Marijuana Use and the Risk of Early Ischemic Stroke: The Stroke Prevention in Young Adults Study.

BACKGROUND AND PURPOSE: Few studies have examined the dose-response and temporal relationships between marijuana use and ischemic stroke while controlling for important confounders, including the amount of tobacco smoking. The purpose of our study was to address these knowledge gaps. METHODS: A population-based case-control study with 1090 cases and 1152 controls was used to investigate the relationship of marijuana use and early-onset ischemic stroke. Cases were first-ever ischemic stroke between the ages of 15 and 49 identified from 59 hospitals in the Baltimore-Washington region. Controls obtained by random digit dialing from the same geographic region were frequency-matched to cases by age, sex, region of residence and, except for the initial study phase, race. After excluding subjects with cocaine and other vasoactive substance use, the final study sample consisted of 751 cases and 813 controls. All participants underwent standardized interviews to characterize stroke risk factors and marijuana use. Unconditional logistic regression analysis was used to assess the relationships between marijuana use and risk of ischemic stroke, adjusting for age, sex, race, study phase, the amount of current tobacco smoking, current alcohol use, hypertension, and diabetes. RESULTS: After adjusting for other risk factors, including the amount of current tobacco smoking, marijuana use was not associated with ischemic stroke, regardless of the timing of use in relationship to the stroke, including ever use, use within 30 days, and use within 24 hours. There was a nonsignificant trend towards increased stroke risk among those who smoked marijuana at least once a week (odds ratio, 1.9 [95% CI, 0.8-4.9]). CONCLUSIONS: These analyses do not demonstrate an association between marijuana use and an increased risk of early-onset ischemic stroke, although statistical power was limited for assessing the association among very heavy users.

The Association of Polycystic Ovary Syndrome and Gestational Hypertensive Disorders in a Diverse Community-Based Cohort.

PURPOSE: To examine the association of polycystic ovary syndrome (PCOS) and pregnancy-induced hypertension (PIH) within a large population of pregnant women in an integrated healthcare system. METHODS: This retrospective study utilized a source cohort of 1023 women with PCOS and 1023 women without PCOS who had a delivered pregnancy within Kaiser Permanente Northern California. Preexisting hypertension was defined by hypertension diagnosis, treatment, or elevated blood pressure prior to 20 weeks of gestation. The development of PIH, including gestational hypertension, preeclampsia/eclampsia, or HELLP (hemolysis, elevated liver enzymes, and low platelet count), was ascertained by chart review. Among women without preexisting hypertension who had a singleton pregnancy, the association of PCOS and PIH was examined using multivariable logistic regression. RESULTS: Among 1902 women (910 PCOS) with singleton pregnancy, 101 (11.1%) PCOS and 36 (3.6%) non-PCOS women had preexisting hypertension and were excluded. Of the remaining 1765 women, those with PCOS (compared to non-PCOS) were slightly older (mean age 31.2 versus 30.7), more likely to be obese (39.6% versus 15.1%), nulliparous (63.8% versus 43.4%), and conceive with fertility treatment (54.1% versus 1.9%); they also had a higher incidence of PIH (10.8% versus 6.6%), including gestational hypertension (5.8% versus 3.6%) and preeclampsia or HELLP (4.9% versus 3.0%; all p<0.05). PCOS was associated with increased odds of PIH (odds ratio, OR 1.7, 95% confidence interval, CI 1.2-2.4), remaining significant after adjusting for age, race/ethnicity, nulliparity, and fertility treatment; however, findings were attenuated and no longer significant after adjusting for weight status (OR 1.1, CI 0.7-1.7). Maternal PCOS was also associated with preeclampsia/HELLP in unadjusted but not adjusted (OR 1.0, CI 0.5-1.9) analyses. Nulliparity and higher prepregnancy BMI were associated with PIH in both groups. CONCLUSION: Compared to women without PCOS, women with PCOS are at higher risk for PIH but this association was not independent of weight status.

MRI-Guided High-Intensity Focused Ultrasound as an Emerging Therapy for Stroke: A Review.

Stroke, either ischemic or hemorrhagic, accounts for significantly high morbidity and mortality rates around the globe effecting millions of lives annually. For the past few decades, ultrasound has been extensively investigated to promote clot lysis for the treatment of stroke, myocardial infarction, and acute peripheral arterial occlusions, with or without the use of tPA or contrast agents. In the age of modern minimal invasive techniques, magnetic resonance imaging-guided high-intensity focused ultrasound is a new emerging modality that seems to promise therapeutic utilities for both ischemic and hemorrhagic stroke. High-intensity focused ultrasound causes thermal heating as the tissue absorbs the mechanical energy transmitted by the ultrasonic waves leading to tissue denaturation and coagulation. Several in-vitro and in-vivo studies have demonstrated the viability of this technology for sonothrombolysis in both types of stroke and have warranted clinical trials. Apart from safety and efficacy, initiation of trials would further enable answers regarding its practical application in a clinical setup. Though this technology has been under study for treatment of various brain diseases for some decades now, relatively very few neurologists and even neurosurgeons seem to be acquainted with it. The aim of this review is to provide basic understanding of this powerful technology and discuss its clinical application and potential role as an emerging viable therapeutic option for the future management of stroke.

Racial and ethnic differences in hip fracture outcomes in men.

OBJECTIVES: To examine temporal trends and racial/ethnic differences in hip fracture incidence and mortality outcome in older men. STUDY DESIGN: Retrospective cohort study. METHODS: We ascertained men 50 years or older with a hip fracture during 2000 to 2010 in a diverse northern California healthcare population. Age, comorbidity index, hip fracture incidence, and all-cause mortality up to 12 months post fracture were examined and compared by race/ethnicity. RESULTS: A total of 6247 men (aged 79.3 ± 9.8 years) experienced a hip fracture during 2000 to 2010: 81.4% were white, 7.5% Hispanic, 3.8% black, and 3.9% Asian. The age-adjusted annual incidence of hip fracture averaged 127 per 100,000, ranging from 116 to 139 per 100,000 during this period. In 2010, the age-adjusted incidence of hip fracture was highest among white men (137), followed by Hispanic (98) and black (80), and was lowest among Asian men (45 per 100,000). Mortality following hip fracture was 11.1%, 19.8%, 25.4%, and 32.9%, within 1, 3, 6, and 12 months, respectively, and increased with age. One-year mortality was similar for whites (33.7%), blacks (32.4%), and Hispanics (31.1%), but lower for Asians (23.1%; P <.05). Adjusting for age, comorbidity index, and calendar year, Asians remained at lower mortality risk compared with whites (adjusted odds ratio, 0.62; 95% confidence interval, 0.45-0.86). CONCLUSIONS: Although hip fracture rates were largely stable among older men, contemporary rates of hip fracture were highest for white and lowest for Asian men. One-year mortality was similar for white, black, and Hispanic men, but significantly lower for Asians. Future studies should investigate factors underlying observed ethnic differences in fracture outcome among US men.

Risk of Type 2 Diabetes Mellitus following Gestational Diabetes Pregnancy in Women with Polycystic Ovary Syndrome.

BACKGROUND: This study examines gestational diabetes mellitus (GDM) in women with polycystic ovary syndrome (PCOS) and the risk of type 2 diabetes mellitus (DM) following GDM pregnancy. METHODS: A cohort of 988 pregnant women with PCOS who delivered during 2002-2005 was examined to determine the prevalence and predictors of GDM, with follow-up through 2010 among those with GDM to estimate the risk of DM. RESULTS: Of the 988 pregnant women with PCOS, 192 (19%) developed GDM. Multivariable predictors of GDM included older age, Asian race, prepregnancy obesity, family history of DM, preconception metformin use, and multiple gestation. Among women with PCOS and GDM pregnancy, the incidence of DM was 2.8 (95% confidence interval (CI) 1.9-4.2) per 100 person-years and substantially higher for those who received pharmacologic treatment for GDM (6.6 versus 1.5 per 100 person-years, p < 0.01). The multivariable adjusted risk of DM was fourfold higher in women who received pharmacologic treatment for GDM (adjusted hazard ratio 4.1, 95% CI 1.8-9.6). The five-year incidence of DM was 13.1% overall and also higher in the pharmacologic treatment subgroup (27.0% versus 7.1%, p < 0.01). CONCLUSIONS: The strongest predictors of GDM among women with PCOS included Asian race and prepregnancy obesity. Pharmacologic treatment of GDM is associated with fourfold higher risk of subsequent DM.

The association of race/ethnicity and risk of atypical femur fracture among older women receiving oral bisphosphonate therapy.

PURPOSE: Several epidemiologic studies suggest that compared to white women, Asians have a greater propensity to suffer an atypical femur fracture (AFF) while taking bisphosphonate therapy. This study examines the relative risk of AFF following bisphosphonate initiation for Asian compared to white women. METHODS: Using data from a large integrated northern California healthcare delivery system, we examined diaphyseal femur fracture outcomes among women age≥50years old who initiated oral bisphosphonate therapy during 2002-2007. An AFF was defined by the 2013 American Society of Bone and Mineral Research Task Force criteria. The risk of radiographically-confirmed AFF was examined for Asian compared to white women, adjusting for differences in bisphosphonate exposure and other potential risk factors. RESULTS: Among 48,390 women (65.3% white, 17.1% Asian) who newly initiated bisphosphonate therapy and were followed for a median of 7.7years, 68 women experienced an AFF. The rate of AFF was 18.7 per 100,000 person-years overall and eight-fold higher among Asian compared to white women (64.2 versus 7.6 per 100,000 person-years). Asians were also more likely to have longer bisphosphonate treatment duration compared to whites (median 3.8 versus 2.7years). The age-adjusted relative hazard for AFF was 8.5 (95% confidence interval 4.9-14.9) comparing Asian to white women, and was only modestly reduced to 6.6 (3.7-11.5) after adjusting for bisphosphonate duration and current use. CONCLUSIONS: Our study confirms marked racial disparity in AFF risk that should be further investigated, particularly the mechanisms accounting for this difference. These findings also underscore the need to further examine the association of bisphosphonate duration and AFF in women of Asian race, as well as differential risk across Asian subgroups. In the interim, counseling of Asian women about osteoporosis drug continuation should include consideration of their potentially higher AFF risk.

Gestational thyrotoxicosis, antithyroid drug use and neonatal outcomes within an integrated healthcare delivery system.

BACKGROUND: Increasing attention has focused on the prevalence and outcomes of hyperthyroidism in pregnancy, given concerns for hepatotoxicity and embryopathy associated with antithyroid drugs (ATDs). METHODS: In an integrated health care delivery system, we examined the prevalence of thyrotoxicosis and gestational ATD use (propylthiouracil [PTU] or methimazole [MMI]) in women with delivered pregnancies from 1996 to 2010. Birth outcomes were compared among all infants and those born to mothers with diagnosed thyrotoxicosis or ATD therapy during gestation, with examination of ATD-associated hepatotoxicity and congenital malformations in the latter subgroups. RESULTS: Among 453,586 mother-infant pairs (maternal age 29.7±6.0 years, 57.1% nonwhite), 3.77 per 1000 women had diagnosed thyrotoxicosis and 1.29 per 1000 had gestational ATD exposure (86.5% PTU, 5.1% MMI, 8.4% both). Maternal PTU-associated hepatotoxicity occurred with a frequency of 1.80 per 1000 pregnancies. Infants of mothers with diagnosed thyrotoxicosis (odds ratio [OR] 1.28, 95% confidence interval [CI 1.05-1.55]) or gestational ATD use (OR 1.31 [1.00-1.72]) had an increased risk of preterm birth compared to those born to mothers without thyrotoxicosis or ATD. The risk of neonatal intensive care unit (NICU) admission was also higher with maternal thyrotoxicosis (OR 1.30 [1.07-1.59]) and ATD exposure (OR 1.64 [CI 1.26-2.13]), adjusting for prematurity. Congenital malformation rates were low and similar among infants born to mothers with thyrotoxicosis or ATD exposure (30-44 per 1000 infants). CONCLUSIONS: Gestational ATD exposure occurred in 1.29 per 1000 mother-infant pairs while a much larger number had maternal diagnosed thyrotoxicosis but no drug exposure during pregnancy. Infants of mothers with gestational ATD use or diagnosed thyrotoxicosis were more likely to be preterm and admitted to the NICU. The rates of congenital malformation were low for mothers diagnosed with thyrotoxicosis and did not differ by ATD use. Among women with gestational PTU therapy, the frequency of PTU-associated hepatotoxicity was 1.8 per 1000 delivered pregnancies. These findings from a large, population-based cohort provide generalizable estimates of maternal and infant risks associated with maternal thyrotoxicosis and related pharmacotherapy.

Femur fracture classification in women with a history of breast cancer.

PURPOSE: Women with breast cancer are at increased risk for femur fracture. Contributing factors include estrogen deficiency, cancer-related therapies, or direct bone involvement. This study examines fracture subtypes in women with prior breast cancer experiencing a femur fracture. METHODS: Women age ≥50 years old with a history of invasive breast cancer who experienced a femur fracture were identified during 2005-2012. Fracture site was classified by hospital diagnosis (for hip) and/or radiologic findings (for femoral diaphysis), with subtype classification as pathologic, atypical or fragility fracture. Clinical characteristics were ascertained using health plan databases and disease registries. RESULTS: There were 802 women with prior breast cancer who experienced a femur fracture. The mean age at fracture was 80.5±9.6 years, with most fractures (93.8%) occurring in the hip and only 6.2% in the femoral diaphysis. However, diaphyseal fractures accounted for 23.6% of fractures in younger women (age ≤65 years). Pathologic fractures comprised 9.6% of total fractures (56.0% of diaphyseal fractures) and accounted for half the fractures in younger women. An atypical fracture pattern was seen in 1% of all femur fractures and 16.0% of diaphyseal fractures, with prior bisphosphonate exposure in all atypical fracture cases. CONCLUSION: Most femur fractures in women with prior breast cancer occurred in the hip. Among younger women and those experiencing diaphyseal fractures, a larger proportion were pathologic and some were found to be atypical. Further studies should examine risk factors for femur fracture in women with breast cancer with specific attention to fracture subtype and pharmacologic exposures.

Atypical femur fractures among breast cancer and multiple myeloma patients receiving intravenous bisphosphonate therapy.

PURPOSE: Atypical femur fractures represent a potential complication of chronic oral bisphosphonate therapy in women with osteoporosis, but the risk of atypical femur fractures among cancer patients receiving intravenous bisphosphonates at higher cumulative doses remains unclear. We examined femur fractures occurring in cancer patients treated with intravenous bisphosphonates (IVBP) to determine whether a subset may be atypical fractures. METHODS: Between 2005 and 2010, we identified patients with known IVBP therapy for multiple myeloma or metastatic breast cancer, who subsequently sustained a femur fracture based on hospitalization, oncology, pharmacy and chemotherapy visit records. Radiographs were examined by an orthopedic surgeon to determine anatomic fracture site and pattern. An atypical fracture was defined as a transverse or short oblique fracture occurring below the lesser trochanter with evidence of focal hypertrophy of the lateral cortex and absence of biopsy-proven malignancy or radiation therapy at the fracture site. RESULTS: A total of 62 patients with breast cancer (N=39) or multiple myeloma (N=23) with femur fracture and prior IVBP treatment for bone malignancy were identified. There were 30 proximal hip, 18 subtrochanteric and 14 femoral shaft fractures. Intraoperative bone samples were sent in 29 of 58 fracture cases undergoing operative repair, with 76% positive for malignancy. Six cases (4 breast cancer, 2 multiple myeloma) of atypical femur fracture were identified, two with negative intraoperative pathology and four with no bone biopsy samples sent. Five of the six patients with atypical fracture had bilateral femur findings, including two with transverse fracture in the contralateral femur and three with focal hypertrophy of the contralateral cortex. Two atypical fracture cases also experienced osteonecrosis of the jaw compared to 3 in the remaining cohort (33% vs. 5%, p=0.07). Patients with atypical fracture received more IVBP (median 55 vs. 15 doses) and zoledronic acid (32 vs. 12 doses) and had longer treatment duration (median 5.9 vs. 1.6 years) compared to patients without atypical fracture (all p≤0.01). CONCLUSIONS: Among 62 patients who received IVBP for skeletal malignancy and experienced a femur fracture, we identified six cases of atypical fracture. While fractures in this population are often assumed to be pathologic, prospective studies investigating fracture pattern, microscopic bone pathology and pharmacologic exposures should be conducted to further examine the association of IVBP and atypical femur fractures.

Clinical correlates of atypical femoral fracture.

BACKGROUND: Reports of atypical femur fracture in bisphosphonate-exposed women have prompted interest in characterizing the clinical profiles of these patients. METHODS: Among women age ≥60 years with hip or femur fracture during 2007-2008, we identified 79 with low-trauma subtrochanteric or femoral shaft fracture. Radiographic images were reviewed to assign fracture pattern and distinguish atypical femur fracture from non-atypical femur fracture. Differences in clinical characteristics and pharmacologic exposures were compared. RESULTS: Among 79 women (38 subtrochanteric and 41 femoral shaft fracture), 38 had an atypical femur fracture. Compared to those with a non-atypical femur fracture, women with atypical femur fracture were significantly younger (74.0 vs 81.0 years), more likely to be Asian (50.0 vs 2.4%) and to have received bisphosphonate therapy (97.4 vs 41.5%). Similarly, the contralateral femur showed a stress or complete fracture in 39.5% of atypical femur fractures vs 2.4% non-atypical femur fracture, and focal cortical hypertrophy of the contralateral femur in an additional 21.1% of atypical cases. CONCLUSIONS: Women suffering atypical femur fractures have a markedly different clinical profile from those sustaining typical fractures. Women with atypical femur fracture tend to be younger, Asian, and bisphosphonate-exposed. The high frequency of contralateral femur findings suggests a generalized process.

Oral health considerations in older women receiving oral bisphosphonate therapy.

Recent reports of bisphosphonate-related osteonecrosis of the jaw (BRONJ) have increased awareness of oral health in patients receiving osteoporosis therapy. This study describes the demographic, oral health, and clinical characteristics of a contemporary population of women aged 50 and older undergoing oral bisphosphonate treatment who returned a mailed questionnaire pertaining to dental symptoms. The study, as previously reported, was conducted within Kaiser Permanente Northern California, a large, integrated healthcare delivery system. The cohort included 7,909 women with bisphosphonate exposure of at least 1 year, with a subset of 923 women reporting dental symptoms who underwent clinical examination. Overall, the average age was 71 ± 9; 70% were white, and 74% had at least some college education. Nearly two-thirds had received oral bisphosphonate therapy for 3 or more years. Most reported daily tooth brushing, 85% had had a dental examination in the past year, 22% reported denture use, and 6% reported moderate to severe periodontal disease. Oral healthcare patterns varied according to age and race and ethnicity. Five hundred seven (6.4%) women reported a tooth extraction in the prior year, of whom two developed BRONJ (0.4%). Tori or exostoses were found in 28% of examined participants with dental symptoms; these were predominantly in the lingual mandible and palate, with palatal BRONJ occurring in 1.6% of symptomatic participants with palatal tori. In summary, among older women with bisphosphonate exposure, oral health varied according to patient characteristics, and BRONJ occurred more frequently after tooth extraction or on palatal tori. These data support efforts to optimize oral health and to identify risk factors for BRONJ in older individuals receiving bisphosphonate drugs.