Comparative effectiveness and cardiovascular safety of abaloparatide and teriparatide in postmenopausal women new to anabolic therapy: A US administrative claims database study.

Real-world evidence on the comparative effectiveness and safety of abaloparatide versus teriparatide in women with osteoporosis may help inform treatment decisions. Following 18 months of treatment, abaloparatide was comparable to teriparatide for prevention of nonvertebral fractures, resulted in a 22% risk reduction for hip fractures, and demonstrated similar cardiovascular safety. Osteoporotic fracture risk can be reduced with anabolic or antiresorptive medications. In addition to efficacy and safety data from controlled clinical trials, real-world evidence on comparative effectiveness and safety may help inform treatment decisions. INTRODUCTION: The real-world effectiveness of abaloparatide versus teriparatide on nonvertebral fracture (NVF) incidence and cardiovascular safety during the 19-month period after treatment initiation were evaluated (NCT04974723). METHODS: Anonymized US patient claims data from Symphony Health, Integrated Dataverse (IDV)®, May 1, 2017 to July 31, 2019, included women aged ≥ 50 years with ≥ 1 prescription of abaloparatide or teriparatide and no prior anabolic therapy. Most were enrolled in commercial and Medicare health plans. Index was the date of the initial prescription dispensed during the identification period. In 1:1 propensity score matched cohorts, time to first NVF following index date, major adverse cardiovascular events (MACE), and MACE + heart failure (HF) were compared between cohorts using a Cox proportional hazards model. RESULTS: Propensity score matching yielded 11,616 patients per cohort. Overall median age (interquartile range) was 67 (61, 75) years, and 25.6% had a fracture history. Over 19 months, 335 patients on abaloparatide and 375 on teriparatide had a NVF (hazard ratio [95% confidence interval]: 0.89 [0.77, 1.03]), and 121 and 154 patients, respectively, had a hip fracture [HR (95% CI): 0.78 (0.62, 1.00)]. The MACE and MACE + HF rates were similar between cohorts. CONCLUSIONS: Following 18 months of treatment, abaloparatide was comparable to teriparatide for prevention of NVF and similar cardiovascular safety was demonstrated between cohorts.

Characterizing patients initiating abaloparatide, teriparatide, or denosumab in a real-world setting: a US linked claims and EMR database analysis.

We characterized patients initiating abaloparatide (ABL), teriparatide (TPTD), or denosumab (DMAB) in a real-world clinical setting from a large medical and pharmacy claims database. Differences were noted in sex, age, pathologic fractures, comorbidity index, and prior bisphosphonate use for patients initiating ABL and TPTD compared with those receiving DMAB. INTRODUCTION: To characterize patients initiating abaloparatide (ABL), teriparatide (TPTD), or denosumab (DMAB) treatment in a real-world clinical setting. METHODS: Patients aged ≥ 18 years initiating ABL, TPTD, or DMAB between May 1, 2017, and September 24, 2018 (without receiving the same drug in the previous 12 months), were identified using the OM1 Data Cloud, which contains medical and pharmacy claims from approximately 200 million US patients. The index date was the date of initial prescription or dispensing for ABL, TPTD, or DMAB during the study period. RESULTS: During the study period, 2666 patients initiated ABL, 9210 TPTD, and 116,718 DMAB. Mean age (standard deviation) was 69.2 (10.6) years for the ABL cohort, 68.6 (11.3) for TPTD, and 72.1 (10.2) for DMAB (P < 0.001; ABL vs DMAB). Proportionally more patients initiating ABL were female (95.2% ABL, 86.9% TPTD, and 91.3% DMAB, P < 0.001 ABL vs TPTD or DMAB). Nearly twice as many patients initiating ABL (19.1%) and TPTD (18.8%) had a previous pathologic/fragility fracture vs DMAB (9.6%; P < 0.001 ABL vs DMAB). Fewer patients initiating ABL (36.3%) or TPTD (39.7%) had Charlson comorbidity index of ≥ 2 vs DMAB (48.4%; P < 0.001 ABL vs DMAB). Before initiating ABL, TPTD, or DMAB, 44.3%, 33.8%, and 33.9% of patients had prior osteoporosis treatment, respectively. Bisphosphonate use was more common before initiating ABL (19.2%) or TPTD (19.6%), than before initiating DMAB (16.6%; P < 0.001 ABL vs DMAB). CONCLUSIONS: Patients initiating ABL and TPTD differed in sex, age, pathologic fractures, comorbidity index, and prior bisphosphonate use compared with those initiating DMAB.

Abaloparatide for risk reduction of nonvertebral and vertebral fractures in postmenopausal women with osteoporosis: a network meta-analysis.

This network meta-analysis assessed the efficacy of abaloparatide versus other treatment options to reduce the risk of fractures in women with postmenopausal osteoporosis. The analysis indicates that abaloparatide reduces the risk of fractures in women with postmenopausal osteoporosis versus placebo and compared with other treatment options. INTRODUCTION: This network meta-analysis (NMA) assessed the relative efficacy of abaloparatide versus other treatments to reduce the risk of fractures in women with postmenopausal osteoporosis (PMO). METHODS: PubMed®, Embase®, and the Cochrane Central Register of Controlled Trials were searched for randomized controlled trials published before December 20, 2017, that included women with PMO who were eligible to receive interventions for primary or secondary fracture prevention. The NMA was conducted by fracture site (vertebral [VF], nonvertebral [NVF], and wrist), with the relative risk (RR) of fracture versus placebo the main clinical endpoint. The NMA used fixed-effects and random-effects approaches. RESULTS: A total of 4978 articles were screened, of which 22 were included in the analysis. Compared with other treatments, abaloparatide demonstrated the greatest treatment effect relative to placebo in the VF network (RR = 0.13; 95% credible interval [CrI] 0.04-0.34), the NVF network (RR = 0.50; 95% CrI 0.28-0.85), and the wrist fracture network (RR = 0.39; CrI 0.15-0.90). Treatment ranking showed that abaloparatide had the highest estimated probability of preventing fractures in each of the networks (79% for VF, 70% for NVF, and 53% for wrist fracture) compared with other treatments. Individual networks demonstrated a good level of agreement with direct trial evidence and direct pair-wise comparisons. CONCLUSIONS: This NMA indicates that abaloparatide reduces the RR of VF, NVF, and wrist fracture in women with PMO with or without prior fracture versus placebo, compared with other treatment options. Limitations include that adverse events and drug costs were not considered, and that generalizability is limited to the trial populations and endpoints included in the NMA.

Tug of war in the haematopoietic stem cell niche: do myeloma plasma cells compete for the HSC niche?

In the adult mammal, normal haematopoiesis occurs predominantly in the bone marrow, where primitive haematopoietic stem cells (HSC) and their progeny reside in specialised microenvironments. The bone marrow microenvironment contains specific anatomical areas (termed niches) that are highly specialised for the development of certain blood cell types, for example HSCs. The HSC niche provides important cell-cell interactions and signalling molecules that regulate HSC self-renewal and differentiation processes. These same signals and interactions are also important in the progression of haematological malignancies, such as multiple myeloma (MM). This review provides an overview of the bone marrow microenvironment and its involvement in normal, physiological HSC maintenance and plasma cell growth throughout MM disease progression.

Magnetic resonance imaging for the study of ovarian follicles in the mouse.

Additional tools to analyze follicle development would be highly advantageous because current methods require sacrifice of animals at specific times and time-consuming sectioning of tissues for histologic analysis. Magnetic resonance imaging (MRI) may provide a less involved, faster and more cost-effective method to analyze follicles in whole ovaries. Fixed ovaries were collected at different stages of the estrus cycle and after stimulation with gonadotrophins (24 and 48 h post pregnant mares serum (PMSG), and 10 and 24 h post human chorionic gonadotrophin (hCG)) with or without administration of the contrast agent gadodiamide. The MR images were generated using a vertical-bore, 11.7 Tesla MR system. Analysis of the MR images revealed large antral follicles in fixed ovaries with the oocyte and cumulus mass identifiable within preovulatory follicles. The use of gadodiamide had no impact on the quality of MR images obtained. The fixed ovaries were paraffin embedded, sectioned, and hematoxylin stained. Follicles were counted using the MR images and the histology sections. Preovulatory follicle numbers determined using MR images were comparable to those using histology; however counts of smaller follicles were inconsistent. MRI of gonadotrophin-stimulated ovaries in situ did not reveal discernable ovarian structures. Therefore, MRI is a useful tool for studying whole fixed ovaries leaving the ovary intact for additional analyses or for selection of samples based on morphology. The MRI is also useful for identifying preovulatory follicles, although analysis of smaller follicles is not possible, and thus the potential exists for cyst analysis in mouse models of polycystic ovarian syndrome (PCOS).

Cytochrome P450 1 enzyme inhibition and anticancer potential of chromene amides from Amyris plumieri.

Cytochrome P450 (CYP) enzyme inhibitory properties of six chromenylated amide compounds (CAs) from Amyris plumieri are described. Inhibition of CYP microsomes (CYP1A1, CYP1A2, CYP1B1, CYP2D6, CYP3A4 and CYP2C19) was monitored using a fluorescent assay. Potent inhibition was found against CYP1A1 with IC(50) and K(i) for CA1 (acetamide), being the lowest at 1.547 ± 1.0 µM and 0.37 µM respectively, displaying non-competitive kinetics. The selectivity for CYP1A1 was increased in CA3 (butanamide), which also exhibited cytotoxicity against breast cancer cells, MCF7 with an IC(50) of 47.46 ± 1.62 µM. Structure-activity relationship studies provide insight at a molecular level for CAs with implications in chemoprevention and chemotherapy.

Genetics of platelet reactivity in normal, healthy individuals.

BACKGROUND: The Platelet Function Analyzer-100 (PFA-100) is widely used to measure platelet reactivity in whole blood under high shear. OBJECTIVE: To characterize the genetic component of platelet reactivity among normal individuals, using the PFA-100. METHODS: We compared baseline platelet reactivity with sex, age, platelet count, hematocrit, plasma von Willebrand factor antigen (VWF:Ag), and alleles of seven candidate genes: integrin subunits alpha2 (ITGA2) and beta3 (ITGB3), platelet glycoproteins GPIbalpha (GP1BA) and GPVI (GP6), purinogenic receptors (P2RY1 and P2RY12) and cyclooxygenase-1 (COX1). RESULTS: Based on linear and logistic regression models, we report an inverse correlation between baseline closure time (CT) initiated by collagen plus epinephrine (CEPI) and plasma VWF:Ag level, ITGA2 807T and P2RY1 893C, and an inverse correlation between baseline CT initiated by collagen plus adenosine diphosphate (CADP) and P2RY1 893C or GP1BA -5C. CONCLUSIONS: These results indicate that genetic polymorphisms in ITGA2 and P2RY1 combine with plasma VWF:Ag levels to modulate baseline platelet reactivity in response to collagen plus EPI, while genetic differences in P2RY1 and GP1BA significantly effect platelet responses to collagen plus ADP. Our results demonstrate that the PFA-100 can be used to evaluate the effects of genetic predictors of platelet function.

A comparison of polyethylene wear rates between cemented and cementless cups. A prospective, randomised trial.

We selected randomly a consecutive series of 162 patients requiring hip replacement to receive either a cementless, hemispherical, modular, titanium acetabular cup or a cemented, all-polyethylene cup. These replacements were performed by two surgeons in four general hospitals. The same surgical technique was used and a 26 mm metal-head femoral component was used in every case. After exclusions, 115 hips were studied for differences in rates of wear and osteolysis. The mean clinical follow-up was eight years and the mean radiological follow-up, 6.5 years. The cementless cups wore at a mean rate of 0.15 mm per year and the cemented cups at 0.07 mm per year. This difference was significant (p < 0.0001). Our findings in this mid-term study suggest that cementless cups wear more than cemented cups.

Post-operative recovery after inguinal herniotomy in ex-premature infants: comparison between sevoflurane and spinal anaesthesia.

We prospectively studied the post-operative recovery profile of 28 ex-premature infants undergoing inguinal herniotomy. All infants had a post-conceptual age of less than 46 weeks at the time of surgery and were randomized to receive either sevoflurane (group 1, 14 patients) or spinal anaesthesia (group 2, 14 patients). All patients received supplemental caudal analgesia before skin incision. Cardiorespiratory function was continuously recorded in all patients before and after surgery. A blinded observer analysed each paired recording for predefined episodes of apnoea, hypoxaemia or bradycardia and the reports were used to compare the two groups. Spinal anaesthesia was attempted unsuccessfully in four patients in group 2. Five patients in group 1 demonstrated an 'excess' number of episodes (median 4, range 3-12) of clinically silent post-operative cardiorespiratory complications. ('Excess' in our study was defined as a 3-fold or greater increase in the number of post-operative episodes of bradycardia or apnoea relative to pre-operative occurrence). Three of these patients had pre-existing abnormal respiratory function and accounted for 80% of the episodes (26/32) of post-operative bradycardia and all five episodes of post-operative apnoea identified. All episodes of bradycardia and apnoea were temporally unrelated. None of the remaining patients in group 2 demonstrated an unacceptable number of post-operative cardiorespiratory complications. Our limited study suggests that general anaesthesia with an inhalational agent such as sevoflurane may induce or unmask abnormalities of cardiopulmonary function in predisposed infants. Spinal anaesthesia may be preferable but it is potentially stressful for the infant and associated with a clinically significant failure rate.

Moderate alcohol consumption and risk of heart failure among older persons.

CONTEXT: Heavy consumption of alcohol can lead to heart failure, but the relationship between moderate alcohol consumption and risk of heart failure is largely unknown. OBJECTIVE: To determine whether moderate alcohol consumption predicts heart failure risk among older persons, independent of the association of moderate alcohol consumption with lower risk of myocardial infarction (MI). DESIGN: Prospective cohort study conducted from 1982 through 1996, with a maximum follow-up of 14 years. SETTING AND PARTICIPANTS: Population-based sample of 2235 noninstitutionalized elderly persons (mean age, 73.7 years; 41.2% male; 21.3% nonwhite) residing in New Haven, Conn, who were free of heart failure at baseline. Persons who reported alcohol consumption of more than 70 oz in the month prior to baseline were excluded. MAIN OUTCOME MEASURE: Time to first fatal or nonfatal heart failure event, according to the amount of alcohol consumed in the month prior to baseline. RESULTS: Increasing alcohol consumption in the moderate range was associated with decreasing heart failure rates. For persons consuming no alcohol (50.0%), 1 to 20 oz (40.2%), and 21 to 70 oz (9.8%) in the month prior to baseline, crude heart failure rates per 1000 years of follow-up were 16.1, 12.2, and 9.2, respectively. After adjustment for age, sex, race, education, angina, history of MI and diabetes, MI during follow-up, hypertension, pulse pressure, body mass index, and current smoking, the relative risks of heart failure for those consuming no alcohol, 1 to 20 oz, and 21 to 70 oz in the month prior to baseline were 1.00 (referent), 0.79 (95% confidence interval [CI], 0.60-1.02), and 0.53 (95% CI, 0.32-0.88) (P for trend =.02). CONCLUSIONS: Increasing levels of moderate alcohol consumption are associated with a decreasing risk of heart failure among older persons. This association is independent of a number of confounding factors and does not appear to be entirely mediated by a reduction in MI risk.

Parental smoking practices and caries experience in pre-school children.

Voluntary and involuntary smoking influence general health. Links between voluntary smoking and oral health are confirmed for periodontal diseases and oral cancer/precancer. Since recent reports have suggested an association between parental smoking and caries experience in young children, this study aimed to explore varying patterns of parental smoking, adjusted for social class, with caries prevalence, using data derived from the UK National Diet and Nutrition Survey (1995). Data analysis was confined to 749 children aged 3.0-4.5 years, to avoid confounding effects of unerupted teeth. Bivariate analysis indicated that the prevalence of maternal rather than paternal smoking was significantly related to caries and substantially attenuated social class differences. The reported number of cigarettes smoked was not important. To compensate for the association between social class and maternal smoking, data were dichotomised by social class (manual/non-manual). With caries prevalence as the dependent variable, logistic regression analysis recorded maternal smoking as a significant independent variable in each case, with odds ratios of 1.55/1.96, respectively. The process was repeated for the combined dataset, using the more extensive (six) social class categories. This further analysis yielded an odds ratio for maternal smoking of 1.54 compared with 1.46 for social class. Nutrition status (as growth parameters) and dietary intake (as household spending on confectionery) were not significant independent variables in these equations. The rationale for these findings is discussed. Further research is required to determine mechanisms underlying these observations. It is concluded that maternal smoking is a significant factor to be considered as an additional risk indicator beyond social class when predicting caries risk in young children.

Social images of medicine and dentistry in Japan. An exploratory study using correspondence analysis.

OBJECTIVE: To investigate social images associated with dentistry in comparison with nine other medical disciplines. DESIGN: A questionnaire survey among members of the general public. Subjects were asked to state, in not more than five words, the images which they associated with each of the ten disciplines. SETTING: Komaki City, Shikatsu Town and Nagoya City in Japan. PARTICIPANTS: 261 respondents from a convenience sample of 300 residents, not associated with any branch of medicine. OUTCOME MEASURES: Frequency distribution of word images used on at least five occasions and a correspondence analysis of the responses for the ten disciplines. RESULTS: Of the 163 coded image items, 60 were related to internal medicine, 56 to dentistry, 55 to dermatology, 51 to orthopaedic surgery, 51 to ophthalmology, 50 to surgery, 47 to obstetrics and gynaecology, 43 to otolaryngology, 40 to paediatrics and 33 to psychiatry. Correspondence analysis applied to the 163 items and 10 medical disciplines indicated that three similar paired image groups were found, namely between dermatology and ophthalmology, surgery and orthopaedic surgery, and between dentistry and internal medicine, which were the more commonly encountered disciplines across all age groups. However, compared with the other specialities, dentistry had a significantly greater association with pain, this response being four times more common than for surgery. CONCLUSIONS: This group of members of the public in Japan perceived dentistry-associated images in a similar way to internal medicine, but the negative associations with pain need to be addressed by the dental profession and health educators alike.

Diagnostic delays in head and neck cancers.

Head and neck cancers are a significant and worsening health problem in the UK. In the absence of screening, minimising diagnostic delay after the onset of symptoms improves prognosis. Delay, from the patient's initial experience of symptoms to the ultimate diagnosis, consists of two elements--the delay prior to presenting to a clinician plus that due to the health professional consulted. This study aimed to establish the period of delay between recognition of the initial tumour symptoms and the formal diagnosis among a sample of patients recently diagnosed with head and neck cancer. Using a semistructured questionnaire, 133 men and 55 women were interviewed by a research nurse, and the results were related to the clinical findings. Tumour size at diagnosis was classified according to T1 (22%), T2 (29%), T3 (27%) and T4 (22%). Of the 186 patients with complete hospital records, 48 (26%) were diagnosed with cancer of the lip and oral cavity (CLOC). From the onset of symptoms to the patients' initial decision to seek professional advice, the median period was 4 weeks among those with CLOC and 3 weeks for those with other head and neck cancers (OHNC). The distribution was highly skewed with delays beyond 6 months occurring among 9% of the OHNC group, compared with 3% of CLOC. From the onset of symptoms to a consultant appointment, the median delay was 8 weeks for OHNC, but 12 weeks for CLOC, with delays beyond 6 months of 13% in each group, respectively. First symptoms included 'change in voice' (26%), 'pain' (27%), 'lump' or 'growth' (12%) as well as dysphagia, 'infection', 'sore throat', 'ulcers' or 'abscess'. No significant association was found between the nature of the first symptoms and the urgency with which patients interpreted their symptoms, nor was this related to diagnostic delay, sex, age or social class. It is concluded that there is substantial variation in time to clinical presentation, particularly for OHNC, although professional delay for the majority of these cases was minimal. For patients with CLOC there was less variation in patient delay, but clinician delay was relatively longer.

Quality and care: patients' perceptions.

Patients and health care professionals view quality nursing care from different perspectives. Health care professionals view competent nursing care as quality nursing care. Patients perceive quality nursing care as caring, interpersonal interactions. Institutions measure quality care through satisfaction surveys that exclude components of nurse caring behaviors. In three studies utilizing the Holistic Caring Inventory (HCI), patients perceived nurse caring behaviors and attitudes that indicated quality nursing care. The way to bridge the gap between institutions' and patients' perceptions of quality care lies in valuing the interactions that patients consider quality care and including these interactions in measures of quality care.

Detection of the filarial parasite Mansonella streptocerca in skin biopsies by a nested polymerase chain reaction-based assay.

To differentiate the skin-dwelling filariae Mansonella streptocerca and Onchocerca volvulus, a nested polymerase chain reaction (PCR) assay was developed from small amounts of parasite material present in skin biopsies. One nonspecific and one specific pair of primers were used to amplify the 5S rDNA spacer region of M. streptocerca. Biopsies with different microfilaria densities obtained from 104 Ugandans living in an area endemic for M. streptocerca were tested using both the nested PCR assay and standard parasitologic assessment of microfilariae. All 82 samples from microfilaria carriers were positive when tested using the nested PCR assay. In addition, M. streptocerca DNA could be detected in 16 samples thought to be microfilaria negative. Furthermore, six days following ivermectin treatment, M. streptocerca DNA was found in 12 of 14 microfilaria-negative biopsies. Control skin samples from patients infected with O. volvulus were all negative in the nested PCR assay. This assay improves the diagnosis of M. streptocerca and will facilitate further epidemiologic studies.

Phosphorothioate substrates for the SfiI restriction endonuclease.

Oligodeoxynucleotides carrying the recognition sequence for the SfiI endonuclease were synthesised with phosphorothioates at the cleavage site. The Rp and Sp diastereoisomers of the oligonucleotides were separated by HPLC using a mobile phase containing L-cysteine. The duplex with Rp phosphorothioates was cleaved very slowly in the presence of Mg2+, though virtually complete cleavage was obtained with Mn2+. No significant cleavage of the duplex with Sp phosphorothioates occurred with either Mg2+ or Mn2+. When added to a plasmid with one SfiI site, the duplexes with either Rp or Sp phosphorothioates inhibited the rate at which SfiI cleaved the plasmid: a control duplex with oxyester linkages enhanced the rate of plasmid cleavage. In contrast to type IIe nucleases such as EcoRII and NaeI, which can be activated by non-hydrolysable analogues of their substrates, SfiI reactions require four susceptible phosphodiester bonds.

Thioredoxin peroxidase from Onchocerca volvulus: a major hydrogen peroxide detoxifying enzyme in filarial parasites.

Random screening of an Onchocerca volvulus third-stage (L3) cDNA library identified a highly abundant cDNA encoding a newly discovered antioxidant enzyme, thioredoxin peroxidase (TPx), a member of the peroxidoxin superfamily. This TPx cDNA (Ov-tpx-2) encodes a polypeptide of 199 amino acid residues with a calculated molecular weight of 21,890 Da. The Ov-tpx-2 cDNA represents roughly 2.5% of the total cDNAs from the L3 cDNA library. The gene was expressed in Escherichia coli and the protein product was shown to have antioxidant activity. Antiserum raised against Ov-TPX-2 recognized a native protein from extracts of both the L3 and adult-stages with a molecular weight of 22 kD. The localization and stage-specificity of Ov-TPX-2 protein was analyzed by immunocytochemistry and immunoelectron microscopy using monospecific antibodies. Expression was detected in late first-stage larvae during development in the vector and increased in intensity during differentiation to the infective L3-stage. The antigen was also detected in post-infective larvae and adult worms. In larvae, Ov-TPX-2 protein was predominantly localized to the hypodermis and cuticle, with additional sites in the hypodermal chords and multivesicular bodies. In adult worms, the primary sites of expression were the uterine epithelium and intestine, with additional labeling of the body wall and cuticle. Developing embryos and microfilariae in utero were bathed in Ov-TPX-2 protein discharged from epithelial cells. These results suggest that Ov-TPX-2 may protect the parasites from being damaged by host-generated oxidative stress and that Ov-TPX-2 protein provides the H2O2-detoxifying activity predicted but not previously identified in filarial parasites. Its highly upregulated expression in infective larvae may aid in parasite establishment following transmission to the definitive host.

Using an outside consultant for staff development.

In this article the author describes the use of a nurse educator/clinical nurse specialist as an outside consultant to provide a program to educate staff nurses about oncology patient care. The continuing education program included a didactic and clinical practicum. The program provided nurses with specialized knowledge about an expanding patient population, improved the level of oncology patient care, and increased the confidence of the physicians and community members in the level of oncology nursing care.