Quality of life in children and adolescents 1-year after cure of Cushing syndrome: a prospective study

Objective  Cushing syndrome (CS) in children is associated with symptoms that may impair health related quality of life (HRQL). There are no prospective reports of HRQL in children with CS.
Methods  Prospective study of 40 children (mean age 13 ± 3·2 years) with CS evaluated prior to and 1-year post-treatment. The Child Health Questionnaire (CHQ) was used to assess HRQL; Wechsler Intelligence Scale for Children (WASI) was used to assess cognitive function, and patient-reported symptoms were assessed with a CS symptom checklist.
Results  Active CS was associated with low physical and psychosocial summary scores compared to US population data ( P <  0·001). Despite improvement from pre- to 1-year postcure, residual impairment remained in physical summary and function, and role-physical, global health and emotional impact (parent) scores. Incomplete recovery of adrenal function at 1-year post-treatment was associated with impaired scores. WASI IQ scores declined and a correlation was noted between age at first evaluation and IQ score changes. Most self-reported CS symptoms showed improvement, but forgetfulness, unclear thinking and decreased attention span did not improve after cure of CS.
Conclusion  CS in children and adolescents is associated with impaired HRQL, with residual impairment 1 year after cure. Our results also suggest that younger children are more likely to experience negative changes in cognitive function. HRQL is an important outcome measure in children and adolescents with CS and identification of factors that contribute to HRQL may help to diminish the physical and psychological burden of disease in this population of patients.     

Exposure density and neighborhood disparities in COVID-19 infection risk

Although there is increasing awareness of disparities in COVID-19 infection risk among vulnerable communities, the effect of behavioral interventions at the scale of individual neighborhoods has not been fully studied. We develop a method to quantify neighborhood activity behaviors at high spatial and temporal resolutions and test whether, and to what extent, behavioral responses to social-distancing policies vary with socioeconomic and demographic characteristics. We define exposure density (Exρ) as a measure of both the localized volume of activity in a defined area and the proportion of activity occurring in distinct land-use types. Using detailed neighborhood data for New York City, we quantify neighborhood exposure density using anonymized smartphone geolocation data over a 3-mo period covering more than 12 million unique devices and rasterize granular land-use information to contextualize observed activity. Next, we analyze disparities in community social distancing by estimating variations in neighborhood activity by land-use type before and after a mandated stay-at-home order. Finally, we evaluate the effects of localized demographic, socioeconomic, and built-environment density characteristics on infection rates and deaths in order to identify disparities in health outcomes related to exposure risk. Our findings demonstrate distinct behavioral patterns across neighborhoods after the stay-at-home order and that these variations in exposure density had a direct and measurable impact on the risk of infection. Notably, we find that an additional 10% reduction in exposure density city-wide could have saved between 1,849 and 4,068 lives during the study period, predominantly in lower-income and minority communities.

As of December 17, 2020, there have been 73 million cases of COVID-19 in more than 200 countries, and 1.6 million people have lost their lives to the disease (1). The COVID-19 pandemic is considered the most severe public health crisis since the 1918 flu pandemic due to its transmission and infection characteristics (2–5). Social distancing (also referred to as physical distancing) has been shown to be an effective behavioral nonpharmaceutical intervention to reduce the transmission rate of COVID-19 (3–7). Social distancing reduces the probability of contacts between individuals who might be infected, resulting in reduced exposure risk (7, 8). Governments have implemented a range of social-distancing policies, including travel bans, restrictions on gatherings, school closures, nonessential business closures, and restaurant restrictions. In particularly hard-hit locations, mandatory “stay-at-home” orders have been issued to limit or avoid unnecessary close contacts outside of the home (7–9).Studies have found that social-distancing measures help to prevent transmission of the virus and reduce the reproduction (R₀) number (5–7, 10–14). These practices help to avoid overwhelming hospital intensive care units and healthcare systems, control doubling time of infections, and ultimately save lives (5, 8, 14, 15). Although not without potentially significant hardship to individuals and communities, social distancing is an important public health tool to flatten the epidemic curve and support longer-term economic and public health benefits (3, 15–17).However, the impact of, and response to, stay-at-home orders and social-distancing guidelines is not uniform across neighborhoods and communities (18, 19). In order to maximize the positive effects of social distancing, individuals need to change their typical behavior, often dramatically (3, 20). Despite government-mandated social-distancing policies (such as New York State’s PAUSE order), socio-behavioral responses vary across neighborhoods, further contributing to disparities in risk of infection (4, 7, 21). Disparities in social-distancing practices—namely, geographic or population subgroup differences in adopting behavior changes in response to the same policy context—may stem from varying levels of awareness, perception, or belief in the severity of the virus threat; differences in social and cultural norms; or the ability of households and communities to alter normal activity patterns given economic constraints or other existing responsibilities (7, 20–23). For example, lower-income households typically do not have the option to work from home, and going to a place of work (often in essential services) is unavoidable, meaning higher risk of exposure to COVID-19 for themselves, as well as their families and communities (7, 24). Within specific neighborhoods, norms can also be reinforcing; if large numbers of residents are essential workers and not socially distancing, other residents may have similar behavioral responses (20).A growing number of outbreaks are occurring in densely populated areas (25), with disproportionate impacts on lower-income and predominantly minority communities (18, 26–28). Measuring and understanding social distancing and behavior change across neighborhoods can provide critical insight into the design and implementation of more effective—and equitable—public health policy. Given the potential heterogeneity in localized responses to social-distancing recommendations, quantifying local patterns of activity represents an emerging tool to understand and eventually reduce local exposure risk and limit community outbreaks (7, 29, 30). Although there has been increasing awareness of the troubling disparities in infection rates and outcomes in vulnerable communities, the effectiveness of behavioral interventions at the scale of individual neighborhoods has not been fully studied. Often, studies that do attempt to observe effects at higher spatial resolutions rely on simulations or are limited to relatively coarse areal units (e.g., county or state) due to data availability and computational constraints (31–34). Absent a more complete understanding of neighborhood activity patterns in response to nonpharmaceutical interventions, disaggregating built-environment, behavioral, and social determinants of health in the context of COVID-19 remains a challenge.We develop a method to quantify neighborhood activity at high spatial and temporal resolutions to test whether—and to what extent—behavioral responses to social-distancing policies vary with socioeconomic, demographic, and built-environment characteristics. We define exposure density (Exρ) as a measure of both the localized volume of activity in a defined area and the proportion of activity occurring in nonresidential and outdoor land uses, areas that can be associated with an increased risk of exposure to others that may be infected. We utilize this approach to capture community inflows/outflows of people as a result of the pandemic and changes in mobility behavior for those that remain.Our focus is on New York City (NYC), the first epicenter of the pandemic in the United States, where a statewide stay-at-home order (NY on PAUSE) was introduced on March 22, 2020. By June 30, 2020, NYC had more than 212,000 confirmed cases of COVID-19, accounting for 8% of the nationwide total, resulting in at least 18,492 confirmed deaths and 4,604 probable deaths (35). Our methodology proceeds in three steps. First, we develop a generalizable method for assessing neighborhood activity levels using smartphone geolocation data over a 3-mo period (February, March, and April) covering more than 12 million unique devices within the Greater New York area, together with land-use classifications at 1-m grid resolution. Second, we measure and analyze disparities in community social distancing by estimating variations in neighborhood activity and associated patterns in community characteristics before and after the stay-at-home order. Finally, we evaluate the effect of exposure density on COVID-19 infection rates associated with localized demographic, socioeconomic, and built-environment characteristics in order to identify disparities in health outcomes related to mobility behavior. Our findings provide insight into the timely evaluation of the effectiveness of social distancing at the scale of individual neighborhoods and support a more equitable allocation of resources to vulnerable and at-risk communities.     

Endocardial cushion defect associated with cor triatriatum sinistrum or supravalve mitral ring

Clinical and angiographic or autopsy data, or both, on three children with a subdivided left atrium (cor triatriatum) and an associated endocardial cushion defect are reviewed. (One child had ostium primum defect, and two had complete atrioventricular [A-V] canal.) A fourth patient demonstrates the difficulties in differentiating subdivided left atrium from supravalve mitral stenosis in the presence of an endocardial cushion defect. The clinical findings are greatly influenced by the endocardial cushion defect. A pressure gradient between the pulmonary wedge and (left or right) ventricular end-diastolic pressures in patients with an endocardial cushion defect indicates pulmonary venous obstruction and should alert one to the possibility of these combined lesions. The exact diagnosis is made with injections of angiographic contrast medium into the proximal and distal left atrial chambers, to document the respective relations of the pulmonary veins, left atrial appendage and A-V valves to these atrial chambers. All three patients with an endocardial cushion defect and a subdivided left atrium had an associated patent ductus arteriosus. The common association of subdivided left atrium with intracardiac, pulmonary venous and aortic anomalies is again demonstrated.     

Treatment of pyogenic liver abscess: prospective randomized comparison of catheter drainage and needle aspiration

This study aims to compare the therapeutic effectiveness of continuous catheter drainage versus intermittent needle aspiration in the percutaneous treatment of pyogenic liver abscesses. Over a 5-year period, 64 consecutive patients with pyogenic liver abscess were treated with intravenous antibiotics (ampicillin, cefuroxime, and metronidazole) and randomized into two percutaneous treatment groups: continuous catheter drainage (with an 8F multi-sidehole pigtail catheter); and intermittent needle aspiration (18G disposable trocar needle). There was no statistically significant difference between the two groups regarding patient demographics, underlying coexisting disease, abscess size, abscess number, number of loculation of abscess, the presenting clinical symptoms such as fever, abdominal pain, and pretreatment liver function test. Although not statistically significant, the duration of intravenous antibiotics treatment before percutaneous treatment was longer with the catheter group, and the change of antibiotics after the sensitivity test was more frequent with the needle group. The needle group was associated with a higher treatment success rate, a shorter duration of hospital stay, and a lower mortality rate, although this did not reach statistical significance. In conclusion, this study suggests that intermittent needle aspiration is probably as effective as continuous catheter drainage for the treatment of pyogenic liver abscess, although further proof with a large-scale study is necessary. Due to the additional advantages of procedure simplicity, patient comfort, and reduced price, needle aspiration deserves to be considered as a first-line drainage approach.     

Clinical and molecular genetics of primary pigmented nodular adrenocortical disease

Carney complex (CNC) is a multiple endocrine neoplasia (MEN) syndrome associated with other, non-endocrine manifestations such as lentigines, cardiac myxomas and schwannomas. Primary pigmented nodular adrenocortical disease (PPNAD), leading to corticotrophin-independent Cushing's syndrome is the most frequent endocrine lesion in CNC. The complex has been mapped to 2p16 and 17q22-24, although additional heterogeneity may exist. The gene coding for the protein kinase A (PKA) type I-a regulatory subunit (RIa), PRKAR1A, had been mapped to 17q. Cloning of the PRKAR1A genomic structure and its sequencing showed mutations in CNC-, CNC with PPNAD- and sporadic PPNAD-patients. In CNC tumors, PKA activity showed increased stimulation by cAMP, whereas PKA activity ratio was decreased, and in CNC tumors, there is LOH of the normal allele, suggesting that normal PRKAR1A may be a tumor suppressor in these tissues. CNC is the first human disease caused by mutations of one of the subunits of the PKA enzyme, a critical component of the cAMP signaling system and a potential participant in many other signaling pathways.     

beta-lapachone,a novel plant product,overcomes drug resistance in human multiple myeloma cells

OBJECTIVE: To evaluate the anti-tumor potential of beta-lapachone in multiple myeloma (MM) cell lines (U266, RPMI8226, and MM.1S); MM cell lines resistant to dexamethasone (MM.1R), melphalan (RPMI8226/LR5), doxorubicin (RPMI8226/DOX40), and mitoxantrone (RPMI8226/ MR20); and MM cells from patients (MM1-MM4). MATERIALS AND METHODS: Cytotoxicity of beta-lapachone was assessed by MTT and [3H]-thymidine uptake assays. Apoptosis was analyzed using propidium iodide staining, DNA fragmentation, TUNEL assay, caspase-9 colorimetric assay, and immunoblotting for caspase-3, poly (ADP-ribose) polymerase (PARP), and caspase-8 cleavage products. Paracrine growth of MM cells was assessed by [3H]-thymidine uptake in cultures of bone marrow stromal cells (BMSCs) and MM cells. Interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) secretion in the culture supernatants was measured by specific enzyme-linked immunosorbent assays (ELISAs). RESULTS: beta-lapachone showed significant cytotoxicity in MM cells (IC(50): 4-8 microM). In contrast, normal peripheral blood mononuclear cells (PBMCs) and BMSCs from MM patients were relatively resistant (IC(50): 8-16 microM). IL-6 did not protect against beta-lapachone-induced apoptosis in MM.1S cells, and dexamethasone showed additive cytotoxicity. beta-lapachone also decreased binding of MM.1S cells to BMSCs; abrogated IL-6 and VEGF secretion triggered by adhesion of BMSCs to MM.1S cells; reduced proliferation of MM.1S cells adherent to BMSCs; and decreased intracellular adhesion molecule-1 (ICAM-1) expression on MM.1S cells. Furthermore, beta-lapachone induced typical PARP cleavage, increased caspase-9 proteolytic activity, and activation of caspase-3, without activation of caspase-8 in U266 cells. CONCLUSION: These studies provide a framework for clinical evaluation of beta-lapachone to improve the outcome for patients with MM.     

Diagnostic usefulness of five screening assays for HIV in an east African city where prevalence of infection is low

Five commercial screening assays for HIV-1, evaluated for their usefulness in detecting infection in high-risk groups in the East African country of Djibouti, produced varying degrees of performance when compared to Western blot and immunofluorescence confirmatory assays. In this population with a low prevalence of HIV infection (16/599), two enzyme-linked immunosorbent assays (ELISA; Abbott and Elavia) and two rapid assays (cambridge latex agglutination and Du Pont's HIV-CHEK) exhibited less than optimal sensitivities. However, with the exception of Elavia, these assays displayed excellent specificities. The fifth test (Serodia gelatin agglutination) produced the highest sensitivity (0.938) and negative predictive value but the lowest specificity and positive predictive value of all five tests. False positive reactions, which occurred only with the Elavia and Serodia tests, could not be explained on the basis of early infection in patients or cross-reactions with the related retroviruses HIV-2 and HTLV-I. We conclude that none of the five tests alone is sufficient in this testing situation, but that a combination of tests could satisfy most requirements for identifying HIV-1 reactive and non-reactive sera.     

Reduced breast cancer incidence in women treated with subcutaneous testosterone,or testosterone with anastrozole: A prospective,observational study

Objectives

There is evidence that androgens are breast protective and that testosterone therapy treats many symptoms of hormone deficiency in both pre and postmenopausal patients. However, unlike estrogen and progestins, there is a paucity of data regarding the incidence of breast cancer in women treated with testosterone therapy. This study was designed to investigate the incidence of breast cancer in women treated with subcutaneous testosterone therapy in the absence of systemic estrogen therapy.

Study design

This is a 5-year interim analysis of a 10-year, prospective, observational, IRB approved study investigating the incidence of breast cancer in women presenting with symptoms of hormone deficiency treated with subcutaneous testosterone (T) implants or, T combined with the aromatase inhibitor anastrozole (A), i.e., T + A implants. Breast cancer incidence was compared with that of historical controls reported in the literature, age specific Surveillance Epidemiology and End Results (SEER) incidence rates, and a representative, similar age group of our patients used as a ‘control’ group. The effect of adherence to T therapy was also evaluated.

Results

Since March 2008, 1268 pre and post menopausal women have been enrolled in the study and eligible for analysis. As of March 2013, there have been 8 cases of invasive breast cancer diagnosed in 5642 person-years of follow up for an incidence of 142 cases per 100 000 person-years, substantially less than the age-specific SEER incidence rates (293/100 000), placebo arm of Women's Health Initiative Study (300/100 000), never users of hormone therapy from the Million Women Study (325/100 000) and our control group (390/100 000). Unlike adherence to estrogen therapy, adherence to T therapy further decreased the incidence of breast cancer (73/100 000).

Conclusion

T and/or T + A, delivered subcutaneously as a pellet implant, reduced the incidence of breast cancer in pre and postmenopausal women. Evidence supports that breast cancer is preventable by maintaining a T to estrogen ratio in favor of T and, in particular, by the use of continuous T or, when indicated, T + A. This hormone therapy should be further investigated for the prevention and treatment of breast cancer.