GM was not detected in plasma separated from the blood sample, indicating that the fungus did not grow in whole blood. The quantities of DNA detected by PCR, and GM, were proportional to the amount of fungal biomass present in vitro. Fungal DNA could be detected in the sera of mice experimentally infected with A. fumigatus with maximum detection in cyclophosphamide-treated mice.

Exercise affects tissue lymphocyte apoptosis via redox-sensitive and Fas-dependent signaling pathways.

Intensive and exhaustive exercise induces an activation of blood T-lymphocytes, which seems to be terminated by apoptotic processes in the postexercise period. Here, we report that exercise-induced T-lymphocyte apoptosis is a systemic phenomenon occurring in various lymphoid and nonlymphoid tissues. The apoptosis rate could be related to exercise intensity and type. Although in some tissues, such as the spleen and Peyer's patches, an early start of apoptosis (1-3 h postexercise) could be detected, a delayed apoptosis (24 h postexercise) was observed in lung, bone marrow, and lymph nodes. Further analysis showed a similar apoptosis distribution among lymphocyte subpopulations. We tested whether components of the extrinsic or the intrinsic apoptotic pathways or both were involved in these processes. Elevated levels of lipid peroxidation-product malondialdehyde (MDA), indicating an increased production of reactive oxygen species (ROS), were found after exercise in Peyer's patches, lung, and spleen, but not in lymph nodes. Application of N-acetyl-cysteine (NAC) prevented exercise-induced T-cell apoptosis completely in spleen and bone marrow, partially in lung and Peyer's patches, while it was ineffective in lymph nodes. Additionally, exercise addressed the Fas-mediated apoptosis. The percentage of Fas-receptor (Fas+) and Fas-ligand positive (FasL+) lymphocytes was enhanced in Peyer's patches after exercise. Moreover, FasL+ T cells were increased in the lung, while in lymph nodes Fas+ cells were increased. The critical role of Fas signaling in exercise-induced apoptosis was supported by using Fas-deficient MRL/lpr-mice. In Fas-deficient mice, exercise-induced T-lymphocyte apoptosis was prevented in spleen, lung, bone marrow, and lymph nodes, but not in Peyer's patches. These data demonstrate that exercise-induced lymphocyte apoptosis is a transient systemic process with tissue-type specific apoptosis-inducing mechanisms, whose relevance for the adaptive immune competence remains to be shown.

Intrathecal ziconotide and baclofen provide pain relief in seven patients with neuropathic pain and spasticity: case reports.

Seven cases of combination of intrathecal (IT) ziconotide and baclofen therapy in patients with refractory neuropathic pain and spasticity were reviewed. Five of the seven adult patients were receiving IT baclofen treatment when ziconotide was initiated. All five patients had experienced at least one previous failed IT treatment regimen. Pain intensity scores improved by a mean of 50.3% with the use of ziconotide-baclofen therapy. Mean time to onset of pain relief was 15 weeks, at a mean ziconotide dose of 3.7 microg/day. Within this group of patients, adverse events were observed in one patient, but they were not considered to be ziconotide related and subsequently resolved. The remaining two patients were receiving ziconotide treatment when baclofen was initiated. Pain intensity scores improved by 75% and 30%, respectively. Pain relief was evident at two weeks and one week, with corresponding ziconotide doses of 2.4 microg/day and 14.4 microg/day, respectively. One patient in this group reported adverse events, but all resolved during continued treatment with the study drugs. Treatment regimens varied between patients in these case series; each regimen used a different titration strategy and different concentrations of ziconotide and baclofen. Combination IT ziconotide and baclofen therapy may be a treatment option for patients with neuropathic pain and spasticity. Future studies are warranted to determine the optimal dosing and titration schedules for ziconotide-baclofen usage.

Estimating selection pressures on HIV-1 using phylogenetic likelihood models.

Human immunodeficiency virus (HIV-1) can rapidly evolve due to selection pressures exerted by HIV-specific immune responses, antiviral agents, and to allow the virus to establish infection in different compartments in the body. Statistical models applied to HIV-1 sequence data can help to elucidate the nature of these selection pressures through comparisons of non-synonymous (or amino acid changing) and synonymous (or amino acid preserving) substitution rates. These models also need to take into account the non-independence of sequences due to their shared evolutionary history. We review how we have developed these methods and have applied them to characterize the evolution of HIV-1 in vivo. To illustrate our methods, we present an analysis of compartment-specific evolution of HIV-1 env in blood and cerebrospinal fluid and of site-to-site variation in the gag gene of subtype C HIV-1.

Development of prognostic nomograms for individualizing 5-year and 10-year fracture risks.

UNLABELLED: We have developed clinical nomograms for predicting 5-year and 10-year fracture risks for any elderly man or woman. The nomograms used age and information concerning fracture history, fall history, and BMD T-score or body weight. INTRODUCTION: Although many fracture risk factors have been identified, the translation of these risk factors into a prognostic model that can be used in primary care setting has not been well realized. The present study sought to develop a nomogram that incorporates non-invasive risk factors to predict 5-year and 10-year absolute fracture risks for an individual man and woman. METHODS: The Dubbo Osteoporosis Epidemiology Study was designed as a community-based prospective study, with 1358 women and 858 men aged 60+ years as at 1989. Baseline measurements included femoral neck bone mineral density (FNBMD), prior fracture, a history of falls and body weight. Between 1989 and 2004, 426 women and 149 men had sustained a low-trauma fracture (not including morphometric vertebral fractures). Two prognostic models based on the Cox's proportional hazards analysis were considered: model I included age, BMD, prior fracture and falls; and model II included age, weight, prior fracture and fall. RESULTS: Analysis of the area under the receiver operating characteristic curve (AUC) suggested that model I (AUC = 0.75 for both sexes) performed better than model II (AUC = 0.72 for women and 0.74 for men). Using the models' estimates, we constructed various nomograms for individualizing the risk of fracture for men and women. If the 5-year risk of 10% or greater is considered "high risk", then virtually all 80-year-old men with BMD T-scores < -1.0 or 80-year-old women with T-scores < -2.0 were predicted to be in the high risk group. A 60-year-old woman's risk was considered high risk only if her BMD T-scores < or = -2.5 and with a prior fracture; however, no 60-year-old men would be in the high risk regardless of their BMD and risk profile. CONCLUSION: These data suggest that the assessment of fracture risk for an individual cannot be based on BMD alone, since there are clearly various combinations of factors that could substantially elevate an individual's risk of fracture. The nomograms presented here can be useful for individualizing the short- and intermediate-term risk of fracture and identifying high-risk individuals for intervention to reduce the burden of fracture in the general population.

Discordance of longitudinal changes in bone density between densitometers.

UNLABELLED: This study examined the concordance in BMD measurement and longitudinal change in BMD between the GE Lunar Prodigy and GE Lunar DPX. Even though a high concordance between the densitometers was observed on a single measurement occasion, a significant discordance in longitudinal changes in BMD was observed. INTRODUCTION: Measurement of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) technology plays an important role in the diagnosis and management of osteoporosis. The present study examined the concordance in BMD measurement and longitudinal change in BMD between GE Lunar Prodigy and DPX. METHODS: BMD at the lumbar spine and femoral neck was measured in 135 individuals (47 men and 88 women, mean age 73+/-9 years) using both GE Lunar DPX and Prodigy densitometers at baseline. In this group, 56 individuals (22 men and 34 women) had repeated BMD measurements using the DPX and Prodigy during a subsequent follow-up visit (average duration: 2.2 years). RESULTS: For a single BMD measurement, the coefficient of concordance between the Prodigy and DPX was greater than 0.98 at the lumbar spine and 0.96 at the femoral neck, with the slope of linear regression being approximately 1.0. During the period of follow-up, the lumbar spine BMD decreased by -0.5% (S.D. 1.8%) when measured by DPX, which was significantly different (p=0.002) from the change measured by Prodigy (mean change=0, S.D. 2.0%). However, there was no significant difference (p=0.95) in the rate of change in femoral neck BMD measured by DPX (mean=-1.6%, S.D.=2.9) and Prodigy (mean=-1%, S.D.=1.8%). The correlation in rates of BMD change between Prodigy and DPX was 0.63 at the lumbar spine and 0.52 at the femoral neck. Simulation analysis showed that the theoretical maximum correlation in rates of BMD change between Prodigy and DPX was 0.71. CONCLUSIONS: Despite both densitometers being highly concordant in a single BMD measurement, discordance in the assessment of BMD changes between the Prodigy and DPX densitometers was observed. These findings have implications regarding the assessment of response to therapy in a multi-centre setting when different densitometers are used.

Motivation to change in recent onset and long-standing bulimia nervosa: are there differences?

UNLABELLED: REASON FOR THE STUDY: Little is known about how motivation to change evolves over the course of an eating disorder. The present study compared 'stage of change' and motivation, confidence and readiness to change in two groups of patients with bulimia nervosa (BN), adolescents with a short duration of illness and adults with a long duration of illness. METHOD: Patients completed the Severity of eating disorder symptomatology scale, Hospital Anxiety and Depression Scale and measures of stage of change and motivation, readiness and confidence to change their bulimic symptomatology at pre-treatment. MAIN FINDINGS: Short- and long duration groups did not differ in illness severity, comorbidity, stage of change, motivation, readiness, and confidence to change. There were, however, some differences between groups in terms of the relationship between motivational measures, illness severity, duration and comorbidity. CONCLUSIONS: There seem to be more similarities than differences between adolescents with short duration of illness and those with well-established BN in terms of their motivation to change.