Expanding the clinical spectrum of biallelic ZNF335 variants.

ZNF335 plays an essential role in neurogenesis and biallelic variants in ZNF335 have been identified as the cause of severe primary autosomal recessive microcephaly in 2 unrelated families. We describe, herein, 2 additional affected individuals with biallelic ZNF335 variants, 1 individual with a homozygous c.1399 T > C, p.(Cys467Arg) variant, and a second individual with compound heterozygous c.2171_2173delTCT, p.(Phe724del) and c.3998A > G, p.(Glu1333Gly) variants with the latter variant predicted to affect splicing. Whereas the first case presented with early death and a severe phenotype characterized by anterior agyria with prominent extra-axial spaces, absent basal ganglia, and hypoplasia of the brainstem and cerebellum, the second case had a milder clinical presentation with hypomyelination and otherwise preserved brain structures on MRI. Our findings expand the clinical spectrum of ZNF335-associated microcephaly.

Effect of TDF-containing regimens on creatinine clearance in HIV patients in Namibia with a baseline CrCl <60ml/min; findings and implications.

Background and aims: The advent of antiretroviral therapy (ART) and early diagnosis of the human immunodeficiency virus (HIV) has resulted in an appreciable reduction in morbidity and mortality among people infected with HIV. However, tenofovir disoproxil fumarate (TDF)-containing ART regimens are associated with a reduction in creatinine clearance (CrCl). No evaluation has been conducted in Namibia to date on the relationship between TDF-containing ART and CrCl among patients with moderate to severe reductions in CrCl to guide future practice. We aimed to address this.Methodology: Retrospective longitudinal study between January 2008 to December 2016 evaluating CrCl in patients with a baseline CrCl <60ml/min who were receiving TDF-containing ART in a leading hospital in Namibia. We identified patients who had experienced an improvement in CrCl and compared their characteristics with those whose CrCl did not improve. We assessed factors for an association with improvement in CrCl using binary logistic regression.Results: 389 patients were included, the majority were female (n = 294). Female vs. male assessments showed no difference in age (p = 0.340), weight (p = 0.920), number who experienced an improvement (105 vs 39, p = 0.349), or absence of improvement (189 vs. 56, p = 0.349). The improvement group (male and female) had a lower baseline CrCl (45.9 vs. 55.0, p < 0.001). The follow-up CrCl for the improvement and no improvement groups were 72.6 and 55.9 respectively. Multivariate analysis showed that the odds of improvement were: 0.905 (0.871-0.940, p < 0.001) for each unit rise in the baseline CrCl, and 0.904(0.880-0.923) for each year of follow-up.Conclusion: More improvement than decline in CrCl was observed. Improvement occurred more in patients with lower baseline CrCl, and occurred in the early period of ART with reduced odds of experiencing this with time. Our findings indicate that TDF may be used in patients with a low baseline CrCl.

Medical care and cost outcomes after pentoxifylline treatment for peripheral arterial disease.

We assessed the medical outcomes and costs associated with the pharmacologic treatment of patients with peripheral arterial disease (PAD) in a population-based historical cohort study of patients enrolled in a health maintenance organization. For up to 2 years, we compared 58 patients who used therapeutic amounts of pentoxifylline with a comparison group of 112 patients who received a minimal subefficacious trial of pentoxifylline. Medical records data were used to assess and control for the severity of PAD and other potentially confounding factors. Continuous use of a therapeutic amount of pentoxifylline during an initial 120-day period significantly reduced the incidence of PAD-related invasive therapeutic and diagnostic procedures in the first year of follow-up (adjusted relative risk, 0.35; 95% confidence interval, 0.12 to 0.99). However, there were no significant differences in the risk of a PAD-related hospitalization or cost of PAD-related care between continuous pentoxifylline users and the comparison group. Pentoxifylline therapy may reduce the risk of vascular surgery while not increasing the total cost of PAD care.

Current use of thiazide diuretics and prevention of femur fractures.

A case control study of a defined population from The Netherlands was performed to evaluate the risk of femur fractures associated with the use of thiazide diuretics. Included were 386 patients hospitalized for femur fractures between 1986 and 1990 who were residents and 45 years of age and older. Per case, one age-, sex-, pharmacy-, and general practitioner-matched control was chosen from the general population. Drug use was ascertained from computerized pharmacy records. The adjusted odds ratio of current use of thiazide diuretics was 0.5 (95% confidence interval, 0.3-0.9). The protective effect of thiazide diuretics was greatest for use of 1 year or longer at relatively high doses of thiazides (odds ratio, 0.3; 95% confidence interval, 0.1-0.9). We also found that patients who discontinued thiazide use longer than 2 months were not protected against femur fractures. These results support the hypothesis that use of thiazide diuretics protects against femur fractures.

Comparison of self-report data and medical records data: results from a case-control study on prostate cancer.

BACKGROUND: Self-report and review of medical records are the most common methods for the assessment of past exposures. However, information obtained from self-reports and medical records may not be consistent. This study compared information provided in a self-administered questionnaire with medical records data. METHODS: Self-report and medical records data came from a case-control study on prostate cancer. Cases were 181 patients with primary prostate cancer and controls were 297 men without the disease, enrolled in Group Health Cooperative (GHC) in Seattle. The consistencies between the two data sources were examined. RESULTS: In general, agreement between the two data sources was almost perfect for demographic and anthropometric variables, substantial for the history of inguinal hernia and kidney stones, and moderate for vasectomy, family history of prostate cancer, smoking and alcohol consumption. However, the two data sources generally were poorly concordant for prior genitourinary diseases that have less explicit diagnostic criteria such as benign prostatic hyperplasia and prostatitis. Analyses of discordant data showed that men were more likely to report an exposure or medical condition that could not be verified from medical records. No discernible patterns in the difference of agreement were found according to age, GHC membership length or case-control status. CONCLUSIONS: This study suggests that agreement between self-reported data and medical records data varies depending upon the study variables. While both data sources are subject to some problems, self-report may provide more complete and comparable information, at least for variables unrelated to diagnosis.

Oral contraceptives and nonfatal vascular disease.

A follow-up study of more than 65,000 healthy women aged 15 to 44 was conducted to assess the association between oral contraceptive use and thromboembolism, stroke, or nonfatal myocardial infarction from 1980 through 1982 at Group Health Cooperative of Puget Sound. A positive association existed between current oral contraceptive use and venous thromboembolism (rate ratio equals 2.8), but there was no positive association between current oral contraceptive use and stroke or myocardial infarction.

First-trimester drug use and congenital disorders.

The authors determined the prevalence of certain major congenital disorders among live-born infants of 6509 mothers in a prepaid health plan for the 30-month period of January 1, 1980 through June 30, 1982 who used a wide variety of drugs during the first trimester of pregnancy. The results were similar to those obtained in this population in a prior 30-month study. No strong associations between any of the commonly used drugs and the congenital disorders studied were present.

Functional ovarian cysts in relation to the use of monophasic and triphasic oral contraceptives.

This population-based case-control study assessed the effect of current use of monophasic or triphasic oral contraceptives (OCs) on the risk of functional ovarian cyst development. The cases were all 15-39-year-old enrollees in the Group Health Cooperative of Puget Sound who had either an inpatient primary diagnosis of functional ovarian cyst in 1988 or 1989 (N = 67) or an outpatient primary diagnosis of functional ovarian cyst from March 1988 through August 1989 at one of five Group Health Cooperative primary care clinics (N = 39). Controls were randomly selected enrollees matched to the cases for age, primary care clinic, and enrollment date (N = 255). Subjects with previous hysterectomy or oophorectomy were excluded from this analysis. Pharmacy and medical record review showed that 16% of cases and 19% of controls were currently using monophasic OCs, whereas 11% of cases and 9% of controls were using triphasic OCs. Compared with women not using hormonal contraception, the relative risks of a diagnosed functional ovarian cyst among women currently using OCs were 0.8 (95% confidence interval [CI] 0.4-1.8) for users of monophasic OCs and 1.3 (95% CI 0.5-3.3) for users of triphasic OCs. In contrast to previous studies of monophasic OCs containing higher steroid dosages, the results of this study suggest that current use of low-dose monophasic OCs does not substantially decrease a woman's risk of functional ovarian cyst formation. In addition, our results do not support recent speculation that current use of triphasic OCs appreciably increases the risk of functional ovarian cysts.

Vaginal douching as a risk factor for cervical Chlamydia trachomatis infection.

OBJECTIVE: To evaluate the association between vaginal douching and cervical Chlamydia trachomatis infection. METHODS: We analyzed cross-sectional data from a study conducted at Group Health Cooperative of Puget Sound, a nonprofit health maintenance organization in western Washington state. Participants were nonpregnant women Group Health enrollees between the ages of 18 and 34 years who were attending two primary care clinics either for nonurgent visits, primarily routine preventive health visits, or in response to an invitation from the study. Before the clinical examination, all completed a self-administered survey assessing demographic and behavioral characteristics, including the timing, frequency, products used, and reasons for douching. Chlamydial infection was ascertained via cell culture isolation of C trachomatis from endocervical specimens obtained at the same visit. RESULTS: Chlamydia trachomatis was isolated from cervical cultures in 58 (3.4%) of 1692 study participants. Women who reported douching in the 12 months before their clinic visit had an increased likelihood of chlamydial infection compared with women who did not douche (prevalence odds ratio [OR] 2.29, 95% confidence interval [CI] 1.22, 4.30, after adjusting for confounding factors). The likelihood was higher for women who reported douching more often: OR 2.60 (95% CI 1.29, 5.24) for women who douched one to three times per month, and OR 3.84 (95% CI 1.26, 11.70) for those douching four times or more per month. These associations were slightly stronger when women who reported douching because of an infection were excluded from the analysis. CONCLUSION: These results support the hypothesis that vaginal douching predisposes to acquisition of cervical chlamydial infection and are compatible with previous studies that report associations between douching and sequelae of chlamydial infection, including pelvic inflammatory disease, ectopic pregnancy, and infertility.

Previous abdominal surgery and tubal pregnancy.

To determine the role of previous abdominal surgery in tubal pregnancy risk, we compared 337 women diagnosed with tubal pregnancy during 1981-1986 with 893 population-based controls concerning their medical, reproductive, and sexual histories. After excluding types of abdominal surgery that involve the fallopian tubes directly and after adjusting for age, gravidity, and reference year, we found no increased risk for tubal pregnancy related to previous cesarean delivery (relative risk 0.6, 95% confidence interval 0.3-1.2), ovarian surgery (relative risk 1.2, 95% confidence interval 0.6-2.5), or removal of an unruptured appendix (relative risk 1.2, 95% confidence interval 0.7-2.2). An increased risk was noted for tubal pregnancy associated with previous ruptured appendix (relative risk 1.8, 95% confidence interval 0.6-5.5), but the increase was well within the limits of chance. With the possible exception of ruptured appendix, our study indicates that abdominal surgery that does not directly involve the fallopian tubes has little or no influence on the occurrence of tubal pregnancy.

Vaginal douching as a risk factor for acute pelvic inflammatory disease.

OBJECTIVE: To conduct a population-based evaluation of vaginal douching as a risk factor for acute pelvic inflammatory disease (PID), emphasizing timing, frequency, and reasons for douching. METHODS: A population-based case-control study was conducted at Group Health Cooperative of Puget Sound, a staff-model health maintenance organization located in western Washington state. The cases (N = 131) were women 18-40 years of age who experienced a first episode of clinically diagnosed acute PID. Both hospitalized and ambulatory-care patients were identified. Medical records were reviewed for clinical inclusion criteria and for additional evidence of inflammation/infection. Controls (N = 294) were chosen from a population-based series of randomly selected women from a concurrent Group Health study of ectopic pregnancy. Of the women identified, 72.4% of cases and 73.4% of controls agreed to participate. RESULTS: Relative to women who reported never having douched, women who douched during the previous 3 months had a risk of PID of 2.1 after controlling for other measured risk factors (95% confidence interval [CI] 1.2-3.9). Women who douched at least once a week had a higher estimated risk (odds ratio 3.9, 95% CI 1.4-10.9) than those who douched less often (odds ratio 1.8, 95% CI 1.0-3.4). The risk was highest in the small group of women who gave infection as the reason for douching (odds ratio 7.9, 95% CI 2.6-24.2). However, exclusion of this group did not eliminate the association among the remaining women (odds ratio 3.0, 95% CI 1.0-9.1 for douching at least once a week). CONCLUSION: These population-based data lend added support to the hypothesis that vaginal douching can predispose a woman to PID.

Antibiotics and Clostridium difficile diarrhea in the ambulatory care setting.

OBJECTIVE: The goal of this study was to determine the prevalence of Clostridium difficile diarrhea (CDD) and the risk for CDD associated with different oral antibiotics commonly used in the ambulatory care setting. METHODS: The prevalence of CDD was determined for enrollees in 4 UnitedHealth Group-affiliated health plans between January 1, 1992, and December 31, 1994. Cases were identified based on the presence of an inpatient or outpatient claim with a primary diagnosis of diarrhea, a pharmacy claim for a prescription drug used to treat CDD, or a physician or facility claim for the C. difficile toxin test, and were confirmed using full-text medical records. Within a retrospective cohort design, periods of risk for CDD were defined on the basis of duration of antibiotic therapy. To control for potential selection bias created by heterogeneous rates of C. difficile testing and to limit confounding due to multiple antibiotic exposures, we used a nested case-control design, restricting eligibility to subjects who underwent screening for C. difficile and who had been exposed to only 1 antibiotic risk period with a single antibiotic. RESULTS: The global prevalence of CDD in 358,389 ambulatory care enrollees was 12 per 100,000 person-years. In the nested case-control study, after controlling for other risk factors, 2 antibiotics demonstrated an increased association with CDD: cephalexin (odds ratio [OR] = 7.5, 95% CI = 1.8 to 34.7) and cefixime (OR = 6.4, 95% CI = 1.2 to 39.0). CONCLUSIONS: Although CDD is thought to occur primarily in hospitalized patients, it was found to be present in an ambulatory care population, but at a low frequency. In this population, it appeared to be associated with 2 cephalosporins but not with other types of antibiotics usually linked with nosocomial CDD. Because the frequency of C. difficile testing was shown to be more common with high-risk antibiotics, CDD may be underdiagnosed in the ambulatory care setting.

Use of nasal preparations and the incidence of sinonasal cancer.

Data from a population based case control study in western Washington were analysed to determine whether the use of nasal sprays and drops was associated with an increased risk of sinonasal cancer. Telephone interviews were conducted with incident cases (n = 53) diagnosed between 1979 and 1983 or their next-of-kin, and with controls (n = 552) regarding their past use of nasal preparations, history of rhinologic problems, smoking history, alcohol consumption, and a number of other known or suspected risk factors. Both cigarette smoking and alcohol consumption were associated with an increased risk of sinonasal cancer; the strongest associations were found with squamous cell tumours. Subjects who reported a history of nasal preparation use were 3.5 times (95% confidence interval = 1.7-7.0) more likely than non-users to develop sinonasal cancer. The risk of sinonasal cancer increased with increasing duration of use of nasal preparations. These findings suggest the need for a more detailed investigation of the possible adverse consequences of long-term use of nasal preparations.

Overview of cost-consequence modeling in outcomes research.

Outcomes research has developed in response to the need for information on costs, risks, and benefits of clinical treatments, including data regarding the effectiveness of prescription drugs. It attempts to consider more than the biologic effects of pharmaceuticals, that is, to encompass wider measures of the results of their use, issues that are not routinely addressed during clinical trials. Cost-effectiveness analysis compares the outcome of different treatment options in terms of monetary cost per unit of effectiveness. Examples of measures of effectiveness are years of life saved, number of days of hospitalization avoided, and number of treatment successes. Cost-consequence models, also referred to as cost-outcome models, deal with costs and a variety of outcomes ranging from clinical to humanistic. Direct medical costs are those for prevention, detection, treatment, and rehabilitation; they are amounts spent to treat an illness, including hospitalization, professional services, pharmaceuticals, and medical supplies. Indirect medical costs are associated with changes in productivity, such as earnings lost because of illness. Humanistic outcomes deal primarily with functional status, quality of life, and satisfaction, and may include pain, anxiety, self-esteem, ability to carry out normal activities, and overall impressions. Since it is not possible to study all effects of treatments with clinical trials, modeling techniques are useful in making therapeutic decisions.

A comparison of wax matrix and microencapsulated potassium chloride in relation to upper gastrointestinal illness requiring hospitalization.

The frequency of hospitalization for documented upper gastrointestinal illness among recipients of either wax matrix or microencapsulated potassium chloride was similar in a study in which clinics were randomly assigned to dispense one or the other preparation. The results indicate that there is no material difference between the two preparations in relation to serious upper gastrointestinal illness.

The role of cost-consequence analysis in healthcare decision-making.

A greater understanding of value associated with new pharmaceutical products should lead to better decision-making. Most commonly cost-effectiveness ratios (CERs) are used to indicate value; however, researchers have recently shown that CER estimates are rarely used by decision-makers in making formulary decisions. In this article, a cost-consequence approach to estimating the value for money of a new treatment for a specific disease is described. Using a cost-consequence approach, the impact of the new treatment on lifetime resource use and costs (including specific healthcare service use and costs, and productivity losses) and health outcomes (including disease symptoms, life expectancy and quality of life) for an individual or group of individuals is estimated and presented in a tabular format. The cost-consequence format is more likely to be approachable, readily understandable and applied by healthcare decision-makers than a simple CER. The decision-maker may use selected items from the cost-consequence analysis to compute composite measures of drug value, such as cost per life-year gained or cost per quality-adjusted life-year (QALY) gained. In general, the cost-consequence approach, by making the impact of the new treatment as comprehensive and transparent as possible, will enable decision-makers to select the components most relevant to their perspective and will also give them confidence that the data are credible to use as the basis for resource allocation decisions.

Incidence of adverse oesophageal and gastric events in alendronate users.

Purpose- To estimate the incidence of adverse gastrointestinal events in alendronate users.Methods- The computerized pharmacy claims of 12 geographically dispersed United Health Group-affiliated health plans were used to identify 1421 persons who received alendronate prescriptions. The medical claims data of these individuals were searched for subsequent diagnoses of oesophagitis, ulcer of the oesophagus, oesophageal perforation, gastric ulcer, and gastritis/duodenitis. The incidence level was estimated as cumulative incidence and incidence density and their 95% confidence intervals.Results- Thirty-nine persons had a diagnostic code indicating an incident oesophageal or gastric diagnosis of interest, including 22 with oesophagitis, two with oesophageal ulcer, one with gastric ulcer, and 15 with gastritis/duodenitis. Thirteen cases (33.3%) underwent upper endoscopic examination. Five (12.8%) patients were hospitalized. Reflecting alendronate use, 95% of patients were female. The cumulative incidence of oesophageal and gastric events for alendronate users was 3.1% in females, 2.0% in males, and 3.0% overall. The incidence density of a diagnosis of oesophageal or gastric events was 9.0 per 100 woman-years of exposure. There was no significant variation in the cumulative incidence among different age groups.Conclusions- These results suggest the incidence of oesophageal and gastric diagnostic codes is high among alendronate users. Further research is needed to assess the possible association between alendronate and adverse upper gastrointestinal events. Copyright (c) 2000 John Wiley & Sons, Ltd.

Principal findings from the Washington State cognitive services demonstration project.

In addition to dispensing, pharmacists are ideally positioned to provide cognitive services that are targeted at optimizing drug therapy through identification and resolution of drug therapy problems. The Washington Cognitive Activities and Reimbursement Effectiveness project sought to determine: (1) if pharmacists would respond to a financial incentive by performing more cognitive services, and (2) the effect on drug cost of cognitive services they performed.

Evaluation of an inpatient decentralized pharmacy team program in an HMO setting.

Decentralized drug distribution and clinical pharmacy services were implemented on two nursing units, orthopedics and oncology, of a health maintenance organization-owned hospital. The use of targeted high-cost drugs was assessed before and during the decentralized pharmacy services intervention on the experimental units and on a comparison unit. Other assessments included a survey of nurses from the experimental units and surveillance of telephone encounters between the central pharmacy and the experimental units. In the experimental units, there were significant changes in cefazolin therapy for prophylaxis, aminoglycoside therapy, and metoclopramide use from baseline to the intervention periods. Cefazolin use for prophylaxis essentially remained the same in the comparison unit. Telephone encounters decreased substantially from the before- to the during-program period. An increase in the proportion of inappropriately drawn aminoglycoside blood levels was also noted in the during-program period. Decentralized pharmacy services appeared to reduce the cost of targeted drugs and improve communications with the nursing units.