Clinical risk factors for fracture among postmenopausal patients at risk for fracture: a historical cohort study using electronic medical record data

Osteoporosis represents a growing health burden, but recognition and screening rates are low. Electronic reminders for osteoporosis have been beneficial but are not based on clinical risk factors. Available risk screening tools may contain useful constructs for creating risk-based electronic medical record (EMR) reminders. Using a cohort study design among women ≥50 years with osteoporosis or osteoporosis risk, we searched the EMR for five World Health Organization (WHO) clinical risk factors including older age, lower body mass index (BMI), low bone mineral density (BMD), history of fracture since age 50, and maternal history of osteoporosis or fracture. Rates of reporting were lower than expected for BMD (6.8%), personal history of fracture (3.5%), and maternal history of fracture (0.3%). Despite the limitations, the EMR data were useful for identifying women at highest risk for fracture. Some evidence of bias in reporting rates was present. EMR data can be useful for identifying high fracture risk patients.     

Glycemic Control and Insulin Treatment Alter Fracture Risk in Older Men With Type 2 Diabetes Mellitus

Diabetes mellitus among older men has been associated with increased bone mineral density but paradoxically increased fracture risk. Given the interactions among medication treatment, glycemic control, and diabetes-associated comorbidities, the relative effects of each factor remains unclear. This retrospective study includes 652,901 male veterans aged ≥65 years with diabetes and baseline hemoglobin A1c (HbA1c) value. All subjects received primary care in the Veterans Health Administration (VHA) from 2000 to 2010. Administrative data included ICD9 diagnoses and pharmacy records and was linked to Medicare fee-for-service data. Hazard ratios (HR) for any clinical fracture and hip fracture were calculated using competing risk hazards models, adjusted for fracture risk factors including age, race/ethnicity, body mass index (BMI), alcohol and tobacco use, rheumatoid arthritis, corticosteroid use, as well as diabetes-related comorbidities including cardiovascular disease, chronic kidney disease, and peripheral neuropathy. HbA1c <6.5% was associated with a higher risk of any clinical fracture (HR = 1.08, 95% confidence interval [CI] 1.06–1.11) compared with the reference HbA1c of 7.5% to 8.5%. Fracture risk was not increased among those with A1c ≥8.5%, nor among those with A1c 6.5% to 7.5%. Use of insulin was independently associated with greater risk of fracture (HR = 1.10, 95% CI 1.07–1.12). There was a significant interaction between insulin use and HbA1c level, (p < 0.001), such that those using insulin with HbA1c <6.5% had HR = 1.23 and those with HbA1c 6.5% to 7.5% had HR = 1.15. Metformin use was associated with decreased fracture risk (HR = 0.88, 95% CI 0.87–0.90). We conclude that among older men with diabetes, those with HbA1c lower than 6.5% are at increased risk for any clinical and hip fracture. Insulin use is associated with higher fracture risk, especially among those with tight glycemic control. Our findings demonstrate the importance of the treatment regimen and avoiding hypoglycemia for fracture prevention in older men with diabetes. © 2019 American Society for Bone and Mineral Research.     

Economic benefits of investigational drug services at an academic institution.

PURPOSE: The drug cost avoidance and revenue associated with the provision of investigational drug services (IDSs) at an academic institution were studied. METHODS: The study protocols and dispensing data for the investigational drug studies conducted at the institution over two fiscal years (2000-01 and 2001-02) were reviewed. Revenue generated was calculated for all studies, and drug cost avoidance was calculated for studies in which patients were likely to have been treated with active drug had they not been included in the study. RESULTS: Of 139 studies in which the IDS was involved, 107 (77%) were eligible for the cost avoidance analysis. The total drug cost avoidance plus revenue over the two fiscal years was $5,300,428. The annualized drug cost avoidance plus revenue was $2.6 million. Cost avoidance varied with the type of study and the disease category involved. CONCLUSION: An IDS accounted for substantial drug cost avoidance over two fiscal years.     

Survival and incidence of acute rejection in heart transplant recipients undergoing successful withdrawal from steroid therapy.

BACKGROUND: Steroid-free immunosuppression is feasible in selected patients after heart transplantation. Survival and incidence of acute rejection are important parameters to evaluate when weighing risks and benefits of steroid withdrawal. METHODS: One hundred thirty-seven patients were retrospectively reviewed who underwent heart transplant at Emory University between January 1988 and April 1994 and survived >1 year. Standard immunosuppression (cyclosporine, azathioprine and prednisone) without induction therapy was used. Weaning from steroids was attempted in all patients. Scheduled endomyocardial biopsy was used for long-term surveillance screening. RESULTS: Seventy-two patients (52.5%) underwent successful prednisone withdrawal (Group P0) at an average of 13 months after heart transplant, whereas 65 patients (47.5%) did not achieve steroid-free immunosuppression (Group P1). Group P0 had a mean of 1.3 treated rejection episodes (ISHLT Grade > or = 1b) during the first post-transplant year and Group P1 a mean of 2.3 (p <0.0001). In Group P0, 40 patients (55.6%) suffered a subsequent acute rejection with an ISHLT Grade > or = 1b, resulting in treatment. Of these, 15% were ISHLT Grade 1b, 47.5% Grade 2, 35% Grade 3a and 2.5% Grade 3b. The estimated risk of suffering from acute rejection of at least Grade 1b after achieving steroid-free immunosuppression was 50% at 21 months. Estimated survival at 5 years after heart transplant was 92.9% in Group P0 and 72.3% in Group P1 (p <0.01). Cox proportional hazard modeling revealed black recipient race as effect modifier of group status with decreased survival time in both groups. CONCLUSION: Steroid-free immunosuppression in white heart transplant recipients is associated with improved survival. A low acute rejection score during the first year predicts successful steroid withdrawal. Black recipient race appears to be negatively associated with survival and deserves further detailed study. Long-term surveillance screening using endomyocardial biopsy is recommended.     

A novel FBXO28 frameshift mutation in a child with developmental delay,dysmorphic features,and intractable epilepsy: A second gene that may contribute to the 1q41‐q42 deletion phenotype

Chromosome 1q41‐q42 deletions have recently been associated with a recognizable neurodevelopmental syndrome of early childhood (OMIM 612530). Within this group, a predominant phenotype of developmental delay (DD), intellectual disability (ID), epilepsy, distinct dysmorphology, and brain anomalies on magnetic resonance imaging/computed tomography has emerged. Previous reports of patients with de novo deletions at 1q41‐q42 have led to the identification of an evolving smallest region of overlap which has included several potentially causal genes including DISP1, TP53BP2, and FBXO28. In a recent report, a cohort of patients with de novo mutations in WDR26 was described that shared many of the clinical features originally described in the 1q41‐q42 microdeletion syndrome (MDS). Here, we describe a novel germline FBXO28 frameshift mutation in a 3‐year‐old girl with intractable epilepsy, ID, DD, and other features which overlap those of the 1q41‐q42 MDS. Through a familial whole‐exome sequencing study, we identified a de novo FBXO28 c.972_973delACinsG (p.Arg325GlufsX3) frameshift mutation in the proband. The frameshift and resulting premature nonsense mutation have not been reported in any genomic database. This child does not have a large 1q41‐q42 deletion, nor does she harbor a WDR26 mutation. Our case joins a previously reported patient also in whom FBXO28 was affected but WDR26 was not. These findings support the idea that FBXO28 is a monogenic disease gene and contributes to the complex neurodevelopmental phenotype of the 1q41‐q42 gene deletion syndrome.     

Risk factors for tick exposure and suboptimal adherence to preventive recommendations

BACKGROUND: Tickborne diseases are the most common vectorborne illnesses in the United States. Understanding risk factors for tick bites and adherence to preventive measures are important in preventing morbidity associated with tickborne disease. METHODS: A random-digit-dialing telephone survey was administered to 1820 residents of 11 counties in Tennessee. RESULTS: Of respondents, 16.4% reported a tick bite within the previous year. Only 29% consistently used insect repellant in high-risk situations, and only 54% always checked their bodies for ticks after leaving potentially infested areas. Nearly one fourth of dog owners removed ticks from their pets with bare hands. Dog ownership, rural residence, and exposure to a farm were associated with increased risk of tick bites. CONCLUSIONS: We identified several groups that were at increased risk of tick bites and might benefit from targeted prevention messages.     

γδ T Cells but Not NK Cells Are Essential for Cell-Mediated Immunity against Plasmodium chabaudi Malaria

Blood-stage Plasmodium chabaudi infections are suppressed by antibody-mediated immunity and/or cell-mediated immunity (CMI). To determine the contributions of NK cells and γδ T cells to protective immunity, C57BL/6 (wild-type [WT]) mice and B-cell-deficient (J_H^−/−) mice were infected with P. chabaudi and depleted of NK cells or γδ T cells with monoclonal antibody. The time courses of parasitemia in NK-cell-depleted WT mice and J_H^−/− mice were similar to those of control mice, indicating that deficiencies in NK cells, NKT cells, or CD8⁺ T cells had little effect on parasitemia. In contrast, high levels of noncuring parasitemia occurred in J_H^−/− mice depleted of γδ T cells. Depletion of γδ T cells during chronic parasitemia in B-cell-deficient J_H^−/− mice resulted in an immediate and marked exacerbation of parasitemia, suggesting that γδ T cells have a direct killing effect in vivo on blood-stage parasites. Cytokine analyses revealed that levels of interleukin-10, gamma interferon (IFN-γ), and macrophage chemoattractant protein 1 (MCP-1) in the sera of γδ T-cell-depleted mice were significantly (P < 0.05) decreased compared to hamster immunoglobulin-injected controls, but these cytokine levels were similar in NK-cell-depleted mice and their controls. The time courses of parasitemia in CCR2^−/− and J_H^−/− × CCR2^−/− mice and in their controls were nearly identical, indicating that MCP-1 is not required for the control of parasitemia. Collectively, these data indicate that the suppression of acute P. chabaudi infection by CMI is γδ T cell dependent, is independent of NK cells, and may be attributed to the deficient IFN-γ response seen early in γδ T-cell-depleted mice.Malaria remains a leading cause of morbidity and mortality, annually killing about 2 million people worldwide (32, 33). Despite decades of research, malaria is a reemerging disease because of increasing drug resistance by malarial parasites and insecticide resistance by the mosquito vector. Most infected individuals do not succumb to malaria but develop clinical immunity where parasite replication is controlled to some degree by the immune system without eliciting clinical disease or sterile immunity (14, 38).Understanding the immunologic pathways leading to the control of blood-stage parasite replication is important for defining the mechanisms of disease pathogenesis and improving vaccines currently in development. The early events of the immune response depend upon activation of the innate immune system, which regulates the downstream adaptive immune response needed to control or cure (44). Natural killer (NK) and γδ T cells function early in the immune response to pathogens as components of the innate immune system. Both cell types have been proposed to play significant roles in the subsequent clearance of blood-stage malarial parasites by activating the adaptive immune system (35, 43, 44). The mechanism by which they accomplish this appears to be mediated via their secretion of gamma interferon (IFN-γ) induced by cytokines such as interleukin-12 (IL-12), tumor necrosis factor alpha (TNF-α), and IL-6 produced by other components of the innate immune system, including macrophages and dendritic cells (17, 25, 26, 37, 49).Blood-stage malaria parasites are cleared by mature isotypes of antibodies and/or by antibody-independent but T-cell-dependent mechanisms of immunity (2, 15, 22). Both responses require CD4⁺ αβ T cells; in addition, the expression of cell-mediated immunity (CMI) during both acute and chronic malaria is dependent on γδ T cells activated by CD4⁺ αβ T cells (29, 47, 49, 50). Wild-type (WT) mice depleted of γδ T cells by antibody treatment or gene knockout suppress P. chabaudi parasitemia by antibody-mediated immunity (AMI) (21, 52). Mice depleted of B cells by the same procedures also cure their acute infections in the same timeframe as intact control mice but then develop chronic low-grade parasitemia of long-lasting duration, indicating that B cells and their antibodies are needed to sterilize the infection as we originally reported (15, 48) and has since been confirmed by others (51). B-cell-deficient mice depleted of γδ T cells cannot suppress P. chabaudi parasitemia (49, 50, 52).The prominent role played by IFN-γ in immunity to malaria is generally accepted by most researchers. P. chabaudi malaria is more severe in WT mice treated with neutralizing antibody and in IFN-γ^−/− mice, as indicated by the increased magnitude and duration of parasitemia and mortality in mice deficient in IFN-γ versus intact controls (24, 39, 46). In B-cell-deficient animals, the similar neutralization of IFN-γ by treatment with anti-IFN-γ monoclonal antibody (MAb) or gene knockout of IFN-γ has an even greater effect on the time course of parasitemia, which remains at high levels and fails to cure (1, 46), indicating that IFN-γ is essential for the expression of anti-parasite CMI and contributes to AMI in this model system.The early source of IFN-γ remains controversial, with both NK cells and γδ T cells being proposed to produce this critical cytokine necessary for the activation of the adaptive immune response and the development of protective immunity (9). The results of earlier genetic studies failed to correlate susceptibility to P. chabaudi infection with NK activity (31, 44). Subsequently, Mohan et al. (25) reported that NK cell activity against tumor cell targets correlates with protection against P. chabaudi; anti-asialo GM1 polyclonal antibody depletion of NK cells results in significantly increased levels of peak parasitemia and a prolonged duration of infection compared to controls. The mode of action by which NK cells function appears to be via the secretion of cytokines (25) rather than direct cytotoxicity against the blood-stage parasites. The surface expression of lysosome-associated membrane protein 1 (LAMP-1) by subsets of human NK cells exposed to Plasmodium falciparum-infected erythrocytes may suggest otherwise (20). NK cells in collaboration with dendritic cells are responsible for optimal IFN-γ production dependent upon IL-12 (17, 36, 39, 40). In contrast to the findings of Mohan et al., other studies indicate similar P. chabaudi parasitemia in depleted mice and intact controls after NK1.1 MAb depletion of NK cells (19, 41, 53). Using microarray analysis of blood cells from P. chabaudi-infected mice, Kim et al. (18) reported a rapid production of IFN-γ and activation of IFN-γ-mediated signaling pathways as early as 8 h after infection; however, NK cells did not express IFN-γ or exhibit IFN-γ-mediated pathways in their analysis. At this time, NK cells are replicating and migrating from the spleen to the blood. In humans with P. falciparum malaria, increased production of IFN-γ by PBMC in response to parasitized RBCs correlates with protection from high-density parasitemia and clinical malaria (10, 11); early IFN-γ production by PBMC obtained from malaria naive donors is primarily by γδ T cells and not by NK cells (26). Animal models by definition do not exactly mimic the human condition, and the experimental malaria in mice uses distinct species from those that infect humans. Nevertheless, analysis of protective immunity provides important information on how a protective immune response to Plasmodium may be elicited.Whether both NK cells and γδ T cells have essential roles during the early stages of the immune response to blood-stage malaria remains to be determined. Likewise, whether these cells function early in CMI to malaria parasites is unknown. To address these issues, we infected NK-cell- or γδ-T-cell-depleted J_H^−/− mice with blood-stage P. chabaudi. The resulting time course of parasitemia was monitored and compared to control mice. In addition, spleen cells from depleted and control mice were profiled by cytofluorimetry, and the serum levels of inflammatory cytokines were measured.