Tumor biomechanical stiffness by magnetic resonance elastography predicts surgical outcomes and identifies biomarkers in vestibular schwannoma and meningioma.

Variations in the biomechanical stiffness of brain tumors can not only influence the difficulty of surgical resection but also impact postoperative outcomes. In a prospective, single-blinded study, we utilize pre-operative magnetic resonance elastography (MRE) to predict the stiffness of intracranial tumors intraoperatively and assess the impact of increased tumor stiffness on clinical outcomes following microsurgical resection of vestibular schwannomas (VS) and meningiomas. MRE measurements significantly correlated with intraoperative tumor stiffness and baseline hearing status of VS patients. Additionally, MRE stiffness was elevated in patients that underwent sub-total tumor resection compared to gross total resection and those with worse postoperative facial nerve function. Furthermore, we identify tumor microenvironment biomarkers of increased stiffness, including αSMA + myogenic fibroblasts, CD163 + macrophages, and HABP (hyaluronic acid binding protein). In a human VS cell line, a dose-dependent upregulation of HAS1-3, enzymes responsible for hyaluronan synthesis, was observed following stimulation with TNFα, a proinflammatory cytokine present in VS. Taken together, MRE is an accurate, non-invasive predictor of tumor stiffness in VS and meningiomas. VS with increased stiffness portends worse preoperative hearing and poorer postoperative outcomes. Moreover, inflammation-mediated hyaluronan deposition may lead to increased stiffness.

Matrix metalloproteinase 9: An emerging biomarker for classification of adherent vestibular schwannoma.

Background: The progression of vestibular schwannoma (VS) is intricately linked with interactions between schwannoma cells and the extracellular matrix. Surgical resection of VS is associated with substantial risks as tumors are adherent to the brainstem and cranial nerves. We evaluate the role of matrix metalloproteinase 9 (MMP9) in VS and explore its potential as a biomarker to classify adherent VS. Methods: Transcriptomic analysis of a murine schwannoma allograft model and immunohistochemical analysis of 17 human VS were performed. MMP9 abundance was assessed in mouse and human schwannoma cell lines. Transwell studies were performed to evaluate the effect of MMP9 on schwannoma invasion in vitro. Plasma biomarkers were identified from a multiplexed proteomic analysis in 45 prospective VS patients and validated in primary culture. The therapeutic efficacy of MMP9 inhibition was evaluated in a mouse schwannoma model. Results: MMP9 was the most highly upregulated protease in mouse schwannomas and was significantly enriched in adherent VS, particularly around tumor vasculature. High levels of MMP9 were found in plasma of patients with adherent VS. MMP9 outperformed clinical and radiographic variables to classify adherent VS with outstanding discriminatory ability. Human schwannoma cells secreted MMP9 in response to TNF-α which promoted cellular invasion and adhesion protein expression in vitro. Lastly, MMP9 inhibition decreased mouse schwannoma growth in vivo. Conclusions: We identify MMP9 as a preoperative biomarker to classify adherent VS. MMP9 may represent a new therapeutic target in adherent VS associated with poor surgical outcomes that lack other viable treatment options.

Mitochondria-ER contact sites expand during mitosis.

Mitochondria-ER contact sites (MERCS) are involved in energy homeostasis, redox and Ca2+ signaling, and inflammation. MERCS are heavily studied; however, little is known about their regulation during mitosis. Here, we show that MERCS expand during mitosis in three cell types using various approaches, including transmission electron microscopy, serial EM coupled to 3D reconstruction, and a split GFP MERCS marker. We further show enhanced Ca2+ transfer between the ER and mitochondria using either direct Ca2+ measurements or by quantifying the activity of Ca2+-dependent mitochondrial dehydrogenases. Collectively, our results support a lengthening of MERCS in mitosis that is associated with improved Ca2+ coupling between the two organelles. This augmented Ca2+ coupling could be important to support the increased energy needs of the cell during mitosis.

Skeletal abnormalities caused by a Connexin43R239Q mutation in a mouse model for autosomal recessive craniometaphyseal dysplasia.

Craniometaphyseal dysplasia (CMD), a rare craniotubular disorder, occurs in an autosomal dominant (AD) or autosomal recessive (AR) form. CMD is characterized by hyperostosis of craniofacial bones and flaring metaphyses of long bones. Many patients with CMD suffer from neurological symptoms. To date, the pathogenesis of CMD is not fully understood. Treatment is limited to decompression surgery. Here, we report a knock in (KI) mouse model for AR CMD carrying a R239Q mutation in CX43. Cx43KI/KI mice replicate many features of AR CMD in craniofacial and long bones. In contrast to Cx43+/+ littermates, Cx43KI/KI mice exhibit periosteal bone deposition and increased osteoclast (OC) numbers in the endosteum of long bones, leading to an expanded bone marrow cavity and increased cortical bone thickness. Although formation of Cx43+/+ and Cx43KI/KI resting OCs are comparable, on bone chips the actively resorbing Cx43KI/KI OCs resorb less bone. Cortical bones of Cx43KI/KI mice have an increase in degenerating osteocytes and empty lacunae. Osteocyte dendrite formation is decreased with reduced expression levels of Fgf23, Sost, Tnf-α, IL-1ß, Esr1, Esr2, and a lower Rankl/Opg ratio. Female Cx43KI/KI mice display a more severe phenotype. Sexual dimorphism in bone becomes more evident as mice age. Our data show that the CX43R239Q mutation results in mislocalization of CX43 protein and impairment of gap junction and hemichannel activity. Different from CX43 ablation mouse models, the CX43R239Q mutation leads to the AR CMD-like phenotype in Cx43KI/KI mice not only by loss-of-function but also via a not yet revealed dominant function.

Steep rise in drug use-associated infective endocarditis in West Virginia: Characteristics and healthcare utilization.

INTRODUCTION: Life-threatening infections such as infective endocarditis (IE) are increasing simultaneously with the injection drug use epidemic in West Virginia (WV). We utilized a newly developed, statewide database to describe epidemiologic characteristics and healthcare utilization among patients with (DU-IE) and without (non-DU-IE) drug use-associated IE in WV over five years. MATERIALS AND METHODS: This retrospective, observational study, incorporating manual review of electronic medical records, included all patients aged 18-90 years who had their first admission for IE in any of the four university-affiliated referral hospitals in WV during 2014-2018. IE was identified using ICD-10-CM codes and confirmed by chart review. Demographics, clinical characteristics, and healthcare utilization were compared between patients with DU-IE and non-DU-IE using Chi-square/Fisher's exact test or Wilcoxon rank sum test. Multivariable logistic regression analysis was conducted with discharge against medical advice/in-hospital mortality vs. discharge alive as the outcome variable and drug use as the predictor variable. RESULTS: Overall 780 unique patients had confirmed first IE admission, with a six-fold increase during study period (p = .004). Most patients (70.9%) had used drugs before hospital admission, primarily by injection. Compared to patients with non-DU-IE, patients with DU-IE were significantly younger (median age: 33.9 vs. 64.1 years; p < .001); were hospitalized longer (median: 25.5 vs. 15 days; p < .001); had a higher proportion of methicillin-resistant Staphylococcus aureus (MRSA) isolates (42.7% vs. 29.9%; p < .001), psychiatric disorders (51.2% vs. 17.3%; p < .001), cardiac surgeries (42.9% vs. 26.6%; p < .001), and discharges against medical advice (19.9% vs. 1.4%; p < .001). Multivariable regression analysis showed drug use was an independent predictor of the combined outcome of discharge against medical advice/in-hospital mortality (OR: 2.99; 95% CI: 1.67-5.64). DISCUSSION AND CONCLUSION: This multisite study reveals a 681% increase in IE admissions in WV over five years primarily attributable to injection drug use, underscoring the urgent need for both prevention efforts and specialized strategies to improve outcomes.

Sex Differences in Characteristics of Patients with Infective Endocarditis: A Multicenter Study.

Infectious diseases like infective endocarditis (IE) may manifest or progress differently between sexes. This study sought to identify the differences in demographic and clinical characteristics among male and female patients with IE. Data were obtained from a newly developed registry comprising all adult patients with first IE admission at the four major tertiary cardiovascular centers in West Virginia, USA during 2014−2018. Patient characteristics were compared between males and females using Chi-square test, Fisher's exact test, and Wilcoxon rank-sum test. A secondary analysis was restricted to IE patients with drug use only. Among 780 unique patients (390 males, 390 females), significantly more women (a) were younger than males (median age 34.9 vs. 41.4, p < 0.001); (b) reported drug use (77.7% vs. 64.1%, p < 0.001); (c) had tricuspid valve endocarditis (46.4% vs. 30.8%, p < 0.001); and (d) were discharged against medical advice (20% vs. 9.5%, p < 0.001). These differences persisted even within the subgroup of patients with drug use-associated IE. In a state with one of the highest incidences of drug use and overdose deaths, the significantly higher incident IE cases in younger women and higher proportion of women leaving treatment against medical advice are striking. Differential characteristics between male and female patients are important to inform strategies for specialized treatment and care.

Ocular manifestations and full house membranous nephropathy as a rare presentation of secondary syphilis.

Syphilis is an often-overlooked diagnosis and without timely diagnosis and treatment, can have serious repercussions. Although its prevalence had decreased with the introduction of penicillin, it has had a resurgence over the years. Discerning the proper patient population to test for syphilis should be led by a patient's risk factors. Here, we present a patient diagnosed with secondary syphilis, with initial concern for a possible concomitant lupus diagnosis. He initially presented with visual symptoms and optic nerve inflammation, along with a positive antinuclear antibody (ANA). Due to an unprotected sexual encounter, there was suspicion for a sexually transmitted infection. Testing revealed reactive rapid plasma reagin (RPR) (≥1:256 titer) and reactive treponemal antibody, consistent with active syphilis. He was immediately started on intravenous Penicillin G. Lumbar puncture was consistent with a reactive venereal disease research laboratory test (VDRL). Urinalysis revealed nephrotic range proteinuria, which along with the positive ANA, prompted renal biopsy. This showed membranous nephropathy with full house staining, which is seen primarily in lupus nephritis and further confounded the diagnosis. He completed a two-week course of penicillin and steroids inpatient with clinical improvement. On follow up, his RPR improved (≥1:64 titer), and lumbar puncture showed a non-reactive VDRL. Due to the resolution of proteinuria, decrease of the ANA titer and no further positive testing or symptoms convincing for a concomitant rheumatologic disorder, the presence of lupus was collectively determined to be of low concern. and the sole diagnosis of secondary syphilis was made.

Cross-talk between EGFR and BMP signals regulates chondrocyte maturation during endochondral ossification.

BACKGROUND: Progressive maturation of growth plate chondrocytes drives long bone growth during endochondral ossification. Signals from the epidermal growth factor receptor (EGFR), and from bone morphogenetic protein-2 (BMP2), are required for normal chondrocyte maturation. Here, we investigated cross-talk between EGFR and BMP2 signals in developing and adult growth plates. RESULTS: Using in vivo mouse models of conditional cartilage-targeted EGFR or BMP2 loss, we show that canonical BMP signal activation is increased in the hypertrophic chondrocytes of EGFR-deficient growth plates; whereas EGFR signal activation is increased in the reserve, prehypertrophic and hypertrophic chondrocytes of BMP2-deficient growth plates. EGFR-deficient chondrocytes displayed increased BMP signal activation in vitro, accompanied by increased expression of IHH, COL10A1, and RUNX2. Hypertrophic differentiation and BMP signal activation were suppressed in normal chondrocyte cultures treated with the EGFR ligand betacellulin, effects that were partially blocked by simultaneous treatment with BMP2 or a chemical EGFR antagonist. CONCLUSIONS: Cross-talk between EGFR and BMP2 signals occurs during chondrocyte maturation. In the reserve and prehypertrophic zones, BMP2 signals unilaterally suppress EGFR activity; in the hypertrophic zone, EGFR and BMP2 signals repress each other. This cross-talk may play a role in regulating chondrocyte maturation in developing and adult growth plates.

Chondrocytes respond both anabolically and catabolically to impact loading generally considered non-injurious.

We aimed to determine the longitudinal effects of low-energy (generally considered non-injurious) impact loading on (1) chondrocyte proliferation, (2) chondroprogenitor cell activity, and (3) EGFR signaling. In an in vitro study, we assessed 127 full-thickness, cylindrical osteochondral plugs of bovine cartilage undergoing either single, uniaxial unconfined impact loads with energy densities in the range of 1.5-3.2mJ/mm3 or no impact (controls). We quantified cell responses at two, 24, 48, and 72 h via immunohistochemical labeling of Ki67, Sox9, and pEGFR antibodies. We compared strain, stress, and impact energy density as predictors for mechanotransductive responses from cells, and fit significant correlations using linear regressions. Our study demonstrates that low-energy mechanical impacts (1.5-3.2mJ/mm3) generally stimulate time-dependent anabolic responses in the superficial zone of articular cartilage and catabolic responses in the middle and deep zones. We also found that impact energy density is the most consistent predictor of cell responses to low-energy impact loading. These spatial and temporal changes in chondrocyte behavior result directly from low-energy mechanical impacts, revealing a new level of mechanotransductive sensitivity in chondrocytes not previously appreciated.

The PAPHIO study protocol: a randomised controlled trial with a 2 x 2 crossover design of physical activity adherence, psychological health and immunological outcomes in breast cancer survivors.

BACKGROUND: The PAPHIO study; a randomized controlled trial with 2X2 crossover design will implement a self-directed physical activity program in which participants will engage in self-monitoring and receive motivational interviewing to enhance physical activity adherence. The study aims to determine the effects of 24 weeks self-directed activity combined with motivational interviewing (MI) on (i) psychological health, (ii) quality of life (QoL) and (iii) immune function in female breast cancer survivors. METHODS: The study will recruit 64 female breast cancer survivors within 3 years of diagnosis and at least 6 months post primary treatments at Western Health Sunshine Hospital, Melbourne, Australia. They will be randomly allocated to immediate intervention (IIG group) or delayed intervention groups (DIG group) in a 1:1 ratio. All participants will be given a wearable device (Fitbit Alta HR) and undertake self-directed physical activity for 24 weeks and will receive MI for 12 weeks (IIG; during week 0 to week 12 and DIG; during week 13 to week 24). Participants' daily step count and the changes of immune cell functionality will be assessed at the beginning (week 1: T1), week 12 (T2) and week 24 (T3) of the program. Physical activity adherence will be assessed at T2 and T3. Participants will also complete four questionnaires assessing exercise self-regulation (BREQ2), exercise barrier and task self-efficacy, mental health (DASS-21) and QoL (FACT-B) at three time points (T1 to T3). Linear-mixed models will be used to assess the relationship between physical activity volume by step counting and mental health (DASS-21), QoL (FACT-B), immune biomarkers, self-regulation (BREQ2) and self-efficacy at T1, T2 and T3;between 2 groups. DISCUSSION: We expect this physical activity intervention to be acceptable and beneficial to the participants in terms of psychological and immunological well-being with the potential outcomes to be implemented more widely at relatively low cost to these or other patient populations. TRIAL REGISTRATION: Australian New Zealand Clinical trials Registry- ACTRN12619001271190. Prospectively registered on 13 September 2019.

Walking the boundaries: using the 6-min walk test for accurate assessment of the level of fitness in breast clinic outpatients.

BACKGROUND: Healthy levels of physical activity and improved fitness have shown better quality of life outcomes and improved survival in women with breast cancer. There is a lack of baseline data for fitness levels in breast cancer outpatients in Australia. METHODS: A single centre cross-sectional study was performed to provide a snapshot of the fitness levels of women attending the Surgical and Oncology Breast Outpatient Clinic at Western Health, Melbourne. A total of 200 women (aged 18-85 years) were surveyed and the 6-min walk test (6MWT) was performed. Single and multiple linear regression analyses were performed. RESULTS: The mean 6-min walk distance (6MWD) was 486.6 m (95% CI ±12.8 m), which was comparable with reference ranges. The mean age of participants was 47.5 years. Ninety-seven (48.5%) participants had diagnosis of breast cancer. Breast cancer diagnosis had a negative effect on 6MWD of -33.6 m walked (P = 0.010). However, multiple regression analysis showed that only age (-2.6 m walked per year older; P < 0.001), body mass index (-4.2 m walked per unit of body mass index increase; P < 0.001) and presence of comorbidities (-56.9 m walked; P < 0.001) had statistically significant negative effects on 6MWD. Self-reported exercise tolerance correlated significantly with 6MWD (walking: P < 0.001 and stairs: P = 0.014). CONCLUSION: The 6MWT was easily performed within outpatient environment to accurately assess baseline level of fitness in breast cancer clinic outpatients. This indicates that 6MWT can be used as a valuable adjunctive tool to assess the level of fitness in breast cancer patients to make therapeutic recommendations in improving breast cancer outcomes.

Barriers to using new needles encountered by rural Appalachian people who inject drugs: implications for needle exchange.

BACKGROUND: Using a new needle for every injection can reduce the spread of infectious disease among people who inject drugs (PWID). No previous study has examined new needle use barriers among PWIDs residing in the rural Appalachian part of the United States, an area currently in the midst of a heroin epidemic. OBJECTIVE: Therefore, our primary aim was to explore self-reported barriers to using a new needle by PWID attending a needle exchange program (NEP). METHODS: We conducted a cross-sectional survey of PWID attending two NEPs in rural West Virginia located in the heart of Central Appalachia. A convenience sample of PWID (n = 100) completed the Barriers to Using New Needles Questionnaire. RESULTS: The median number of barriers reported was 5 (range 0-19). Fear of arrest by police (72% of PWID "agreed" or "strongly agreed") and difficulty with purchasing needles from a pharmacy (64% "agreed" or "strongly agreed") were the most frequently cited barriers. CONCLUSIONS/IMPORTANCE: Congruent with previous findings from urban locations, in rural West Virginia, the ability of PWID to use a new needle obtained from a needle exchange for every injection may be compromised by fear of arrest. In addition, pharmacy sales of new needles to PWID may be blunted by an absence of explicit laws mandating nonprescription sales. Future studies should explore interventions that align the public health goals of NEPs with the occupational safety of law enforcement and health outreach goals of pharmacists.

Vertebral osteomyelitis due to Candida species.

OBJECTIVE: We have noted an increased number of cases of vertebral osteomyelitis secondary to Candida species over the past few years at our facility. Our aim was to identify and review these cases to elucidate risk factors, treatment regimens and outcomes. METHODS: We performed a retrospective chart review using our electronic medical record and microbiology laboratory database to identify cases of vertebral osteomyelitis due to Candida at a single teaching hospital from 2006-2018. RESULTS: We found 15 cases of Candida vertebral osteomyelitis. The majority of cases were due to Candida albicans and affected either the lumbar or the thoracic spine. Injection drug use and previous spine surgery were the two most common risk factors identified. Treatment was largely with intravenous antifungal induction followed by prolonged therapy with oral fluconazole. There was no short-term mortality though we lacked long-term follow-up on most patients. CONCLUSIONS: The number of vertebral infections due to Candida may be increasing. This may be partially driven by both a rise in intravenous drug use as well as the growing rate of spine surgery. Management following currently available guidelines seems favorable, though further studies are necessary to determine the optimal treatment regimen.

Intimate Partner Violence Experiences Among Men Living with HIV in Rural Appalachia.

There has been limited study of the syndemic link between HIV and intimate partner violence (IPV) among rural populations in the United States. We utilized the Revised Conflict Tactics Scale-2 to examine the past year prevalence, type (psychological aggression, physical assault, and sexual assault), and the impact of IPV on HIV clinical outcomes among men living with HIV in rural Appalachia. Approximately 39% of participants experienced some type of IPV in the preceding year, with 67% of those individuals experiencing more than 1 type of IPV. Approximately 77% of participants endorsing IPV exposure experienced psychological aggression. Most participants exposed to psychological aggression (70%) and/or physical assault (57%) were both victims and perpetrators, and those experiencing sexual assault reported being exclusively victims (65%). There were no significant differences in clinical outcomes including viral load and CD4 count, which may be secondary to small sample size derived from a clinic population with a high rate of virologic suppression (94%). This study demonstrates the need to assess IPV exposure in men living with HIV and further highlights the intricacies of relationship violence in these individuals.

Student nurses' lived experience of patient safety and raising concerns.

INTRODUCTION: Following the investigation into the Mid Staffordshire Hospital (United Kingdom) and the subsequent Francis reports (2013 and 2015), all healthcare staff, including students, are called upon to raise concerns if they are concerned about patient safety. Despite this advice, it is evident that some individuals are reluctant to do so and the reasons for this are not always well understood. STUDY AIM: This research study provides an insight into the factors that influence student nurses to speak up or remain silent when witnessing sub-optimal care. DESIGN: An interpretive phenomenological study using the principles of hermeneutics. The study took place in one university in the North of England and the sample consisted of twelve adult nursing students. METHODS: Following ethical approval and informed consent, each participant took part in individual semi-structured interviews over a three-year period. Data was transcribed and analysed using 'Framework for Applied Policy Research'. FINDINGS: Four key themes were identified: context of exposure, fear of punitive action, team culture and hierarchy. On the one hand, students recognised there was a professional obligation bestowed upon them to raise concerns if they witnessed sub-optimal practice, however, their willingness to do so was influenced by intrinsic and extrinsic factors. Students have to navigate their moral compass, taking cognisance of their own social identity and the identity of the organisations in which they are placed.

Qualitative case study of needle exchange programs in the Central Appalachian region of the United States.

BACKGROUND: The Central Appalachian region of the United States is in the midst of a hepatitis C virus epidemic driven by injection of opioids, particularly heroin, with contaminated syringes. In response to this epidemic, several needle exchange programs (NEP) have opened to provide clean needles and other supplies and services to people who inject drugs (PWID). However, no studies have investigated the barriers and facilitators to implementing, operating, and expanding NEPs in less populous areas of the United States. METHODS: This qualitative case study consisted of interviews with program directors, police chiefs, law enforcement members, and PWID affiliated with two NEPs in the rural state of West Virginia. Interview transcripts were coded inductively and analyzed using qualitative data analysis software. Final common themes related to barriers and facilitators of past program openings, current program operations, and future program plans, were derived through a consensus of two data coders. RESULTS: Both NEPs struggled to find existing model programs, but benefited from broad community support that facilitated implementation. The largest operational barrier was the legal conundrum created by paraphernalia laws that criminalize syringe possession. However, both PWID and law enforcement appreciated the comprehensive services provided by these programs. Program location and transportation difficulties were additional noted barriers. Future program operations are threatened by funding shortages and bans, but necessitated by unexpected program demand. CONCLUSION: Despite broad community support, program operations are threatened by growing participant volumes, funding shortages, and the federal government's prohibition on the use of funds to purchase needles. Paraphernalia laws create a legal conundrum in the form of criminal sanctions for the possession of needles, which may inadvertently promote needle sharing and disease transmission. Future studies should examine additional barriers to using clean needles provided by rural NEPs that may blunt the effectiveness of NEPs in preventing disease transmission.

Physical activity and breast cancer survivors: Importance of adherence, motivational interviewing and psychological health.

Behavioral change theories have been used to support interventions that increase both motivation for and adherence to physical activity programs for breast cancer survivors. Most of the programs can improve psychological health-related quality of life. Depressive and anxious symptoms seem to be associated with some stressors, such as the perception of breast cancer, prognosis, long-term treatment-related side-effects and fear of cancer recurrence. Beyond physical fitness, several physical activity programs for breast cancer survivors have been reported to improve psychosocial wellness and life satisfaction. However, many physical activity programs have failed to motivate breast cancer survivors due to barriers such as general health issues and lack of time. More specifically, women may have little confidence in the benefits of physical activity and breast cancer outcomes. Therefore, engaging breast cancer survivors in physical activity is challenging for health care professionals. Herein, we identify cancer-related mental distress, coping style and behavioral theories applied to physical activity programs in breast cancer survivors. More specifically, we discuss the effectiveness and limitations of 3 psychological theories and 2 concepts related to behavioral change, including the theory of planned behavior, social cognitive theory, self-determination theory, transtheoretical model and motivational interviewing for physical activity adherence in breast cancer survivors.

Dephosphorylation of the NPR2 guanylyl cyclase contributes to inhibition of bone growth by fibroblast growth factor.

Activating mutations in fibroblast growth factor (FGF) receptor 3 and inactivating mutations in the NPR2 guanylyl cyclase both cause severe short stature, but how these two signaling systems interact to regulate bone growth is poorly understood. Here, we show that bone elongation is increased when NPR2 cannot be dephosphorylated and thus produces more cyclic GMP. By developing an in vivo imaging system to measure cyclic GMP production in intact tibia, we show that FGF-induced dephosphorylation of NPR2 decreases its guanylyl cyclase activity in growth plate chondrocytes in living bone. The dephosphorylation requires a PPP-family phosphatase. Thus FGF signaling lowers cyclic GMP production in the growth plate, which counteracts bone elongation. These results define a new component of the signaling network by which activating mutations in the FGF receptor inhibit bone growth.

Needle exchange programs for the prevention of hepatitis C virus infection in people who inject drugs: a systematic review with meta-analysis.

BACKGROUND: Previous research on the effectiveness of needle exchange programs (NEP) in preventing hepatitis C virus (HCV) in people who inject drugs (PWID) has shown mixed findings. The purpose of this study was to use the meta-analytic approach to examine the association between NEP use and HCV prevention in PWIDs. METHODS: Study inclusion criteria were (1) observational studies, (2) PWIDs, (3) NEP use, (4) HCV status ascertained by serological testing, (5) studies published in any language since January 1, 1989, and (6) data available for measures of association. Studies were located by searching four electronic databases and cross-referencing. Study quality was assessed using the Newcastle Ottawa (NOS) scale. A ratio measure of association was calculated for each result from cohort or case-control studies and pooled using a random effects model. Odds ratio (OR) and hazard ratio (HR) models were analyzed separately. Results were considered statistically significant if the 95% confidence interval (CI) did not cross 1. Heterogeneity was estimated using Q and I 2 with alpha values for Q ≤ 0.10 considered statistically significant. RESULTS: Of the 555 citations reviewed, 6 studies containing 2437 participants were included. Studies had an average NOS score of 7 out of 9 (77.8%) stars. Concerns over participant representativeness, unclear adjustments for confounders, and bias from participant nonresponse and loss to follow-up were noted. Results were mixed with the odds ratio model indicating no consistent association (OR, 0.51, 95% CI, 0.05-5.15), and the hazard ratio model indicating a harmful effect (HR, 2.05, 95% CI, 1.39-3.03). Substantial heterogeneity (p ≤ 0.10) and moderate to large inconsistency (I 2 ≥ 66%) were observed for both models. CONCLUSIONS: The impact of NEPs on HCV prevention in PWIDs remains unclear. There is a need for well-designed research studies employing standardized criteria and measurements to clarify this issue. TRIAL REGISTRATION: PROSPERO CRD42016035315.

FGF2 High Molecular Weight Isoforms Contribute to Osteoarthropathy in Male Mice.

Humans with X-linked hypophosphatemia (XLH) and Hyp mice, the murine homolog of the disease, develop severe osteoarthropathy and the precise factors that contribute to this joint degeneration remain largely unknown. Fibroblast growth factor 2 (FGF2) is a key regulatory growth factor in osteoarthritis. Although there are multiple FGF2 isoforms the potential involvement of specific FGF2 isoforms in joint degradation has not been investigated. Mice that overexpress the high molecular weight FGF2 isoforms in bone (HMWTg mice) phenocopy Hyp mice and XLH subjects and Hyp mice overexpress the HMWFGF2 isoforms in osteoblasts and osteocytes. Given that Hyp mice and XLH subjects develop osteoarthropathies we examined whether HMWTg mice also develop knee joint degeneration at 2, 8, and 18 mo compared with VectorTg (control) mice. HMWTg mice developed spontaneous osteoarthropathy as early as age 2 mo with thinning of subchondral bone, osteophyte formation, decreased articular cartilage thickness, abnormal mineralization within the joint, increased cartilage degradative enzymes, hypertrophic markers, and angiogenesis. FGF receptors 1 and 3 and fibroblast growth factor 23 were significantly altered compared with VectorTg mice. In addition, gene expression of growth factors and cytokines including bone morphogenetic proteins, Insulin like growth factor 1, Interleukin 1 beta, as well as transcription factors Sex determining region Y box 9, hypoxia inducible factor 1, and nuclear factor kappa B subunit 1 were differentially modulated in HMWTg compared with VectorTg. This study demonstrates that overexpression of the HMW isoforms of FGF2 in bone results in catabolic activity in joint cartilage and bone that leads to osteoarthropathy.