Inbal Goldshtein

Cell Free Expression of hif1α and p21 in Maternal Peripheral Blood as a Marker for Preeclampsia and Fetal Growth Restriction

Preeclampsia, a severe unpredictable complication of pregnancy, occurs in 6% of pregnancies, usually in the second or third trimester. The specific etiology of preeclampsia remains unclear, although the pathophysiological hallmark of this condition appears to be an inadequate blood supply to the placenta. As a result of the impaired placental blood flow, intrauterine growth restriction (IUGR) and consequential fetal oxidative stress may occur. Consistent with this view, pregnancies complicated by preeclampsia and IUGR are characterized by up-regulation of key transcriptional regulators of the hypoxic response including, hif1α and as well as p53 and its target genes. Recently, the presence of circulating cell-free fetal RNA has been documented in maternal plasma. We speculated that pregnancies complicated by preeclampsia and IUGR, will be associated with an abnormal expression of p53 and/or hif1α related genes in the maternal plasma. Maternal plasma from 113 singleton pregnancies (72 normal and 41 complicated pregnancies) and 19 twins (9 normal and 10 complicated pregnancies) were collected and cell free RNA was extracted. The expression of 18 genes was measured by one step real-time RT-PCR and was analyzed for prevalence of positive/negative expression levels. Results indicate that, among the genes examined, cell free plasma expressions of p21 and hif1α were more prevalent in pregnancies complicated by hypoxia and/or IUGR (p<0.001). To conclude, we present in this manuscript data to support the association between two possible surrogate markers of hypoxia and common complications of pregnancy. More work is needed in order to implement these findings in clinical practice.

Ocular Adverse Effects of Systemic Treatment With Isotretinoin

OBJECTIVE To examine whether isotretinoin therapy could result in deleterious ocular effects, as previously described in case report studies. DESIGN Retrospective cohort study. SETTING The study was conducted using the electronic medical databases of a large health maintenance organization in Israel. PATIENTS The study population consisted of 14 682 adolescents and young adults who were new users of isotretinoin for acne and 2 age- and sex-matched comparison groups (isotretinoin-naive patients with acne and acne-free patients). MAIN OUTCOME MEASURES Ocular adverse effects (AEs) or purchases of ophthalmic medications within 1 year after the first dispensed isotretinoin prescription. RESULTS In total, 13.8% of the isotretinoin group experienced ocular AEs vs 9.6% of the isotretinoin-naive group and 7.1% of the acne-free group. During a 1-year follow-up period, the isotretinoin group had significantly higher risk for any ocular AEs (hazard ratio, 1.70; P.001) compared with the acne-free group. No such increased risk was observed for the isotretinoin-naive group. The isotretinoin group had higher relative risks for inflammatory and structural AEs. CONCLUSION Isotretinoin use may be associated with short-term ocular events, especially conjunctivitis, underscoring the importance of educating patients and caregivers about these potentially important AEs of the therapy.

Statin use and the Risk of Age Related Macular Degeneration in a Large Health Organization in Israel

Objective: To investigate the association between persistent use of statins and the risk of age-related macular degeneration (AMD). Design: A population-based retrospective cohort among adults who began statin therapy between 1998 and 2006 in a large health organization in Israel. The organization’s central computerized databases were used to collect data on incident AMD cases diagnosed by ophthalmologists. Results: A total of 108,973 individuals aged 55 or older were identified. During the study follow-up period 409,113 person-years, there were 2,732 incident AMD cases (6.68 per 1,000 person-years). The crude incidence density rate of AMD among patients at the lowest quintile of persistence with statins (7.18 per 1,000) was comparable to that of highest persistence quintile (7.13 per 1,000). After adjustment for potential confounders, patients in the highest quintile of persistence with statins had a hazard ratio of 0.99 (95% Confidence Interval: 0.78–1.26) for AMD compared with patients in the lowest proportion of days covered (PDC) quintile. In addition to age, AMD was found to associate with past smoking, asthma, diabetes and frequent visits to ophthalmologists or primary physicians prior to index date Conclusions: Our study agrees with previous studies that showed no association between persistent use of statins and reduced risk of AMD. These results suggest that the early reports on a strong protective effect of statins against AMD development were probably a result of a small study effect.

Development and validation of a predictive model for detection of colorectal cancer in primary care by analysis of complete blood counts: a binational retrospective study

Abstract Objective The use of risk prediction models grows as electronic medical records become widely available. Here, we develop and validate a model to identify individuals at increased risk for colorectal cancer (CRC) by analyzing blood counts, age, and sex, then determine the model’s value when used to supplement conventional screening. Materials and Methods Primary care data were collected from a cohort of 606 403 Israelis (of whom 3135 were diagnosed with CRC) and a case control UK dataset of 5061 CRC cases and 25 613 controls. The model was developed on 80% of the Israeli dataset and validated using the remaining Israeli and UK datasets. Performance was evaluated according to the area under the curve, specificity, and odds ratio at several working points. Results Using blood counts obtained 3–6 months before diagnosis, the area under the curve for detecting CRC was 0.82 ± 0.01 for the Israeli validation set. The specificity was 88 ± 2% in the Israeli validation set and 94 ± 1% in the UK dataset. Detecting 50% of CRC cases, the odds ratio was 26 ± 5 and 40 ± 6, respectively, for a false-positive rate of 0.5%. Specificity for 50% detection was 87 ± 2% a year before diagnosis and 85 ± 2% for localized cancers. When used in addition to the fecal occult blood test, our model enabled more than a 2-fold increase in CRC detection. Discussion Comparable results in 2 unrelated populations suggest that the model should generally apply to the detection of CRC in other groups. The model’s performance is superior to current iron deficiency anemia management guidelines, and may help physicians to identify individuals requiring additional clinical evaluation. Conclusions Our model may help to detect CRC earlier in clinical practice.

Association between persistence with statin therapy and reduction in low-density lipoprotein cholesterol level: analysis of real-life data from community settings.

To validate the use of drug dispensing data as a measure of drug exposure and to quantify the association between persistence with statin therapy and low‐density lipoprotein cholesterol (LDL) levels using real‐life community data.

Urinary albumin excretion with sitagliptin compared to sulfonylurea as add on to metformin in type 2 diabetes patients with albuminuria: A real-world evidence study

AIM To compare the change in urinary albumin to creatinine ratio (UACR) in type 2 diabetes (T2DM) patients with albuminuria who initiate sitagliptin to those who initiate a sulfonylurea (SU) as add-on to metformin monotherapy. METHOD A cohort of T2DM patients with albuminuria (UACR >30mg/g) who initiated sitagliptin or SU as add-on dual therapy to metformin between 2008 and 2014 was extracted from the computerized medical records of a large managed care organization in Israel. Patients with albuminuria and UACR measurements available at treatment initiation and 120-365days afterwards were included. Propensity scores were calculated based on 17 factors, including demography, comorbidities, baseline levels of HbA1c, UACR, BMI, eGFR, and ACE/ARB use, and patients were matched in a 1:1 ratio. Changes in UACR were compared between the matched pairs using generalized estimating equations. RESULTS A total of 282 eligible pairs (sitagliptin:SU) were identified. During a mean follow-up of 9months, median UACR changes were -35% (IQR=-73% to 5%) and -31% (IQR=-72% to 21%) in the sitagliptin and SU groups, respectively. Mean absolute HbA1c reductions among sitagliptin and SU groups were 0.9% and 1.0%, respectively. The magnitude of UACR reduction generally increased with greater magnitude of HbA1c reduction in both treatment groups. However, after controlling for HbA1c reduction and the interaction between HbA1c reduction and UACR reduction, sitagliptin users demonstrated a trend toward an increased likelihood of UACR reduction compared to SU users (odds ratio=1.20; 95% confidence interval: 0.99-1.47, P=0.063). CONCLUSION Our results suggest that both sitagliptin and SU reduce albuminuria as an add-on therapy to metformin, but that sitagliptin may provide greater reductions in albuminuria independent of glycemic control when compared to SU. Larger population studies are required to further explore this.

Variations in hemoglobin before colorectal cancer diagnosis.

We have conducted the present case-control study to examine whether long-term variations in blood hemoglobin (Hb) levels within the normal range could detect subtle gastrointestinal bleeding in the early development of colorectal cancer (CRC). A total of 1074 CRC cases aged 45–75 years that have been diagnosed with CRC and had normal Hb levels were frequency matched for age and sex with cancer-free individuals at a ratio of 10 controls per case. Our retrospective analysis indicates that starting from 4 years prior to cancer diagnosis, a progressive significant (P<0.001) decrement in Hb levels (0.28 g/dl per 6 months) was found among cases but not among controls. CRC patients were characterized in an on-going, long-term, logarithmic decrement in Hb levels. Such small changes within the normal Hb range could be missed by health providers, but automatically detected by computerized alert algorithms..

Managing Osteoporosis: A Survey of Knowledge, Attitudes and Practices among Primary Care Physicians in Israel

Background Osteoporosis is a systemic skeletal disorder characterized by impaired bone quality and microstructural deterioration leading to an increased propensity to fractures. This is a major health problem for older adults, which comprise an increasingly greater proportion of the general population. Due to a large number of patients and the insufficient availability of specialists in Israel and worldwide, osteoporosis is treated in large part by primary care physicians. We assessed the knowledge of primary care physicians on the diagnosis and treatment of osteoporosis. Methods Physicians knowledge, sources of knowledge acquisition and self-evaluation of knowledge were assessed using a multiple choice questionnaire. Professional and demographic characteristics were assessed as well. Results Of 490 physicians attending a conference, 363 filled the questionnaires (74% response rate). The physicians demonstrated better expertise in diagnosis than in medications (mechanism of action, side effects or contra-indications) but less than for other treatment related decisions. Overall, 50% demonstrated adequate knowledge of calcium and vitamin D supplementation, 51% were aware of the main therapeutic purpose of osteoporosis pharmacotherapy and 3% were aware that bisphosphonates should be avoided in patients with impaired renal function. Respondents stated frontal lectures at meetings as their main source of information on the subject. Conclusion The study indicates the need to intensify efforts to improve the knowledge of primary care physicians regarding osteoporosis, in general; and osteoporosis pharmacotherapy, in particular.

Non-adherence with bisphosphonates among patients with osteoporosis: impact on fracture risk and healthcare cost

ABSTRACT Osteoporosis-related fractures at the spine and hip have a substantial impact on mortality, morbidity, and quality of life in older adults worldwide. Adherence to bisphosphonates is essential for effective treatment and fracture prevention. Nevertheless, numerous studies from various populations and study designs clearly indicated that adherence and persistence are poor with more than 50% of patients discontinuing therapy within one year. This is primarily explained by mild adverse effects, dosing regimens, and costs. Studies have also shown that good adherence is associated with reduced osteoporosis-related and non-related healthcare costs as soon as 2 years from therapy initiation. Nonetheless, we found only little improvement in adherence rates over the years. In light of the importance of medication adherence and the limited success of previous programs, other than reducing dosing frequency, new directions should be explored to engage patients and care givers in order to improve adherence and prevent fractures.

Cost and Consequences of Nonadherence With Oral Bisphosphonate Therapy Findings From a Real-World Data Analysis

Background: Adherence to osteoporosis treatment remains poor despite available treatments and physician and patient education. This study aims to determine the effect of low adherence in real-world data. Objective: To examine the association between adherence with oral bisphosphonate therapy and fracture risk as well as health care resource utilization. Methods: Women included in this retrospective analysis were 55 years or older and had started oral bisphosphonate therapy between 2005 and 2011 in a large not-for-profit health care center in Israel. Adherence to therapy was measured by the medication possession ratio (MPR) during the first year from therapy initiation. Patients with MPR lower than 70% were considered nonadherent. Study outcomes were osteoporotic fracture events and health care utilization (including physician visits and hospitalizations) during the second year from therapy initiation. Results: Among the 17 770 women included in the analysis (mean age = 66.5 years; SD = ±8.3 years), 48.9% were nonadherent to therapy during the first year of treatment. Osteoporotic fracture risks during the second year among adherent and nonadherent patients were 2.1% and 2.5%, respectively (P = 0.1). When analysis was limited to patients 75 years or older, nonadherence with bisphosphonates was associated with an adjusted odds ratio of 1.49 (95% CI = 1.08-2.04) for osteoporotic fractures compared with adherent patients. Nonadherent patients had 13.4% higher medical costs than their adherent counterparts among patients 75 years and older (P = 0.002). Conclusions: In patients 75 years and older, nonadherence with oral bisphosphonates can be associated with significantly greater short-term risk of osteoporotic fractures and higher utilization of health care services.