Addressing Social Determinants of Health: A Care Coordination Approach for Professional Case Managers.

PURPOSE: Social determinants of health (SDOH) continue to gain attention as the factors that weigh heavily on physical and mental health. In response, professional case managers need to develop a deeper understanding of the entrenched nature of SDOH, particularly the spiraling and compounding effects of economic, environmental, and social factors on the health and well-being of individuals and populations. Professional case managers are essential to helping identify both the barriers experienced by individuals in accessing and receiving the care they need and the resources to eliminate or mitigate those barriers. These responsibilities should be most keenly felt by case managers who are board-certified and therefore held accountable by codes of ethics to ensure justice and fairness. By embedding greater awareness of SDOH into the case management process-from intake and assessment through implementation, evaluation, and across care transitions-case managers can establish rapport with clients (known as "patients" in some care settings) and support improved outcomes through best practices in care coordination, thus contributing to the Triple Aim of improving the health of people and populations and reducing the per capita cost of care. PRIMARY PRACTICE SETTINGS: SDOH impact individuals across the health and human services, including acute care, subacute care, primary care, community-based care, and workers' compensation. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: Case management plays a vital role in providing people with episodic care and ensuring adequate follow-up. The latter includes if and how people are able to access the ongoing care they need, including medications (access and affordability), doctors' visits, therapies and other services, healthy nutrition, and more. However, a lack of affordability undermines an individual's ability to receive preventive care and treatment of chronic illnesses and potentially more serious and life-threatening conditions such as cancer. Compounding the impact of affordability can be a lack of transportation that inhibits access to health care professionals, which can affect individuals in both rural and inner-city environments. Although poverty and homelessness play a direct role in SDOH, case managers cannot assume which clients are impacted by these factors and which are not. Higher costs of living, loss of job or reduced income, unexpected expenses, and death of, or divorce from, a partner/spouse can negatively impact a client's ability to access and afford care. With this understanding, case managers can meet individuals where they are to explore how SDOH affects their lives, without judgment, bias, or assumption.

Safety of apraclonidine eye drops in diagnosis of Horner syndrome in an outpatient pediatric ophthalmology clinic.

PURPOSE: To describe the efficacy and systemic side effects of apraclonidine drops 0.5% in children clinically suspected of having Horner syndrome. METHODS: The medical records of patients with clinically suspected Horner syndrome who underwent testing with apraclonidine 0.5% eyedrops were reviewed retrospectively. The following data were retrieved from the record: allergic reactions, somnolence, shallow respiration, pallor, or excessive fussiness noted by the examiner or parents. RESULTS: A total of 46 patients presenting with anisocoria and tested with apraclonidine 0.5% were included. Of these, 15 had a positive result, with reversal of anisocoria. The mean age of patients was 3.2 years (median, 0.91; mode, 0.25 years). Twenty-four patients were ≤1 year of age; 19 were ≤6 months. No systemic side effects were noted during the examination or reported by parents in any patients. CONCLUSIONS: The use of topical apraclonidine eyedrops has been described as an effective test for Horner syndrome. However, concerns have been raised regarding the potential systemic side effects in children, especially those under the age of 6 months. In our cohort, no systemic side effects were reported, including in those under 6 months of age.

Comparing Outcomes of a Digital Commercial Weight Loss Program in Adult Cancer Survivors and Matched Controls with Overweight or Obesity: Retrospective Analysis.

Maintaining a healthy weight is beneficial for cancer survivors. However, weight loss program effectiveness studies have primarily been in highly controlled settings. This is a retrospective study exploring real-world outcomes (weight loss and program engagement) after use of a digital commercial weight loss program (Noom) in cancer survivors and matched controls. All participants had voluntarily self-enrolled in Noom. Weight and engagement data were extracted from the program. Cancer-related quality of life was secondarily assessed in a one-time cross-sectional survey for survivors. Controls were a sample of Noom users with overweight/obesity who had no history of cancer but 0-1 chronic conditions. Primary outcomes were weight change at 16 weeks and program engagement over 16 weeks. Engagement included frequency of weight, food, and physical activity logging, as well as number of coach messages. Multiple regression controlling for baseline age, gender, engagement, and BMI showed that survivors lost less weight than controls (B = -2.40, s.e. = 0.97, p = 0.01). Survivors also weighed in less (survivors: 5.4 [2.3]; controls: 5.7 [2.1], p = 0.01) and exercised less (survivors: 1.8 [3.2]; controls: 3.2 [4.1], p < 0.001) than controls. However, survivors sent more coach messages (survivors: 2.1 [2.4]; controls: 1.7 [2.0], p < 0.001). Despite controls losing more weight than cancer survivors (-7.0 kg vs. -5.3 kg), survivors lost significant weight in 4 months (M = -6.2%). Cancer survivors can have success on digital commercial programs available outside of a clinical trial. However, they may require additional support to engage in weight management behaviors.

Neuroophthalmological manifestations of congenital aqueductal stenosis.

OBJECTIVE: Congenital aqueductal stenosis (CAS) is a common etiology of hydrocephalus that occurs in a subset of infants and may be linked to an increased incidence of ophthalmological abnormalities and delayed developmental milestones. Although hydrocephalus is common and widely studied, sparse literature exists on patients with isolated (no identifiable genetic link) CAS along with analysis of ophthalmological manifestations. In this study, the authors sought to describe the ophthalmological abnormalities and delayed developmental milestones of patients with isolated CAS. METHODS: Data of patients with CAS were prospectively entered and monitored in a surgical database maintained by the Department of Neurological Surgery at Children's Hospital of Pittsburgh from January 2005 to October 2016. Patients with a family history of congenital hydrocephalus, positive testing for genetic forms of aqueductal stenosis, other congenital abnormalities suggesting an underlying genetic syndrome, and stenosis/obstruction due to secondary causes were excluded from this study. Prenatal and perinatal history, CSF diversion history, and a variety of outcomes, including ophthalmological deficits and developmental milestones, were collected and analyzed. RESULTS: A total of 41 patients with isolated CAS were identified, with a mean follow-up duration of 6 years. Among that cohort, 26 patients (63.4%) developed neuroophthalmological complications, which were further stratified. Fourteen patients (34.1%) developed strabismus and 11 (26.8%) developed astigmatism, and 1 patient (2.4%) with papilledema was recorded. Among patients with ophthalmological abnormalities, 76.9% had delayed developmental milestones (p = 0.045). CONCLUSIONS: Patients with CAS were found to have increased risk of ophthalmological abnormalities requiring correction, along with an increased risk of delayed developmental milestones. Importantly, there was a significant correlation between the development of ophthalmological abnormalities and delayed developmental milestones that was independent of CSF diversion history. Larger patient cohort studies are required to explore whether earlier development of hydrocephalus, as is the case in CAS, causes elevated rates of neurological and ophthalmological complications, and if earlier CSF diversion correlates with improved outcomes.

Transitioning to the menopausal transition: a scoping review of research on the late reproductive stage in reproductive aging.

IMPORTANCE AND OBJECTIVE: In 2001 Staging Reproductive Aging Workshop conferees described the late reproductive stage (LRS) of reproductive aging as preceding the onset of the menopausal transition, yet there has been little attention to this aspect of reproductive aging. The aim of this scoping review was to examine scientific publications characterizing the LRS to map what is known about this stage with particular focus on reproductive endocrine patterns, menstrual cycle changes, and symptoms. METHODS: The initial search strategy included PubMed and CINAHL searches for the phrase LRS and "human." Given a low yield of research articles, a second stage used "late reproductive age" (LRA) as a search term. These strategies yielded 9 and 26 research articles, respectively. Publications meeting inclusion criteria (data-based research studies, focus on LRS or LRA and hormonal patterns, menstrual characteristics, and symptoms) published in English were reviewed by coinvestigators. Excluded studies were related to specific diseases, such as cardiovascular disease, and treatment studies. Data were summarized using qualitative methods. To ensure adequate coverage of published research we expanded our review to a third phase in which we identified longitudinal studies of the menopausal transition. DISCUSSION AND CONCLUSIONS: Studies of the LRS focused on: symptoms (anxiety and mood symptoms, bladder symptoms, urinary incontinence, urinary frequency, and nocturia) and associated factors, such as endocrine levels and gene polymorphisms; symptom clusters women experienced during the LRS; cognitive function testing results; changing patterns of physiology such as cytokines and chemokines, lipids, hormone patterns/levels; and association of lifestyle factors such as smoking with hormone levels and symptoms. The LRA search yielded a preponderance of studies of reproductive hormones (such as anti-Mullerian hormone) and menstrual cycle patterns. Remaining studies focused on symptoms, gene variants, health-related behaviors and approaches to classifying menstrual cycles. Longitudinal studies revealed reports of symptoms as well as attempts to classify the progression from the reproductive years to the menopausal transition. Study of the LRS has not been systematic and the limited number and scope of completed studies have yet to contribute a clear and complete picture of the LRS. In some, LRS provided a comparison stage against which to evaluate menopausal transition hormonal and cycle patterns and symptoms. Harmonizing the results of studies of the LRS and LRA is essential to understand more completely women's experiences of the LRS and to allow clinicians to provide better support for women during this time. The LRS also represents an ideal inflection point to promote lifestyle choices that could alter the trajectories of chronic diseases that arise in the fifth, sixth, and seventh decades of women's lives.

Video Summary:http://links.lww.com/MENO/A694.

Developing a pediatric ophthalmology telemedicine program in the COVID-19 crisis.

PURPOSE: To describe our methodology for implementing synchronous telemedicine during the 2019 novel coronavirus (COVID-19) pandemic. METHODS: A retrospective review of outpatient records at a single children's hospital from March 21 to April 10, 2020, was carried out to determine the outcome of already-scheduled face-to-face outpatient appointments. The week leading up to the March 21, all appointments in the study period were categorized as follows: (1) requiring an in-person visit, (2) face-to-face visit that could be postponed, and (3) consultation required but could be virtual. Teams of administrators, schedulers, and ophthalmic technicians used defined scripts and standardized emails to communicate results of categorization to patients. Flowcharts were devised to schedule and implement telemedicine visits. Informational videos were made accessible on social media to prepare patients for the telemedicine experience. Simultaneously our children's hospital launched a pediatric on-demand e-consult service, the data analytics of which could be used to determine how many visits were eye related. RESULTS: A total of 237 virtual ophthalmology consult visits were offered during the study period: 212 were scheduled, and 206 were completed, of which 43 were with new patients and 163 with returning patients. Following the initial virtual visit, another was required on average in 4 weeks by 21 patients; in-person follow-up was required for 170 patients on average 4.6 months after the initial virtual visit. None needed review within 72 hours. The pediatric on-demand service completed 290 visits, of which 25 had eye complaints. CONCLUSIONS: With proper materials, technology, and staffing, a telemedicine strategy based on three patient categories can be rapidly implemented to provide continued patient care during pandemic conditions. In our study cohort, the scheduled clinic e-visits had a low no-show rate (3%), and 8% of the on-demand virtual access for pediatric care was eye related.

Bone geometry and microarchitecture deficits in children with Alagille syndrome.

Alagille syndrome (ALGS) is an autosomal dominant disorder attributed to mutations in the Notch signaling pathway. Children with ALGS are at increased risk for fragility fracture of unknown etiology. Our objective was to characterize bone mass, geometry, and microarchitecture in children with ALGS. This was a cross-sectional study of 10 children (9 females), ages 8-18 years, with a clinical diagnosis of ALGS. Bone density was assessed via DXA (Hologic Discovery A) at several skeletal regions. Tibia trabecular and cortical bone was assessed via pQCT (Stratec XCT 2000) at the distal 3% and 38% sites, respectively. Tibia bone microarchitecture was assessed via HR-pQCT (Scanco XtremeCT II) at an ultradistal site located at 4% of tibia length and a cortical site at 30% of tibia length. Z-scores were calculated for DXA and pQCT measures. In the absence of XtremeCT II HR-pQCT reference data, these outcome measures were descriptively compared to a sample of healthy children ages 5-20 years (n = 247). Anthropometrics and labs were also collected. Based on one-sample t-tests, mean Z-scores for height and weight (both p < .05), were significantly less than zero. DXA bone Z-scores were not significantly different from zero, but were highly variable. For pQCT bone measures, Z-scores for total bone mineral content at the distal 3% site and cortical bone mineral content, cortical area, and cortical thickness at the distal 38% site were significantly less than zero (all p < .05). There was good correspondence between pQCT measures of cortical thickness Z-scores and DXA Z-scores for aBMD at the whole body less head, 1/3 radius, and femoral neck (all p < .05). Compared to healthy children, those with ALGS generally had lower trabecular number and greater trabecular separation despite having greater trabecular thickness (measured via HR-pQCT). Bilirubin and bile acids, markers of hepatic cholestasis, were associated with poorer bone measures. For example, greater bilirubin was associated with lower trabecular number (Spearman's rho [ρ] = -0.82, p = .023) and greater trabecular separation (ρ = 0.82, p = .023) measured via HR-pQCT, and greater bile acids were associated with lower cortical area measured via pQCT (ρ = -0.78, p = .041) and lower serum insulin-like growth factor-1 (ρ = -0.86, p = .002). In summary, deficits in cortical bone size and trabecular bone microarchitecture were evident in children with ALGS. Further investigation is needed to understand the factors contributing to these skeletal inadequacies, and the manner in which these deficits contribute to increased fracture risk.

The Incidence of Tuberculosis in Infants, Siaya District, Western Kenya.

BACKGROUND: Infants are a target population for new tuberculosis (TB) vaccines. TB incidence estimates are needed to guide the design of trials. To determine the TB incidence and cohort retention among young children using comprehensive diagnostic methods in a high burden area. METHODS: Infants 0-42 days were enrolled. Through 4 monthly follow-up and unscheduled (sick) visits up to the age of 2 years, infants with presumptive TB based on a history of contact, TB symptoms or pre-determined hospitalization criteria were admitted to a case verification ward. Two induced sputa and gastric aspirates were collected for culture and GeneXpert. Mantoux and HIV tests were done. Clinical management was based on the Keith Edwards score. Cases were classified into microbiologically confirmed or radiologic, diagnosed by blinded expert assessment. Cox regression was used to identify risk factors for incident TB and study retention. RESULTS: Of 2900 infants enrolled, 927 (32%) developed presumptive TB, 737/927 (80%) were investigated. Sixty-nine TB cases were diagnosed (bacteriologic and radiologic). All TB incidence was 2/100 person-years of observation (pyo) (95% CI: 1.65-2.65). Nine were bacteriologic cases, incidence 0.3/100 pyo. The radiologic TB incidence was 1.82/100 pyo. Bacteriologic TB was associated with infant HIV infection, higher Keith Edwards scores. Completeness of 4-month vaccinations and HIV infection were positively associated with retention. CONCLUSIONS: TB incidence was high. An all TB endpoint would require a sample size of a few thousand children, but tens of thousands, when limited to bacteriologic TB.

Community health care workers in pursuit of TB: Discourses and dilemmas.

Community-led tuberculosis (TB) active case finding is widely promoted, heavily funded, but many efforts fail to meet expectations. The underlying reasons why TB symptom screening programs underperform are poorly understood. This study examines Nigerian stakeholders' insights to characterize the mechanisms, enabling structures and influences that lead programs to succeed or fail. Eight focus group discussions were held with Community Health Workers (CWs) from four models of community-based TB screening and referral. In-depth interviews were conducted with 2 State TB program managers, 8 Community based organizations (CBOs), and 6 state TB and Leprosy Local Government supervisors. Transcripts were coded using Framework Analysis to assess how divergent understandings of CWs' roles, expectations, as well as design, political and structural factors contributed to the observed underperformance. Altruism, religious faith, passion, and commitment to the health and well-being of their communities were reasons CWs gave for starting TB symptom screening and referral. Yet politicized or donor-driven CWs' selection processes at times yielded implementers without a firm grounding in TB or the social, cultural, and physical terrain. CWs encountered suspicion, stigma, and hostility in both health facilities and communities. As the interface between the TB program and communities, CWs often bore the brunt of frustrations with inadequate TB services and CBO/iNGO collaboration. Some CWs expended their own social and financial capital to cover gaps in the active case finding (ACF) programs and public health services or curtailed their screening activities. Effective community-led TB active case finding is challenging to design, implement and sustain. Contrary to conventional wisdom, CWs did not experience it as inherently empowering. Sustainable, supportive models that combine meaningful engagement for communities with effective program stewardship and governance are needed. Crucially effective and successful implementation of community-based TB screening and referral requires a functional public health system to which to refer.

Obesity, smoking, and risk of vasomotor menopausal symptoms: a pooled analysis of eight cohort studies.

BACKGROUND: Frequent and severe vasomotor symptoms during menopause are linked with adverse health outcomes. Understanding modifiable lifestyle factors for the risk of vasomotor menopausal symptoms is important to guide preventive strategies. OBJECTIVE: We investigated the associations between body mass index and smoking, their joint effects with the risk of vasomotor symptoms, and whether the associations differed by menopausal stage. STUDY DESIGN: The International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events pooled data on 21,460 midlife women from 8 studies (median age, 50 years; interquartile range, 49-51 years) for the cross-sectional analysis. Four studies provided data for the prospective analysis (n=11,986). Multinomial logistic regression models with 4 categories of frequency/severity for the outcome of vasomotor symptoms were used to estimate relative risk ratios and 95% confidence intervals that were adjusted for within-study correlation and covariates. RESULTS: At baseline, nearly 60% of the women experienced vasomotor symptoms. One-half of them were overweight (30%) or obese (21%), and 17% were current smokers. Cross-sectional analyses showed that a higher body mass index and smoking more cigarettes with longer duration and earlier initiation were all associated with more frequent or severe vasomotor symptoms. Never smokers who were obese had a 1.5-fold (relative risk ratio, 1.52; 95% confidence interval, 1.35-1.73) higher risk of often/severe vasomotor symptoms, compared with never smokers who were of normal-weight. Smoking strengthened the association because the risk of often/severe vasomotor symptoms was much greater among smokers who were obese (relative risk ratio, 3.02; 95% confidence interval, 2.41-3.78). However, smokers who quit at <40 years of age were at similar levels of risk as never smokers. Prospective analyses showed a similar pattern, but the association attenuated markedly after adjustment for baseline vasomotor symptoms. Furthermore, we found that the association between body mass index and vasomotor symptoms differed by menopausal status. Higher body mass index was associated with increased risk of vasomotor symptoms in pre- and perimenopause but with reduced risk in postmenopause. CONCLUSION: High body mass index (≥25 kg/m2) and cigarette smoking substantially increased women's risk for experiencing frequent or severe vasomotor symptoms in a dose-response manner, and smoking intensified the effect of obesity. However, the effect of body mass index on the risk of vasomotor symptoms was opposite among postmenopausal women. Maintaining a normal weight before the menopausal transition and quitting smoking at <40 years of age may mitigate the excess risk of vasomotor symptoms in midlife.

CDK4/6 inhibition mitigates stem cell damage in a novel model for taxane-induced alopecia.

Taxanes are a leading cause of severe and often permanent chemotherapy-induced alopecia. As the underlying pathobiology of taxane chemotherapy-induced alopecia remains poorly understood, we investigated how paclitaxel and docetaxel damage human scalp hair follicles in a clinically relevant ex vivo organ culture model. Paclitaxel and docetaxel induced massive mitotic defects and apoptosis in transit amplifying hair matrix keratinocytes and within epithelial stem/progenitor cell-rich outer root sheath compartments, including within Keratin 15+ cell populations, thus implicating direct damage to stem/progenitor cells as an explanation for the severity and permanence of taxane chemotherapy-induced alopecia. Moreover, by administering the CDK4/6 inhibitor palbociclib, we show that transit amplifying and stem/progenitor cells can be protected from paclitaxel cytotoxicity through G1 arrest, without premature catagen induction and additional hair follicle damage. Thus, the current study elucidates the pathobiology of taxane chemotherapy-induced alopecia, highlights the paramount importance of epithelial stem/progenitor cell-protective therapy in taxane-based oncotherapy, and provides preclinical proof-of-principle in a healthy human (mini-) organ that G1 arrest therapy can limit taxane-induced tissue damage.

Stigma in health facilities: why it matters and how we can change it.

Stigma in health facilities undermines diagnosis, treatment, and successful health outcomes. Addressing stigma is fundamental to delivering quality healthcare and achieving optimal health. This correspondence article seeks to assess how developments over the past 5 years have contributed to the state of programmatic knowledge-both approaches and methods-regarding interventions to reduce stigma in health facilities, and explores the potential to concurrently address multiple health condition stigmas. It is supported by findings from a systematic review of published articles indexed in PubMed, Psychinfo and Web of Science, and in the United States Agency for International Development's Development Experience Clearinghouse, which was conducted in February 2018 and restricted to the past 5 years. Forty-two studies met inclusion criteria and provided insight on interventions to reduce HIV, mental illness, or substance abuse stigma. Multiple common approaches to address stigma in health facilities emerged, which were implemented in a variety of ways. The literature search identified key gaps including a dearth of stigma reduction interventions in health facilities that focus on tuberculosis, diabetes, leprosy, or cancer; target multiple cadres of staff or multiple ecological levels; leverage interactive technology; or address stigma experienced by health workers. Preliminary results from ongoing innovative responses to these gaps are also described.The current evidence base of stigma reduction in health facilities provides a solid foundation to develop and implement interventions. However, gaps exist and merit further work. Future investment in health facility stigma reduction should prioritize the involvement of clients living with the stigmatized condition or behavior and health workers living with stigmatized conditions and should address both individual and structural level stigma.

More than just caffeine: psychopharmacology of methylxanthine interactions with plant-derived phytochemicals.

In general, preparations of coffee, teas, and cocoa containing high levels of polyphenols, L-theanine and other bioactive compounds selectively enhance mood and cognition effects of caffeine. This review summarizes the bioactive components of commonly consumed natural caffeine sources (e.g. guayusa, mate and camellia teas, coffee and cocoa) and analyzes the psychopharmacology of constituent phytochemicals: methylxanthines, polyphenols, and L-theanine. Acute and chronic synergistic effects of these compounds on mood and cognition are compared and discussed. Specific sets of constituent compounds such as polyphenols, theobromine and L-theanine appear to enhance mood and cognition effects of caffeine and alleviate negative psychophysiological effects of caffeine. However, more research is needed to identify optimal combinations and ratios of caffeine and phytochemicals for enhancement of cognitive performance.

Relationships between intensity, duration, cumulative dose, and timing of smoking with age at menopause: A pooled analysis of individual data from 17 observational studies.

BACKGROUND: Cigarette smoking is associated with earlier menopause, but the impact of being a former smoker and any dose-response relationships on the degree of smoking and age at menopause have been less clear. If the toxic impact of cigarette smoking on ovarian function is irreversible, we hypothesized that even former smokers might experience earlier menopause, and variations in intensity, duration, cumulative dose, and age at start/quit of smoking might have varying impacts on the risk of experiencing earlier menopause. METHODS AND FINDINGS: A total of 207,231 and 27,580 postmenopausal women were included in the cross-sectional and prospective analyses, respectively. They were from 17 studies in 7 countries (Australia, Denmark, France, Japan, Sweden, United Kingdom, United States) that contributed data to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE). Information on smoking status, cigarettes smoked per day (intensity), smoking duration, pack-years (cumulative dose), age started, and years since quitting smoking was collected at baseline. We used multinomial logistic regression models to estimate multivariable relative risk ratios (RRRs) and 95% confidence intervals (CIs) for the associations between each smoking measure and categorised age at menopause (<40 (premature), 40-44 (early), 45-49, 50-51 (reference), and ≥52 years). The association with current and former smokers was analysed separately. Sensitivity analyses and two-step meta-analyses were also conducted to test the results. The Bayesian information criterion (BIC) was used to compare the fit of the models of smoking measures. Overall, 1.9% and 7.3% of women experienced premature and early menopause, respectively. Compared with never smokers, current smokers had around twice the risk of experiencing premature (RRR 2.05; 95% CI 1.73-2.44) (p < 0.001) and early menopause (1.80; 1.66-1.95) (p < 0.001). The corresponding RRRs in former smokers were attenuated to 1.13 (1.04-1.23; p = 0.006) and 1.15 (1.05-1.27; p = 0.005). In both current and former smokers, dose-response relationships were observed, i.e., higher intensity, longer duration, higher cumulative dose, earlier age at start smoking, and shorter time since quitting smoking were significantly associated with higher risk of premature and early menopause, as well as earlier menopause at 45-49 years. Duration of smoking was a strong predictor of age at natural menopause. Among current smokers with duration of 15-20 years, the risk was markedly higher for premature (15.58; 11.29-19.86; p < 0.001) and early (6.55; 5.04-8.52; p < 0.001) menopause. Also, current smokers with 11-15 pack-years had over 4-fold (4.35; 2.78-5.92; p < 0.001) and 3-fold (3.01; 2.15-4.21; p < 0.001) risk of premature and early menopause, respectively. Smokers who had quit smoking for more than 10 years had similar risk as never smokers (1.04; 0.98-1.10; p = 0.176). A limitation of the study is the measurement errors that may have arisen due to recall bias. CONCLUSIONS: The probability of earlier menopause is positively associated with intensity, duration, cumulative dose, and earlier initiation of smoking. Smoking duration is a much stronger predictor of premature and early menopause than others. Our findings highlight the clear benefits for women of early smoking cessation to lower their excess risk of earlier menopause.

Alagille Syndrome.

Alagille syndrome is a complex multisystem autosomal dominant disorder with a wide variability in penetrance of clinical features. A majority of patients have pathogenic mutations in either the JAG1 gene, encoding a Notch pathway ligand, or the receptor NOTCH2. No genotype-phenotype correlations have been found in any organ system. Liver disease is a major cause of morbidity in this population, whereas cardiac and vascular involvement accounts for most of the mortality. Current therapies are supportive, but the future is promising for the development of targeted interventions to augment Notch pathway signaling in involved tissues.

Polymorphisms in Estrogen Synthesis Genes and Symptom Clusters During the Menopausal Transition and Early Postmenopause: Observations From the Seattle Midlife Women's Health Study.

During the menopausal transition and early postmenopause, participants in the Seattle Midlife Women's Health Study (SMWHS) experienced one of the three symptom severity clusters identified through latent class analysis: severe hot flashes with moderate sleep, mood, cognitive, and pain symptoms (high-severity hot flash); low-severity hot flashes with moderate levels of all other symptom groups (moderate severity); and low levels of all symptom groups (low severity). In an effort to determine whether gene polymorphisms were associated with these symptom severity classes, we tested associations between gene polymorphisms in the estrogen synthesis pathways (cytochrome P450 19 [CYP 19] and 17 beta hydroxysteroid dehydrogenase [ 17HSDB1]) and the three symptom severity clusters. SMWHS participants ( N = 137) recorded symptoms monthly in diaries and provided buccal smears for genotyping. Multilevel latent class analysis with multinomial regression was used to determine associations between gene polymorphisms and symptom severity clusters. Only the 17HSDB1 polymorphisms ( rs615942 and rs592389) were associated significantly with the high-severity hot flash cluster versus the low-severity symptom cluster. None of the polymorphisms was associated with the moderate-severity cluster versus the low-severity symptom cluster. Findings of associations of the 17HSDB1 polymorphisms with the high-severity hot flash symptom cluster are consistent with those of an association between 17HSDB1 polymorphisms and hot flashes in the Study of Women and Health Across the Nation population and our previous findings of associations between these polymorphisms with greater estrone levels.

Bilateral Cavernous Sinus Thrombosis in a Patient with Tacrolimus-Associated Posttransplant Thrombotic Microangiopathy.

Purpose To report a case of bilateral cavernous sinus thrombosis (CST) in a patient with tacrolimus-associated posttransplant thrombotic microangiopathy. Methods Case report. Results An 8-year-old boy with a medical history of orthotopic heart transplant, posttransplant lymphoproliferative disease, and recurrent infections was hospitalized for nausea, vomiting, and diarrhea. His ocular history included accommodative esotropia, hyperopia with astigmatism, Molluscum contagiosum lid lesions, and idiopathic intracranial hypertension. Shortly after presentation, he developed increased intraocular pressure, an afferent pupillary defect, a layered hyphema, and tense proptosis of the left globe requiring an emergent canthotomy and cantholysis. Over the next month, the patient's hospital course included subdural and subarachnoid hemorrhage, temporal lobe stroke, serotonin syndrome, bilateral CST, and systemic microangiopathy. After an extensive workup, a diagnosis of tacrolimus-associated thrombotic microangiopathy was made. At this point, vision was 20/20 in the right eye and light perception in the left eye. Eight months after the canthotomy and cantholysis, the patient's vision in the left eye deteriorated to no light perception and remained so after 13 months of follow-up. Conclusions An idiosyncratic drug reaction should be considered in the differential diagnosis of CST, especially in a patient on calcineurin inhibitors after solid organ transplant without sinus disease or orbital cellulitis.

Liver Disease in Alpha-1 Antitrypsin Deficiency: Current Approaches and Future Directions.

PURPOSE OF REVIEW: The aim of the study is to review the liver disease caused by alpha-1 antitrypsin deficiency (A1ATD), including pathogenesis, epidemiology, diagnostic testing, and recent therapeutic developments. RECENT FINDINGS: Therapeutic approaches target several intracellular pathways to reduce the cytotoxic effects of the misfolded mutant globular protein (ATZ) on the hepatocyte. These include promoting ATZ transport out of the endoplasmic reticulum (ER), enhancing ATZ degradation, and preventing ATZ globule-aggregation. SUMMARY: A1ATD is the leading genetic cause of liver disease among children. It is a protein-folding disorder in which toxic insoluble ATZ proteins aggregate in the ER of hepatocytes leading to inflammation, fibrosis, cirrhosis, and increased risk of hepatocellular carcinoma. The absence of the normal A1AT serum protein also predisposes patients to pan lobar emphysema as adults. At this time, the only approved therapy for A1ATD-associated liver disease is orthotopic liver transplantation, which is curative. However, there has been significant recent progress in the development of small molecule therapies with potential both to preserve the native liver and prevent hepatotoxicity.