A Case of Pyrexia of Unknown Origin Diagnosed as Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease that is even rarer in the adult population. It requires a high degree of suspicion from the treating physician, and if diagnosed early, patients might have a survival benefit from this highly fatal condition. HLH is a disorder of immune regulation where the hyperactivity of cytokines attacks different cells, which leads to multiple organ dysfunctions. Varying presentations and similarities with other diseases make diagnosis difficult. Familial HLH is commonly seen in the pediatric population, while acquired or secondary HLH is seen in adults. Secondary HLH is commonly triggered by neoplasms, infections, rheumatological diseases, and other autoimmune diseases. Here is a case of HLH that presented as chronic undiagnosed fever. In this case report, we have discussed in detail this disease, its presentation, investigations, treatment, and other important information that will help practicing doctors better diagnose and treat HLH patients.

Higher Dietary Vitamin K Intake is Associated with Better Physical Function and Lower Long-Term Injurious Falls Risk in Community-Dwelling Older Women.

BACKGROUND: In recent years, a potential beneficial role of Vitamin K in neuromuscular function has been recognised. However, the optimal dietary intake of Vitamin K to support muscle function in the context of falls prevention remains unknown. OBJECTIVE: To examine the relationship of dietary Vitamin K1 and K2 with muscle function and long-term injurious fall-related hospitalisations in older women. DESIGN: Cohort study. PARTICIPANTS: 1347 community-dwelling older Australian women ≥70 years. MEASUREMENTS: A new Australian Vitamin K nutrient database, supplemented with published data, was used to calculate Vitamin K1 and K2 intake from a validated food frequency questionnaire at baseline (1998). Muscle function (grip strength and timed-up-and-go; TUG) as well plasma Vitamin D status (25OHD) were also assessed at baseline. Fall-related hospitalisations over 14.5 years were obtained from linked health records. Multivariable-adjusted logistic regression and Cox-proportional hazard models were used to analyse the data. RESULTS: Over 14.5 years of follow-up (14,774 person-years), 535 (39.7%) women experienced a fall-related hospitalisation. Compared to women with the lowest Vitamin K1 intake (Quartile 1, median 49 µg/d), those with the highest intake (Quartile 4, median 120 µg/d) had 29% lower odds (OR 0.71 95%CI 0.52-0.97) for slow TUG performance (>10.2 s), and 26% lower relative hazards of a fall-related hospitalisation (HR 0.74 95%CI 0.59-0.93) after multivariable adjustment. These associations were non-linear and plateaued at moderate intakes of ~70-100 µg/d. There was no relation to grip strength. Vitamin K2 intakes were not associated with muscle function or falls. CONCLUSION: A higher habitual Vitamin K1 intake was associated with better physical function and lower long-term injurious falls risk in community-dwelling older women. In the context of musculoskeletal health, Vitamin K1 found abundantly in green leafy vegetables should be promoted.

Antiviral activity of natural phenolic compounds in complex at an allosteric site of SARS-CoV-2 papain-like protease.

SARS-CoV-2 papain-like protease (PLpro) covers multiple functions. Beside the cysteine-protease activity, facilitating cleavage of the viral polypeptide chain, PLpro has the additional and vital function of removing ubiquitin and ISG15 (Interferon-stimulated gene 15) from host-cell proteins to support coronaviruses in evading the host's innate immune responses. We identified three phenolic compounds bound to PLpro, preventing essential molecular interactions to ISG15 by screening a natural compound library. The compounds identified by X-ray screening and complexed to PLpro demonstrate clear inhibition of PLpro in a deISGylation activity assay. Two compounds exhibit distinct antiviral activity in Vero cell line assays and one inhibited a cytopathic effect in non-cytotoxic concentration ranges. In the context of increasing PLpro mutations in the evolving new variants of SARS-CoV-2, the natural compounds we identified may also reinstate the antiviral immune response processes of the host that are down-regulated in COVID-19 infections.

Calcaneal quantitative ultrasound is associated with all-cause and cardiovascular disease mortality independent of hip bone mineral density.

Osteoporosis has been linked with increased risk of cardiovascular disease previously. However, few studies have detailed bone and vascular information. In a prospective study of older women, we demonstrated heel quantitative ultrasound measures were associated with increased cardiovascular and all-cause mortality, independent of established cardiovascular risk factors. INTRODUCTION: Osteoporosis and low bone mineral density (BMD) have been previously linked to cardiovascular disease (CVD) and mortality. Calcaneal quantitative ultrasound (QUS) is used to evaluate bone material properties, especially in older women. However, it is uncertain whether it is related to risk of mortality. This study was aimed to investigate the association between calcaneal QUS measurements and 15-year all-cause and CVD mortality in 1404 older women (mean age 75.2 ± 2.7 years). METHODS: One thousand four hundred four older women, participants of Calcium Intake Fracture Outcome study (CAIFOS), had calcaneal bone measured at baseline (1998) and followed for 15 years. The primary outcomes, any deaths, and deaths attributable to cardiovascular causes ascertained by using linked data were obtained from Western Australia data linkage system. RESULTS: Over the 15 years of follow-up (17,955 person years), 584 of the women died, and 223 from CVD. For every standard deviation (SD), reduction in broadband ultrasound attenuation (BUA) in minimally and multivariable-adjusted model including cardiovascular risk factors increased relative hazards for all-cause (multivariable-adjusted HR 1.15; 95%CI: 1.06-1.26, p = 0.001) and CVD mortality (multivariable-adjusted HR 1.20; 95%CI: 1.04-1.38, p = 0.010). Such relationships also persisted when hip BMD was included in the model (all-cause mortality HR 1.19; 95%CI: 1.07-1.33, p = 0.002; CVD mortality HR 1.28; 95%CI: 1.07-1.53, p = 0.008). CONCLUSION: BUA is associated with all-cause and CVD mortality in older women independent of BMD and established CVD risk factors. Understanding why and how these are related may provide further insights about the bone-vascular nexus as well as therapeutic targets benefiting both systems.

Sex differences in recovery of quality of life 12 months post-fracture in community-dwelling older adults: analyses of the Australian arm of the International Costs and Utilities Related to Osteoporotic Fractures Study (AusICUROS).

In this study of 695 Australian older adults (aged ≥50 years), we found that men and women had a similar trajectory of health-related quality of life (HRQoL) recovery following fragility fracture at any skeletal site. These results provide us with critical knowledge that improves our understanding of health outcomes post-fracture. INTRODUCTION: Mortality is higher in men than that in women following a fragility fracture, but it is unclear whether recovery of patient-reported outcomes such as health-related quality of life (HRQoL) differs between sexes. This study aimed to identify sex differences in HRQoL recovery 12 months post-fracture. METHODS: Data were from the Australian arm of the International Costs and Utilities Related to Osteoporotic Fractures Study (AusICUROS). Participants recruited to AusICUROS were adults aged ≥50 years who sustained a fragility fracture. HRQoL was measured using the EQ-5D-3L at three time-points post-fracture: within 2 weeks (including pre-fracture recall) and at 4 and 12 months. Multivariate logistic regression analyses were undertaken, adjusting for confounders including age, education, income, and healthcare utilization post-fracture. RESULTS: Overall, 695 AusICUROS participants (536 women, 77.1%) were eligible for analysis with fractures at the hip (n = 150), distal forearm (n = 261), vertebrae (n = 61), humerus (n = 52), and other skeletal sites (n = 171). At the time of fracture, men were younger, reported a higher income, and were more likely to be employed, compared with women. For all fracture sites combined, there were no differences between men and women in recovery to pre-fracture HRQoL at 12-month follow-up (adjusted OR = 1.09; 95% CI: 0.75-1.61). When stratified by fracture site, no significant sex differences were seen for hip (OR = 1.02; 95% CI: 0.42-2.52), distal forearm (OR = 1.60; 95% CI: 0.68-3.78), vertebral (OR = 2.28; 95% CI: 0.61-8.48), humeral (OR = 1.62; 95% CI: 0.16-9.99), and other fractures (OR = 1.00; 95% CI: 0.44-2.26). CONCLUSION: Community-dwelling men and women who survived the 12 months following fragility fracture had a similar trajectory of HRQoL recovery at any skeletal site.

A Comprehensive Comparison of Early-Onset and Average-Onset Colorectal Cancers.

BACKGROUND: The causative factors for the recent increase in early-onset colorectal cancer (EO-CRC) incidence are unknown. We sought to determine if early-onset disease is clinically or genomically distinct from average-onset colorectal cancer (AO-CRC). METHODS: Clinical, histopathologic, and genomic characteristics of EO-CRC patients (2014-2019), divided into age 35 years and younger and 36-49 years at diagnosis, were compared with AO-CRC (50 years and older). Patients with mismatch repair deficient tumors, CRC-related hereditary syndromes, and inflammatory bowel disease were excluded from all but the germline analysis. All statistical tests were 2-sided. RESULTS: In total, 759 patients with EO-CRC (35 years, n = 151; 36-49 years, n = 608) and AO-CRC (n = 687) were included. Left-sided tumors (35 years and younger = 80.8%; 36-49 years = 83.7%; AO = 63.9%; P < .001 for both comparisons), rectal bleeding (35 years and younger = 41.1%; 36-49 years = 41.0%; AO = 25.9%; P = .001 and P < .001, respectively), and abdominal pain (35 years and younger = 37.1%; 36-49 years = 34.0%; AO = 26.8%; P = .01 and P = .005, respectively) were more common in EO-CRC. Among microsatellite stable tumors, we found no differences in histopathologic tumor characteristics. Initially, differences in TP53 and Receptor Tyrosine Kinase signaling pathway (RTK-RAS)alterations were noted by age. However, on multivariate analysis including somatic gene analysis and tumor sidedness, no statistically significant differences at the gene or pathway level were demonstrated. Among advanced microsatellite stable CRCs, chemotherapy response and survival were equivalent by age cohorts. Pathogenic germline variants were identified in 23.3% of patients 35 years and younger vs 14.1% of AO-CRC (P = .01). CONCLUSIONS: EO-CRCs are more commonly left-sided and present with rectal bleeding and abdominal pain but are otherwise clinically and genomically indistinguishable from AO-CRCs. Aggressive treatment regimens based solely on the age at CRC diagnosis are not warranted.

A Risk Score Model for Locoregional Recurrence Following Upfront Surgery for Pancreatic Adenocarcinoma: Implications for Adjuvant Therapy.

AIMS: The aims of the study were to identify predictors of locoregional failure (LRF) following surgery for pancreatic adenocarcinoma, develop a prediction risk score model of LRF and evaluate the impact of postoperative radiation therapy (PORT) on LRF. MATERIALS AND METHODS: A retrospective review was conducted on patients with stages I-III pancreatic adenocarcinoma who underwent surgery at our institution (2005-2016). Univariable and then multivariable analyses were used to evaluate clinicopathological factors associated with LRF for patients who did not receive PORT. The risk score of LRF was calculated based on the sum of coefficients of the predictors of LRF. The model was applied to the entire cohort to evaluate the impact of PORT on the high- and low-risk groups for LRF. RESULTS: In total, 467 patients were identified (median follow-up 22 months). Among patients who did not receive PORT (n = 440), predictors of LRF were pN+, involved or close ≤1 mm margin(s), moderately and poorly differentiated tumour grade and lymphovascular invasion. After adding patients who received PORT, the 2-year LRF in the high-risk group was 57% for patients who did not receive PORT (n = 242) and 32% among patients who received PORT (n = 22), with an absolute benefit to LRF of 25% (95% confidence interval 5-52%, P = 0.07). The 2-year overall survival for the high-versus the low-risk group was 36% versus 67% (P < 0.001). CONCLUSION: This risk group classification could be used to identify pancreatic adenocarcinoma patients with higher risk of LRF who may benefit from PORT. However, validation and prospective evaluation are warranted.

Effects of calcium supplementation on circulating osteocalcin and glycated haemoglobin in older women.

One year of calcium supplementation in older women led to modest reductions in total osteocalcin and undercarboxylated osteocalcin (ucOC), with no changes in muscle or fat mass, or glycated haemoglobin. Future studies should explore whether treatments with more profound effects of suppressing ucOC may lead to impaired glycaemic control. INTRODUCTION: Total osteocalcin (TOC) is a marker of bone turnover, while its undercarboxylated form has beneficial effects on glucose metabolism in mice. This post hoc analysis of a randomised double-blind, placebo-controlled trial examined whether 1 year of calcium supplementation affected circulating TOC, undercarboxylated osteocalcin (ucOC) or glycated haemoglobin (HbA1c) in 1368 older community-dwelling women (mean age 75.2 ± 2.7 years). METHODS: Women enrolled in the Calcium Intake Fracture Outcome Study trial (1998-2003) were supplemented with 1.2 g/d of elemental calcium (in the form of calcium carbonate) or placebo. Circulating TOC, ucOC and HbA1c was measured at 1 year (1999). RESULTS: After 1 year of calcium supplementation, TOC and ucOC levels were 17% and 22% lower compared with placebo (mean 22.7 ± 9.1 vs. 27.3 ± 10.9 µg/L and 11.1 ± 4.9 vs. 13.0 ± 5.7 µg/L, both P < 0.001). Carboxylated osteocalcin/ucOC was 6% lower after calcium supplementation (P < 0.05). Despite this, no differences in HbA1c were observed (calcium, 5.2 ± 0.6 vs. placebo, 5.3 ± 0.8%; P = 0.08). Calcium supplementation did not affect BMI, whole body lean or fat mass. In exploratory analyses, total calcium (dietary and supplemental) was inversely related to TOC and ucOC, indicating calcium intake is an important dietary determinant of osteocalcin levels. CONCLUSION: One year of calcium supplementation in older women led to modest reductions in TOC and ucOC, with no changes in muscle or fat mass, or HbA1c. Future studies should explore whether treatments with more profound effects of suppressing ucOC may lead to impaired glycaemic control.

Dietary protein and bone health across the life-course: an updated systematic review and meta-analysis over 40 years.

We undertook a systematic review and meta-analysis of published papers assessing dietary protein and bone health. We found little benefit of increasing protein intake for bone health in healthy adults but no indication of any detrimental effect, at least within the protein intakes of the populations studied. This systematic review and meta-analysis analysed the relationship between dietary protein and bone health across the life-course. The PubMed database was searched for all relevant human studies from the 1st January 1976 to 22nd January 2016, including all bone outcomes except calcium metabolism. The searches identified 127 papers for inclusion, including 74 correlational studies, 23 fracture or osteoporosis risk studies and 30 supplementation trials. Protein intake accounted for 0-4% of areal BMC and areal BMD variance in adults and 0-14% of areal BMC variance in children and adolescents. However, when confounder adjusted (5 studies) adult lumbar spine and femoral neck BMD associations were not statistically significant. There was no association between protein intake and relative risk (RR) of osteoporotic fractures for total (RR(random) = 0.94; 0.72 to 1.23, I2 = 32%), animal (RR (random) = 0.98; 0.76 to 1.27, I2 = 46%) or vegetable protein (RR (fixed) = 0.97 (0.89 to 1.09, I2 = 15%). In total protein supplementation studies, pooled effect sizes were not statistically significant for LSBMD (total n = 255, MD(fixed) = 0.04 g/cm2 (0.00 to 0.08, P = 0.07), I2 = 0%) or FNBMD (total n = 435, MD(random) = 0.01 g/cm2 (-0.03 to 0.05, P = 0.59), I2 = 68%). There appears to be little benefit of increasing protein intake for bone health in healthy adults but there is also clearly no indication of any detrimental effect, at least within the protein intakes of the populations studied (around 0.8-1.3 g/Kg/day). More studies are urgently required on the association between protein intake and bone health in children and adolescents.

Utility of four sarcopenia criteria for the prediction of falls-related hospitalization in older Australian women.

Numerous sarcopenia definitions are not associated with increased falls-related hospitalization risk over 5 years to 9.5 years in older community-dwelling Australian women. Measures of muscle strength and physical function, but not appendicular lean mass (measured by dual-energy X-ray absorptiometry) may help discriminate the risk of falls-related hospitalization. INTRODUCTION: The aim of this prospective, population-based cohort study of 903 Caucasian-Australian women (mean age 79.9 ± 2.6 years) was to compare the clinical utility of four sarcopenia definitions for the prediction of falls-related hospitalization over 9.5 years. METHODS: The four definitions were the United States Foundation for the National Institutes of Health (FNIH), the European Working Group on Sarcopenia in Older People (EWGSOP), and modified FNIH (AUS-POPF) and EWGSOP (AUS-POPE) definitions using Australian population-specific cut points (< 2 SD below the mean of young healthy Australian women). Components of sarcopenia including muscle strength, physical function, and appendicular lean mass (ALM) were quantified using hand grip strength, timed-up-and-go (TUG), and dual-energy X-ray absorptiometry (DXA), respectively. Incident 9.5-year falls-related hospitalization were captured by linked data. RESULTS: Baseline prevalence of sarcopenia according to FNIH (9.4%), EWGSOP (24.1%), AUS-POPF (12.0%), and AUS-POPE (10.7%) differed substantially. Sarcopenia did not increase the relative hazard ratio (HR) for falls-related hospitalization before or after adjustment for age (aHR): FNIH aHR 1.00 95%CI (0.69-1.47), EWGSOP aHR 1.20 95%CI (0.93-1.54), AUS-POPF aHR 0.96 95%CI (0.68-1.35), and AUS-POPE aHR 1.33 95%CI (0.94-1.88). When examining individual components of sarcopenia, only muscle strength and physical function but not ALM (adjusted for height2 or BMI) were associated with falls-related hospitalization. CONCLUSION: Current definitions of sarcopenia were not associated with falls-related hospitalization risk in this cohort of community-dwelling older Australian women. Finally, measures of muscle strength and physical function, but not ALM (measured by DXA) may help discriminate the risk of falls-related hospitalization.

Ageing Effects on 3-Dimensional Femoral Neck Cross-Sectional Asymmetry: Implications for Age-Related Bone Fragility in Falling.

This paper explores the effects of aging on femoral neck (FN) anatomy in a study of women aged 20-90years in relation to implications for FN fracture propensity in buckling. Five hundred and four participants were scanned by Quantitative Computed Tomography and analyzed using Quantitative Computed Tomography Pro BIT (Mindways). FN cross-section was split through geometric center into superior and inferior sectors. Bone mass, structural measurements, and bone mineral density were analyzed. Buckling ratio was calculated as ratio of buckling radius to cortical thickness. Between 2nd decade and 8th decade, age-related integral bone mass reduction in superior sector was substantially larger than in inferior sector (33% compared to 21%), especially in cortical bone superiorly compared to inferiorly (53% vs 21%; p < 0.001), principally due to reduction in cortical thickness, averaged cortical thickness (56%) with little difference in density. Superior and inferior sector trabecular bone mineral density reduction was similar at 41% and 43% respectively. Differential cortical bone loss in superior sector resulted in a 59% inferior displacement (δ) of center-of-mass from geometric center. Differences in δ and averaged cortical thickness with age accounted for a 151% increase in mean superior buckling ratio from 9 to 23. Analysis confirms significant progressive age-related superior cortical bone loss as the major age effect on FN structure with relative preservation of inferior cortex probably related to maintenance of inferior sector by regular loading as a result of standing and walking. Computation of buckling ratio may allow prediction of fracture propensity in a sideways fall.

Overnight sleep duration and obesity in 2-5 year-old American Indian children.

BACKGROUND: Sleep has emerged as a potentially modifiable risk factor for obesity in children. OBJECTIVES: The purpose of this investigation was to evaluate the association between overnight sleep duration and obesity among American Indian (AI) children ages 2-5 years. METHODS: Data were examined from the baseline assessment of children enrolling in the Healthy Children, Strong Families study, which is a randomized lifestyle intervention trial in five diverse rural and urban AI communities nationally among children ages 2-5 years. Multivariable models were built to assess the relationship between sleep duration and BMI z-score while controlling for potential sociodemographic and behavioural covariates. RESULTS: Three hundred and ninety-eight children had sufficient data to be included in analysis. In multivariable models controlling for potential covariates, overnight sleep duration was significantly and inversely associated with BMI z-score (B = -0.158, t = -1.774, P = 0.006). Similarly, when controlling for covariates, children who slept 12 or more hours had significantly lower BMI z-scores compared with those who slept 8 to 10 h (P = 0.018) or less than 8 h (P = 0.035); the difference between 12+ hours and 10 to 12-h groups did not reach statistical significance (P = 0.073) but supported a linear relationship between overnight sleep duration and BMI. Weekday-to-weekend variability in overnight sleep duration was not associated with BMI z-score (B = 0.010, t = 0.206, P = 0.837). CONCLUSIONS: Overnight sleep duration is independently and inversely related to BMI z-score among AI children ages 2-5 years, even when controlling for important sociodemographic and obesogenic lifestyle factors. This represents the first report, to our knowledge, of sleep duration as a risk factor for obesity among AI children.

The Impact of Dietary Protein or Amino Acid Supplementation on Muscle Mass and Strength in Elderly People: Individual Participant Data and Meta-Analysis of RCT's.

OBJECTIVES: Increasing protein or amino acid intake has been promoted as a promising strategy to increase muscle mass and strength in elderly people, however, long-term intervention studies show inconsistent findings. Therefore, we aim to determine the impact of protein or amino acid supplementation compared to placebo on muscle mass and strength in older adults by combining the results from published trials in a meta-analysis and pooled individual participant data analysis. DESIGN: We searched Medline and Cochrane databases and performed a meta-analysis on eight available trials on the effect of protein or amino acid supplementation on muscle mass and strength in older adults. Furthermore, we pooled individual data of six of these randomized double-blind placebo-controlled trials. The main outcomes were change in lean body mass and change in muscle strength for both the meta-analysis and the pooled analysis. RESULTS: The meta-analysis of eight studies (n=557) showed no significant positive effects of protein or amino acid supplementation on lean body mass (mean difference: 0.014 kg: 95% CI -0.152; 0.18), leg press strength (mean difference: 2.26 kg: 95% CI -0.56; 5.08), leg extension strength (mean difference: 0.75 kg: 95% CI: -1.96, 3.47) or handgrip strength (mean difference: -0.002 kg: 95% CI -0.182; 0.179). Likewise, the pooled analysis showed no significant difference between protein and placebo treatment on lean body mass (n=412: p=0.78), leg press strength (n=121: p=0.50), leg extension strength (n=121: p=0.16) and handgrip strength (n=318: p=0.37). CONCLUSIONS: There is currently no evidence to suggest that protein or amino acid supplementation without concomitant nutritional or exercise interventions increases muscle mass or strength in predominantly healthy elderly people.

Differences in femoral neck structure between elderly Caucasian and Chinese populations: a cross-sectional study of Perth-Beijing cohorts.

Structural skeletal differences of the femoral neck of older Beijing-Chinese and Perth-Caucasian women were compared; adjusting for frame size-related differences, Beijing-Chinese have lower periosteal width; however, indices of internal bone distribution suggest that Beijing-Chinese may exhibit increased resistance to fracture that may relate to the reduced hip fracture incidence. INTRODUCTION: Ethnic differences in skeletal structure may relate to differences in hip fracture risk in Chinese and Caucasian populations. 2D mass, size, and structural biomechanics were compared in the two populations. METHODS: Quantitative computed tomography-derived geometric variables were compared in age-matched community-derived female populations, 196 Beijing-Chinese 76.5 ± 4.8 (mean ± SD) years and 237 Perth-Caucasians 77.1 ± 5.0 years. These included scanned area (A), periosteal width (W), bone mineral content (BMC), aBMD, bone cross-sectional area (bCSA), section modulus (Z) and buckling ratio (BR). Assumption-free measures included sigma (σ), related to the distribution of bone in the scanned image previously identified as a predictor of hip fracture, and delta (δ), the center-of-mass displacement from the geometric center. RESULTS: Compared to Beijing-Chinese, Perth-Caucasians were heavier (Beijing-Chinese 58.7 ± 11.8; Perth-Caucasians 66.1 ± 11.0 kg), taller (154.9 ± 16.7 vs 158.9 ± 6.0 cm), and had higher BMC, A, and W. After adjustment for frame size, BMC was not significantly different but W remained higher in Perth-Caucasians. Differences in variables aBMD, Z, BR, and σ favored higher resistance to failure with Beijing-Chinese before and after adjustment for frame size. δ was similar in both populations; bCSA was higher in Beijing-Chinese before adjustment for frame size but not after. CONCLUSIONS: Bone mass differences in two populations were related to frame size differences. However, femoral neck width remained smaller in Beijing-Chinese suggesting effects of local genetic and environmental factors. In Beijing-Chinese participants compared to Perth-Caucasians, internal bone distribution suggests increased resistance to deformation if exposed to same force that may, in-part, relate to reduced incidence of hip fracture in Beijing-Chinese.

Reconsideration of the Effects of Age on Proximal Femur Structure: Implications for Joint Replacement and Hip Fracture.

OBJECTIVES: In recent years quantitative computed tomography (QCT) has allowed precise non-invasive, three dimensional, in vivo measurement of hip structure in large numbers of individuals. The effects of ageing on proximal femur structure are reported and implications for the prevention of hip prosthesis loosening and hip fracture considered. DESIGN, SETTING AND PARTICIPANTS: An observational cross-sectional study of proximal femur QCT in 719 unselected female European descent aged 20 to 89 years recruited from US and Australian populations. MAIN OUTCOMES MEASURES: QCT scans were obtained using software that separates cortical and cancellous bone by a thresholding technique. Voxel based mineral volume and mass was computed for the integral (external), cancellous and cortical compartments of 1 mm wide sections through the femoral neck (FN), trochanter (TR) and intertrochanter (IT) regions. RESULTS: Over the adult life span total integral volumes at the FN, TR and IT sites expand linearly by between 18 and 37% at the same time as bone mass decreased by 22 to 25% resulting in massive reductions in true volumetric BMD (vBMD) of 40 to 50%. Cancellous volume expansion was larger at 65 to 79% at the three sites. Between the ages of 65 and 75 the average increase in cancellous volume at the IT site was 3.74 cm3 (12.1%). Voxel determined FN cortical volume decreased linearly by 43%, as did cortical bone mass so that vBMD did not change substantially. TR and IT cortical volumes decreased 54 and 28% respectively, small reductions in TR and IT cortical vBMD also occurred. CONCLUSIONS: Large endosteal expansion in the area in which hip replacement stem placement occurs may contribute to loosening. Regarding the propensity to hip fracture, periosteal expansion contributes to increased resistance to bending but cortical thinning contributes to loss of bone to resistance to bending forces. Understanding individual hip structure may contribute to individualisation of risk and subsequent targeting of management using pharmaceutical agents.

Evaluation of antimicrobial activity and probiotic properties of wild-strain Pichia kudriavzevii isolated from frozen idli batter.

The present research was undertaken to study the probiotic characteristics of Pichia kudriavzevii isolated from frozen idli batter. Polymerase chain reaction amplification with 18S rRNA primers confirmed Pichia kudriavzevii, a xylose-utilizing probiotic strain. It was resistant to physiological concentrations of bile salts, pepsin and pancreatic enzyme. It also showed efficient auto-aggregation as well as co-aggregation ability with four commercial probiotic yeasts and exhibited good hydrophobicity in xylene and toluene. The strain inhibited the growth of 13 enteropathogens and showed a commensal relationship with four commercial probiotic yeast and bacteria. Moreover, it was resistant to 30 antibiotics with different modes of action. The yeast exhibited thermotolerance up to 95 °C for 2 h. The cell-free supernatants were also found to be heat stable, indicating the presence of thermostable secondary metabolites. Hence it could be exploited as starter culture, co-culture or probiotic in the preparation of fermented products or incorporated in heatable foods as well. Copyright © 2016 John Wiley & Sons, Ltd.

Evaluation of a simplified hip structure analysis method for the prediction of incident hip fracture events.

UNLABELLED: Many attempts have been made to improve the predictive ability of areal bone mineral density (aBMD) which integrates bone mass and area. The addition of an extra variable derived from the hip dual-energy X-ray (DXA) image TR_σ, which describes distribution of mass within the scanned area of the trochanter, improved prediction of 15-year hip fracture probability in elderly women. INTRODUCTION: Two-dimensional DXA imaging of the proximal femur to produce an aBMD is a clinically useful predictor of future fracture risk. Further analysis of the DXA image to produce an eight-variable hip structure analysis (Beck HSA) has been developed to improve understanding of structural factors determining hip bone strength at each of three proximal femur sites, the narrow femoral neck (NN), intertrochanter (TR) and shaft (S). Recently, data on four measurements derived from the currently used eight Beck HSA variables were used to capture population variation in bone structure at each site. These include two previously used variables, the localised aBMD and the sub-periosteal width (W) applying to 5-mm sections (at each sites), and two new variables, standard deviation of normalised mineral-mass projection profile distribution (σ), and displacement between centre-of-mineral mass and geometric centre-of-mineral mass of projection profile (δ). METHODS: Using a cohort of 1159 women, mean baseline age 75, who sustained 139 hip fractures over 15 years, we determined whether these measures significantly improved 15-year hip fracture prediction compared to current approach utilising age and total hip aBMD. To describe the most parsimonious model for hip fracture risk prediction, the 12 base measures (4 from each site), total hip aBMD and age were evaluated in stepwise logistic regression models. RESULTS: The final model included TR_σ, total hip aBMD and age and provided improved utility for hip fracture prediction compared to total hip aBMD and age alone (C-statistic 0.73 vs. 0.69, P = 0.009 and net reclassification improvement 0.164, P < 0.001, respectively). CONCLUSIONS: Addition of TR_σ to total hip aBMD and age substantially improved prediction of 15-year hip fracture risk in this cohort of elderly women.

Changes in quality of life associated with fragility fractures: Australian arm of the International Cost and Utility Related to Osteoporotic Fractures Study (AusICUROS).

UNLABELLED: We investigated change in health-related quality of life due to fracture in Australian adults aged over 50 years. Fractures reduce quality of life with the loss sustained at least over 12 months. At a population level, the loss was equivalent to 65 days in full health per fracture. PURPOSE: We aimed to quantify the change in health-related quality of life (HRQoL) that occurred as a consequence of a fracture using the EQ-5D-3 L questionnaire. METHODS: Adults aged ≥50 years with a low to moderate energy fracture were recruited from eight study centres across Australia. This prospective study included an 18-month follow-up of participants recruited within 2 weeks of a fracture (hip, wrist, humerus, vertebral and ankle). Information collected at baseline and 4, 12 and 18 months included characteristics of participants such as income level, education and prior fracture status. At 12 months post-fracture, the cumulative loss of quality of life was estimated using multivariate regression analysis to identify the predictors of HRQoL loss. RESULTS: Mean HRQoL for all participants before fracture was 0.86, with wrist fracture having the highest pre-fracture HRQoL (0.90), while vertebral fracture had the lowest (0.80). HRQoL declined to 0.42 in the immediate post-fracture period. Only participants with a wrist, humerus or ankle fracture returned to their pre-fracture HRQoL after 18 months. An increased loss of HRQoL over 12 months was associated with HRQoL prior to the fracture, hospitalisation, education and fracture site. The multiple regression explained 30 % of the variation in the cumulative HRQoL loss at 12 months post-fracture for all fractures. CONCLUSION: Low to moderate energy fractures reduce HRQoL, and this loss is sustained for at least 12 months or, in the case of hip and spine fractures, at least 18 months. At a population level, this represents an average loss of 65 days in full health per fragility fracture. This significant burden reinforces the need for cost-effective fracture prevention strategies.

Consumption of a whey protein-enriched diet may prevent hepatic steatosis associated with weight gain in elderly women.

BACKGROUND AND AIMS: Protein consumption has been associated with cardio-metabolic benefits, including weight loss and improved insulin sensitivity, and may have potential benefits for individuals with fatty liver disease (FLD). We investigated the effect of increasing dietary protein intake from whey relative to carbohydrate on hepatic steatosis. METHODS AND RESULTS: A two-year randomized, double-blind, placebo-controlled trial of 30 g/day whey protein-supplemented beverage (protein) or an energy-matched low-protein high-carbohydrate beverage (control) for cardio-metabolic and bone health in 219 healthy elderly women, recruited from the Western Australian general population. Hepatic steatosis was quantified using computed tomographic liver-to-spleen (L/S) ratio. FLD was defined as liver-to-spleen difference <10 Hounsfield units. At baseline, FLD prevalence was 11.4%. Control and protein groups were similar in body mass index (BMI), insulin resistance, L/S ratio and FLD prevalence at baseline. At two-years, dietary protein increased by 20 g in the protein, but not the control, group. Total energy intake and physical activity remained similar between groups. At two-years, BMI and FLD prevalence increased in both groups, with no between group differences. L/S ratio increased in control, but not protein, group at two-years, with no between group differences. In a within group comparison, change in BMI correlated with changes in L/S ratio in control (r = 0.37, P = 0.0007), but not with protein group (r = 0.04, P = 0.73). CONCLUSION: Increasing dietary protein intake from whey relative to carbohydrate does not reduce weight, hepatic steatosis or the prevalence of FLD in elderly women. However, it may prevent worsening of hepatic steatosis associated with weight gain. CLINICAL TRIALS REGISTRATION: Australian New Zealand Clinical Trials Registry (Registration no. ACTRN012607000163404).

The effect of yoghurt and its probiotics on blood pressure and serum lipid profile; a randomised controlled trial.

BACKGROUND AND AIMS: Despite strong mechanistic data, and promising results from in vitro and animal studies, the ability of probiotic bacteria to improve blood pressure and serum lipid concentrations in humans remains uncertain. The aim of this study was to determine the effect of Lactobacillus acidophilus La5 and Bifidobacterium animalis subsp lactis Bb12, provided in either yoghurt or capsule form, on home blood pressure and serum lipid profile. METHODS AND RESULTS: Following a 3-week washout period, 156 overweight men and women over 55 y were randomized to a 6-week double-blinded, factorial, parallel study. The four intervention groups were: A) probiotic yoghurt plus probiotic capsules; B) probiotic yoghurt plus placebo capsules; C) control milk plus probiotic capsules; and D) control milk plus placebo capsules. Each probiotic test article provided a minimum L. acidophilus La5 and B. animalis subsp. lactis Bb12 dose of 3.0 × 109 CFU/d. Home blood pressure monitoring, consisting of 7-day bi-daily repeat measurements, were collected at baseline and week 6. Fasting total cholesterol, low density lipoprotein cholesterol (LDLC), high density lipoprotein cholesterol (HDLC), and serum triglyceride were performed at baseline and week 6. When compared to control milk, probiotic yoghurt did not significantly alter blood pressure, heart rate or serum lipid concentrations (P > 0.05). Similarly, when compared to placebo capsules, supplementation with probiotic capsules did not alter blood pressure or concentrations of total cholesterol LDLC, HDLC, or triglycerides (P > 0.05). CONCLUSIONS: The probiotic strains L. acidophilus La5 and B. animalis subsp. lactis Bb12 did not improve cardiovascular risk factors.