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Quality of life in chronic kidney disease (CKD) is impaired by a large burden of symptoms including some that overlap with the symptoms of heart failure (HF). We studied a group of individual with CKD to understand the patterns and trajectories of HF-type symptoms in this setting.Prospective cohort study.3,044 participants in the Chronic Renal Insufficiency Cohort (CRIC) without prior diagnosis of HF.Sociodemographics, medical history, medications, vital signs, laboratory values, echocardiographic and EKG parameters.Trajectory over 5.5 years of a HF-type symptom score (modified Kansas City Cardiomyopathy Questionnaire [KCCQ] Overall Summary Score with a range of 0-100 where75 reflects clinically significant symptoms).Latent class mixed models were used to model trajectories. Multinomial logistic regression was used to model relationships of predictors with trajectory group membership.Five trajectories of KCCQ score were identified in the cohort of 3,044 adults, 45% of whom were female, and whose median age was 61 years. Group 1 (41.7%) had a stable high score (minimal symptoms, average score of 96); Groups 2 (35.6%) and 3 (15.6%) had stable but lower scores (mild symptoms, average 81, and clinically significant symptoms, average 52, respectively). Group 4 (4.9%) had a substantial worsening in symptoms over time (mean 31-point decline) and Group 5 (2.2%) had a substantial improvement (mean 33-point increase) in KCCQ score. A majority of Group 1 was male, non-diabetic, non-obese, and had higher baseline kidney function. A majority of Groups 2 and 3 had diabetes and obesity. A majority of Group 4 was male and had substantial proteinuria. Group 5 had the highest proportion of baseline cardiovascular disease (CVD).No validation cohort available, CKD management changes in recent years may alter trajectories, and latent class models depend on the missing at random assumption.Distinct HF-type symptom burden trajectories were identified in the setting of CKD, corresponding to different baseline characteristics. These results highlight the diversity of HF-type symptom experiences in individuals with CKD.

To determine the utility of adrenal vein sampling (AVS) and post-adrenalectomy outcomes in patients with a normal plasma aldosterone concentration (PAC) and elevated aldosterone-to-renin ratio (ARR).The study sample included 106 patients with an ARR greater than 20 and PAC between 5 ng/dL and 15 ng/dL ("normal PAC group") who underwent AVS from 2005-2021. These patients were compared to a cohort of 106 patients with an ARR20 and PAC15 ng/dL ("high PAC group") who underwent AVS during the same time period. Data regarding baseline clinical characteristics, lateralization indices from AVS, and outcomes after adrenalectomy were analyzed.AVS was technically successful in 210 patients (210/212, 99%). A smaller proportion of patients in the normal PAC group had a lateralization index4 compared to the high PAC group (44% vs. 64%, p0.01). A similar proportion of patients in the normal PAC group experienced improved or cured hypertension following adrenalectomy compared to the high PAC group (94% vs. 88%, p = 0.31). Hypokalemia was cured in all patients in the normal PAC group following adrenalectomy, compared to 98% of patients in the high PAC group (100% vs. 98%, p = 1).Although lateralization is less frequent for patients with a normal PAC, patients who do lateralize have similar blood pressure response and correction of hypokalemia following adrenalectomy, regardless of initial plasma aldosterone levels. Therefore, patients with a PAC less than 15 ng/dL should still be considered for AVS provided the ARR is elevated.

The evidence linking chronic kidney disease (CKD) to spontaneous intracerebral hemorrhage (ICH) is inconclusive owing to possible confounding by comorbidities that frequently coexist in patients with these 2 diseases.To determine whether there is an association between CKD and ICH risk.A 3-stage study that combined observational and genetic analyses was conducted. First, the association between CKD and ICH risk was tested in the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study, a multicenter case-control study in the US. All participants with available data on CKD from ERICH were included. Second, this analysis was replicated in the UK Biobank (UKB), an ongoing population study in the UK. All participants in the UKB were included in this study. Third, mendelian randomization analyses were implemented in the UKB using 27 CKD-related genetic variants to test for genetic associations. ERICH was conducted from August 1, 2010, to August 1, 2017, and observed participants for 1 year. The UKB enrolled participants between 2006 and 2010 and will continue to observe them for 30 years. Data analysis was performed from November 11, 2019, to May 10, 2022.CKD stages 1 to 5.The outcome of interest was ICH, ascertained in ERICH via expert review of neuroimages and in the UKB via a combination of self-reported data and International Statistical Classification of Diseases, Tenth Revision, codes.In the ERICH study, a total of 2914 participants with ICH and 2954 controls who had available data on CKD were evaluated (mean [SD] age, 61.6 [14.0] years; 2433 female participants [41.5%]; 3435 male participants [58.5%]); CKD was found to be independently associated with higher risk of ICH (odds ratio [OR], 1.95; 95% CI, 1.35-2.89; P .001). This association was not modified by race and ethnicity. Replication in the UKB with 1341 participants with ICH and 501 195 controls (mean [SD] age, 56.5 [8.1] years; 273 402 female participants [54.4%]; 229 134 male participants [45.6%]) confirmed this association (OR, 1.28; 95% CI, 1.01-1.62; P = .04). Mendelian randomization analyses indicated that genetically determined CKD was associated with ICH risk (OR, 1.56; 95% CI, 1.13-2.16; P = .007).In this 3-stage study that combined observational and genetic analyses among study participants enrolled in 2 large observational studies with different characteristics and study designs, CKD was consistently associated with higher risk of ICH. Mendelian randomization analyses suggest that this association was causal. Further studies are needed to identify the specific biological pathways that mediate this association.

Background Improvement in clinical outcomes and normalisation of objective markers of inflammation, high-sensitivity C-reactive protein (hs-CRP) and faecal calprotectin (FCP), are considered treatment targets per STRIDE-II guidelines.1 We evaluated the effect of the oral selective Janus kinase inhibitor upadacitinib (UPA) on changes in hs-CRP, FCP, and clinical outcomes in patients with Crohn’s disease (CD). Methods In 2 phase 3, randomized, double-blind, placebo-controlled induction studies (U-EXCEL, NCT03345849; U-EXCEED, NCT03345836), patients with moderate-to-severe CD received 12-week treatment with UPA 45 mg (UPA45) once daily (QD) or placebo (PBO). Patients with clinical response to UPA45 were rerandomised in U-ENDURE (NCT03345823) to receive 52-week maintenance treatment with UPA 30 mg QD (UPA30), UPA 15 mg QD (UPA15), or PBO. Endpoints included marker normalisation (hs-CRP ≤ 5 mg/L, FCP ≤ 250 µg/g) in patients with elevated baseline marker levels, normal marker and clinical remission by Crohn’s Disease Activity Index (CDAI < 150) or very soft/liquid stool frequency (SF)/abdominal pain score (APS) (average daily SF ≤ 2.8 and average daily APS ≤ 1, neither greater than baseline), and ≥ 50% reduction from baseline in marker values with a decrease of at least 100 points in CDAI from baseline. Median changes from baseline in marker levels were also evaluated. Non-responder imputation with no special data handling for missing data due to COVID-19 was used. Results Of 1021 enrolled patients, 645 (63.2%) had elevated hs-CRP (> 5 mg/L) and 750 (73.5%) had elevated FCP (> 250 µg/g) levels at baseline. Significantly greater proportions of patients with elevated baseline marker levels achieved normalisation with UPA compared with PBO at week 12 (Fig 1A/B) and week 52 (Fig 2A/B; nominal P < .001 for all). Decreases in marker levels from baseline with UPA were observed as early as week 2 and were significantly greater than with PBO through week 12 (Fig 1C) and week 52 (Fig 2C; nominal P < .001 for all). Patients achieved clinical endpoints and improvements in markers at significantly higher rates with UPA45 vs PBO at week 12 (Fig 1D–F) and with UPA15 and UPA30 vs PBO at week 52 (Fig 2D–F; P < .001 for all). The safety profile of UPA in CD was previously reported and no new safety concerns were identified. Conclusion Improvements in clinical endpoints and normalisation of objective markers of inflammation were achieved as early as week 2 with UPA45 induction and sustained with UPA15 and UPA30 maintenance therapy in patients with CD. Median changes in hs-CRP and FCP with UPA support continued improvement of inflammation up to week 52. 1. Turner D., et al. Gastroenterology. 2021;160(5):1570–1583.

PURPOSE Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (FAK) inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically driven phase II study in recurrent or progressive grade 1-3 meningiomas. PATIENTS AND METHODS Eligible patients whose tumors screened positively for NF2 mutations were treated with GSK2256098, 750 mg orally twice daily, until progressive disease. Efficacy was evaluated using two coprimary end points: progression-free survival at 6 months (PFS6) and response rate by Macdonald criteria, where PFS6 was evaluated separately within grade-based subgroups: grade 1 versus 2/3 meningiomas. Per study design, the FAK inhibitor would be considered promising in this patient population if either end point met the corresponding decision criteria for efficacy. RESULTS Of 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients with NF2 mutations were enrolled and treated: 12 grade 1 and 24 grade 2/3 patients. Across all grades, one patient had a partial response and 24 had stable disease as their best response to treatment. In grade 1 patients, the observed PFS6 rate was 83% (10/12 patients; 95% CI, 52 to 98). In grade 2/3 patients, the observed PFS6 rate was 33% (8/24 patients; 95% CI, 16 to 55). The study met the PFS6 efficacy end point both for the grade 1 and the grade 2/3 cohorts. Treatment was well tolerated; seven patients had a maximum grade 3 adverse event that was at least possibly related to treatment with no grade 4 or 5 events. CONCLUSION GSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive NF2-mutated meningiomas, compared with historical controls. The criteria for promising activity were met, and FAK inhibition warrants further evaluation for this patient population.

Aim: To develop a cognitive dysfunction (CD) focused questionnaire to evaluate caregiver burden in glioblastoma. Materials & methods: The survey was developed from stakeholder consultations and a pilot study, and disseminated at eight US academic cancer centers. Caregivers self-reported caring for an adult with glioblastoma and CD. Results: The 89-item survey covered demographics, CD symptoms and caregiver burden domains. Among 185 caregivers, most were white, educated females and reported memory problems as the most common CD symptom. An exposure-effect was observed, with increase in number of CD symptoms significantly associated with greater caregiver burden. Conclusion: This questionnaire could guide caregiver interventions and be adapted for use longitudinally, in community cancer settings, and in patients with brain metastases.

Purpose To empirically assign severity levels (e.g., mild, moderate) to four relatively new patient-reported outcome measures (PROMs) for adults with acquired cognitive/language disorders. They include the Communicative Participation Item Bank, the Aphasia Communication Outcome Measure, and Neuro-QoL’s item banks of Cognitive Function (v2.0) and Ability to Participate in Social Roles and Activities (v1.0). Method We conducted 17 focus groups that comprised 22 adults with an acquired cognitive/language disorder from stroke, Parkinson’s disease, or traumatic brain injury; 30 care partners of an adult with an acquired cognitive/language disorder; and 42 speech-language pathologists who had experience assessing/treating individuals with those and other cognitive/language disorders. In a small, moderated focus-group format, participants completed “PROM-bookmarking” procedures: They discussed hypothetical vignettes based on PROM item responses about people with cognitive/language disorders and had to reach consensus regarding whether their symptoms/function should be categorized as within normal limits or mild, moderate, or severe challenges. Results There was generally good agreement among the stakeholder groups about how to classify vignettes, particularly when they reflected very high or low functioning. People with aphasia described a larger range of functional communication challenges as “mild” compared to other stakeholder types. Based on a consensus across groups, we present severity levels for specific score ranges for each PROM. Conclusion Standardized, stakeholder-informed severity levels that aid interpretation of PROM scores can help clinicians and researchers derive better clinical meaning from those scores, for example, by identifying important clinical windows of opportunity and assessing when symptoms have returned to a “normal” range.

Sleep disruption is common in older adults and is associated with many poor health outcomes. It is vital for providers to understand insomnia and other sleep disorders in this population. This article outlines age-related changes in sleep, and medical, psychiatric, environmental, and psychosocial factors that may impact sleep. It addresses the evaluation of sleep symptoms and diagnosis of sleep disorders. It aims to examine the evidence for non-pharmacological and pharmacologic treatment options for insomnia while weighing factors particularly germane to the aging adult..

Rare genetic disorders affect as many as 3%-5% of all babies born. Approximately 10,000 such disorders have been identified or hypothesized to exist. Treatment is supportive except in a limited number of instances where specific therapies exist. Development of new therapies has been hampered by at least two major factors: difficulty in diagnosing diseases early enough to enable treatment before irreversible damage occurs, and the high cost of developing new drugs and getting them approved by regulatory agencies. Whole-genome sequencing (WGS) techniques have become exponentially less expensive and more rapid since the beginning of the human genome project, such that return of clinical data can now be achieved in days rather than years and at a cost that is comparable to other less expansive genetic testing. Thus, it is likely that WGS will ultimately become a mainstream, first-tier NBS technique at least for those disorders without appropriate high-throughput functional tests. However, there are likely to be several steps in the evolution to this end. The clinical implications of these advances are profound but highlight the bottlenecks in drug development that still limit transition to treatments. This article summarizes discussions arising from a recent National Institute of Health conference on nucleic acid therapy, with a focus on the impact of WGS in the identification of diagnosis and treatment of rare genetic disorders.

Tuberous sclerosis complex (TSC) is associated with focal brain "tubers" and a high incidence of autism spectrum disorder (ASD). The location of brain tubers associated with autism may provide insight into the neuroanatomical substrate of ASD symptoms.We delineated tuber locations for 115 TSC participants with ASD (n = 31) and without ASD (n = 84) from the Tuberous Sclerosis Complex Autism Center of Excellence Research Network. We tested for associations between ASD diagnosis and tuber burden within the whole brain, specific lobes, and at 8 regions of interest derived from the ASD neuroimaging literature, including the anterior cingulate, orbitofrontal and posterior parietal cortices, inferior frontal and fusiform gyri, superior temporal sulcus, amygdala, and supplemental motor area. Next, we performed an unbiased data-driven voxelwise lesion symptom mapping (VLSM) analysis. Finally, we calculated the risk of ASD associated with positive findings from the above analyses.There were no significant ASD-related differences in tuber burden across the whole brain, within specific lobes, or within a priori regions derived from the ASD literature. However, using VLSM analysis, we found that tubers involving the right fusiform face area (FFA) were associated with a 3.7-fold increased risk of developing ASD.Although TSC is a rare cause of ASD, there is a strong association between tuber involvement of the right FFA and ASD diagnosis. This highlights a potentially causative mechanism for developing autism in TSC that may guide research into ASD symptoms more generally. ANN NEUROL 2022.

Anomalous left coronary artery from the pulmonary artery (ALCAPA) is a congenital malformation that classically presents within the first year of life. Few patients survive into adulthood, and initial presentation after the fourth decade of life is rare. We describe a 55-year-old woman who presented after cardiac arrest. She initially refused surgery and underwent automated implantable cardioverter defibrillator placement, followed later by surgical repair involving reimplantation of the left coronary artery to the aorta and pulmonary artery reconstruction using interposition grafts. We report this late presentation of ALCAPA and successful surgical management.

Postoperative delirium (POD) is an acute syndrome including inattention and impaired cognition that affects approximately 42% of older cardiac surgical patients. POD is linked to adverse outcomes including morbidity, mortality, and further cognitive decline. Less is known about the subjective psychological experience of POD and its ongoing impact on well-being.We performed a qualitative analysis of the long-term psychological sequelae of older adults who experience POD after cardiac surgery. We sampled 30 patients aged 60 years and older who experienced at least 2 episodes of POD during a prior hospital admission. We administered semistructured interviews with participants via telephone 3 to 5 years postoperatively. Interviews were transcribed and thematically analyzed. Data were interpreted in accordance with the naturalist paradigm.Three overarching themes emerged in our qualitative analysis. The first reflected the multifaceted presentation of POD, including distortion of time and reality; feelings of isolation; and a loss of self, identity, and control. The second theme reflected the psychological challenges associated with functional decline after surgery. Common examples of functional decline included cognitive difficulties, excessive fatigue, and a perceived loss of independence. The final theme captured the emotional sequelae of acute illness, which included low mood, reduced motivation, and social comparisons.Our findings emphasize the multidimensional experience of POD and long-term effects on psychological wellbeing. Our research highlights the beneficial role multidisciplinary clinicians play in managing POD including strategies that may be embedded into clinical practice and helps anesthesiologists understand why patients who have experienced POD in the past may present with specific concerns should they require subsequent surgery.

The SYMPLICITY HTN-3 (Renal Denervation in Patients With Uncontrolled Hypertension) trial showed the safety but not efficacy of the Symplicity system (Medtronic, Santa Rosa, CA, USA) at 6 months follow-up in patients with treatment-resistant hypertension. This final report presents the 36-month follow-up results.SYMPLICITY HTN-3 was a single-blind, multicentre, sham-controlled, randomised clinical trial, done in 88 centres in the USA. Adults aged 18-80 years, with treatment-resistant hypertension on stable, maximally tolerated doses of three or more drugs including a diuretic, who had a seated office systolic blood pressure of 160 mm Hg or more and 24 h ambulatory systolic blood pressure of 135 mm Hg or more were randomly assigned (2:1) to receive renal artery denervation using the single electrode (Flex) catheter or a sham control. The original primary endpoint was the change in office systolic blood pressure from baseline to 6 months for the renal artery denervation group compared with the sham control group. Patients were unmasked after the primary endpoint assessment at 6 months, at which point eligible patients in the sham control group who met the inclusion criteria (office blood pressure ≥160 mm Hg, 24 h ambulatory systolic blood pressure ≥135 mm Hg, and still prescribed three or more antihypertensive medications) could cross over to receive renal artery denervation. Changes in blood pressure up to 36 months were analysed in patients in the original renal artery denervation group and sham control group, including those who underwent renal artery denervation after 6 months (crossover group) and those who did not (non-crossover group). For comparisons between the renal artery denervation and sham control groups, follow-up blood pressure values were imputed for patients in the crossover group using their most recent pre-crossover masked blood pressure value. We report long-term blood pressure changes in renal artery denervation and sham control groups, and investigate blood pressure control in both groups using time in therapeutic blood pressure range analysis. The primary safety endpoint was the incidence of all-cause mortality, end stage renal disease, significant embolic event, renal artery perforation or dissection requiring intervention, vascular complications, hospitalisation for hypertensive crisis unrelated to non-adherence to medications, or new renal artery stenosis of more than 70% within 6 months. The trial is registered with ClinicalTrials.gov, NCT01418261.From Sep 29, 2011, to May 6, 2013, 1442 patients were screened, of whom 535 (37%; 210 [39%] women and 325 [61%] men; mean age 57·9 years [SD 10·7]) were randomly assigned: 364 (68%) patients received renal artery denervation (mean age 57·9 years [10·4]) and 171 (32%) received the sham control (mean age 56·2 years [11·2]). 36-month follow-up data were available for 219 patients (original renal artery denervation group), 63 patients (crossover group), and 33 patients (non-crossover group). At 36 months, the change in office systolic blood pressure was -26·4 mm Hg (SD 25·9) in the renal artery denervation group and -5·7 mm Hg (24·4) in the sham control group (adjusted treatment difference -22·1 mm Hg [95% CI -27·2 to -17·0]; p≤0·0001). The change in 24 h ambulatory systolic blood pressure at 36 months was -15·6 mm Hg (SD 20·8) in the renal artery denervation group and -0·3 mm Hg (15·1) in the sham control group (adjusted treatment difference -16·5 mm Hg [95% CI -20·5 to -12·5]; p≤0·0001). Without imputation, the renal artery denervation group spent a significantly longer time in therapeutic blood pressure range (ie, better blood pressure control) than patients in the sham control group (18% [SD 25·0] for the renal artery denervation group vs 9% [SD 18·8] for the sham control group; p≤0·0001) despite a similar medication burden, with consistent and significant results with imputation. Rates of adverse events were similar across treatment groups, with no evidence of late-emerging complications from renal artery denervation. The rate of the composite safety endpoint to 48 months, including all-cause death, new-onset end-stage renal disease, significant embolic event resulting in end-organ damage, vascular complication, renal artery re-intervention, and hypertensive emergency was 15% (54 of 352 patients) for the renal artery denervation group, 14% (13 of 96 patients) for the crossover group, and 14% (10 of 69 patients) for the non-crossover group.This final report of the SYMPLICITY HTN-3 trial adds to the totality of evidence supporting the safety of renal artery denervation to 36 months after the procedure. From 12 months to 36 months after the procedure, patients who were originally randomly assigned to receive renal artery denervation had larger reductions in blood pressure and better blood pressure control compared with patients who received sham control.Medtronic.

A dose reduction imaging paradigm utilizing chest x-ray (CXR) to triage between computed tomography pulmonary angiography (CTPA) and lung scintigraphy (LS) was introduced in 2001 and adopted in 2012 by the American Thoracic Society/Society of Thoracic Radiology (ATS) guideline for the evaluation of pulmonary embolism in pregnancy. We aimed to assess the utilization of this imaging paradigm preadoption and postadoption by the ATS guideline, and identify factors associated with its utilization.This retrospective cohort study evaluated consecutive pregnant patients who received CTPA or LS for the evaluation of pulmonary embolism in pregnancy at 2 tertiary hospitals between September 2008 and March 2017, excluding 2012 for guideline release washout. Utilization of the imaging paradigm was defined per patient by the use of CXR before advanced imaging, with CTPA performed following positive CXR and LS performed following negative CXR. Multivariate analyses were performed to assess factors associated with utilization of the imaging paradigm. P0.05 is considered significant.Overall, 9.8% (63/643) of studies utilized the dose reduction imaging paradigm, 13.3% (34/256) before the guidelines, and 7.5% (29/387) after. Multivariable analysis showed that the dose reduction imaging paradigm utilization was higher for inpatients (odds ratio [OR]: 4.5) and outpatients (OR: 3.1) relative to the emergency department patients, and lower for second (OR: 0.3) and third (OR: 0.2) trimester patients, without significant differences by study priority, patient age, or patient race.Guideline-recommended dose reduction imaging paradigm utilization was low, and decreased after guideline publication. Utilization varied by patient setting and trimester, which are potential targets for interventions to improve guideline compliance.

In May 2022, CDC learned of three children in California hospitalized concurrently for brain abscess, epidural empyema, or subdural empyema caused by Streptococcus intermedius. Discussions with clinicians in multiple states raised concerns about a possible increase in pediatric intracranial infections, particularly those caused by Streptococcus bacteria, during the past year and the possible contributing role of SARS-CoV-2 infection (1). Pediatric bacterial brain abscesses, epidural empyemas, and subdural empyemas, rare complications of respiratory infections and sinusitis, are often caused by Streptococcus species but might also be polymicrobial or caused by other genera, such as Staphylococcus. On June 9, CDC asked clinicians and health departments to report possible cases of these conditions and to submit clinical specimens for laboratory testing. Through collaboration with the Children's Hospital Association (CHA), CDC analyzed nationally representative pediatric hospitalizations for brain abscess and empyema. Hospitalizations declined after the onset of the COVID-19 pandemic in March 2020, increased during summer 2021 to a peak in March 2022, and then declined to baseline levels. After the increase in summer 2021, no evidence of higher levels of intensive care unit (ICU) admission, mortality, genetic relatedness of isolates from different patients, or increased antimicrobial resistance of isolates was observed. The peak in cases in March 2022 was consistent with historical seasonal fluctuations observed since 2016. Based on these findings, initial reports from clinicians (1) are consistent with seasonal fluctuations and a redistribution of cases over time during the COVID-19 pandemic. CDC will continue to work with investigation partners to monitor ongoing trends in pediatric brain abscesses and empyemas.

One strategy to encourage college students to meet physical activity and public health guidelines is the Exercise is Medicine on Campus Initiative (EIM-OC), whose goal is to promote physical activity as a vital health sign within universities. To develop, implement, and evaluate the EIM-OC Initiative, it is critical to understand the mechanics of the program via a logic model.

Studies of the Bronze Age in the ancient world traditionally have focused on mainstream populations, together with their social organization, and the economic subsistence strategies implemented by them. As a result, those people who lived on the edges of society, whether defined geographically, socially, demographically, or economically, have received correspondingly less attention. Yet, peoples on the margins of mainstream populations fulfilled roles integral to the primary economic and social systems in Bronze Age cultures in the ancient Near Eastern and North African world. This concept of marginal and/or liminal groups in the ancient world, the importance of examining them, and different methods of addressing them, are presented here, as the introduction to the collected papers on marginality and liminality in the Bronze Age world of the ancient Near East and North Africa in this special issue of the Journal of Ancient Near Eastern History.

The northern Negev—a region both geographically peripheral and environmentally marginal for human habitation—experienced increased settlement and activity in the Intermediate Bronze Age in the southern Levant (ca. 2500–2000/1950 BCE). Most interpretations link this phenomenon with Egyptian demand for copper and the accompanying development of trade networks that transported this valuable resource. However, the function of these networks, the subsistence of the peoples who operated them, and the social and economic systems that supported them remain unclear. This paper examines the means of subsistence and sustenance of the populations of these sites in the northern Negev, together with their role in supporting connections between Egypt and the southern Levant, and suggests that while their location may have been marginal, their identity and role in the social and economic system of the Intermediate Bronze Age southern Levant was not.

To investigate the association between assisted reproductive technology (ART) use and childhood cancer subtype.We deployed a cross-sectional survey of 1701 parents of children with cancer about their ART use, demographics, and gestational and perinatal factors. Multivariable logistic regression modeled the association between ART use, birthweight and multiple gestation status with childhood cancer, by subtype.ART use was highest among children with osteosarcoma relative to children with other cancer types, and this association was statistically significant in multivariable models (OR = 4.4; 95% CI = 1.7-11.3; p = 0.0020). ART use was also elevated among children with hepatoblastoma, but this relationship appeared to be due to the strong associations between ART use and lower birthweight in our sample. No specific ART modality appeared to drive these associations. In univariate models, multiple gestation was associated with a 2.7-fold increased odds of hepatoblastoma (OR = 2.71; 95% CI = 1.14-6.42; p = 0.02) and a 1.6-fold increased odds of neuroblastoma (OR = 1.62; 95% CI = 1.03-2.54; p = 0.03), but these associations were not retained in multivariable models.Associations between ART use and hepatoblastoma risk may be attributable to birthweight, a known hepatoblastoma risk factor. ART use may also be associated with osteosarcoma, independent of birthweight, an association not previously observed in studies limited to cancers diagnosed before adolescence. Evaluating long-term health outcomes in children conceived by ART, throughout adolescence and potentially into adulthood, appears warranted.

Background and Aims Integrated IBD care is effective but not routinely implemented. Validated methods that simultaneously address mind and body targets such as resilience may improve access and outcomes. We describe the development and implementation of the GRITTTM Method and its impact on resilience, health care resource utilization (HCRU) and opioid use in IBD. Methods Consecutive patients from an academic IBD center were evaluated for low resilience based on provider referral. Low resilience patients were invited to participate in the GRITTTM program. Primary outcome was % reduction in HCU. Secondary outcomes were change in resilience, corticosteroid and opioid use. Patients were allocated into 2 groups for analysis: GRITT Participants (GP) and Non-Participants (NP). Clinical data and HCU in the year prior to enrollment were collected at baseline and 12 months. One-way repeated measures MANCOVA evaluated group X time interactions for the primary outcome. Effect size was calculated for changes in resilience over time. Results Of 456 screened IBD patients 394 were eligible; 184 GP and 210 NP. GP had greater reduction in HCU than NP: 71% reduction in ED visits; 94% reduction in unplanned hospitalizations. There was a 49% reduction in opioid use and 73% reduction in corticosteroid use in GP. Resilience increased by 27.3 points (59%), yielding a large effect size (d=2.4). Conclusion Mind-body care that focuses on building resilience in the context of IBD care may be a novel approach to reduce unplanned health care utilization and opioid use but large, multi-center, randomized, controlled trials are needed.

This chapter synthesizes research on the influence of parasocial experiences in audience health-related perceptions and behavior. Exposure to health messages may be part of routine media use or result from active seeking of health-related information and guidance. Drawing on research in the domains of entertainment–education, media figure health events, and strategic health messaging, this review discusses theoretical mechanisms of parasocial influence on health outcomes, including message salience and issue involvement, diffusion, modeling, overcoming resistance, social norms, and source credibility. After reviewing research on specific health outcomes (including physical disease awareness, prevention, and treatment; mental health/mental illness; everyday health behaviors; social connection and well-being; and public health outcomes), the chapter concludes with recommendations for future research.

This chapter reviews existing research on how mediated contact with media figures (e.g., celebrities, fictional characters, public figures, and others) can affect intergroup relations. The review is organized around two parasocial experiences through which mediated intergroup encounters with media figures are theorized to affect audience prejudice: parasocial contact and vicarious contact. The chapter concludes with several recommendations for advancing theory and research on media figure intergroup contact effects and understanding how intergroup media figure involvement can be most advantageous for members of marginalized social groups. Moving forward, any theorizing of media figure contact effects should be not only comprehensive enough to explain how diverse groups of people respond to different media figures, but also just enough to inform and promote social change that is beneficial to the groups that have been most victimized by the prejudices that intergroup contact theory has always sought to remedy.

The presence of amyloid kuru plaques is a pathological hallmark of sporadic Creutzfeldt–Jakob disease (sCJD) of the MV2K subtype. Recently, PrP plaques (p) have been described in the white matter of a small group of CJD (p-CJD) cases with the 129MM genotype and carrying resPrPD type 1 (T1). Despite the different histopathological phenotype, the gel mobility and molecular features of p-CJD resPrPD T1 mimic those of sCJDMM1, the most common human prion disease. Here, we describe the clinical features, histopathology, and molecular properties of two distinct PrP plaque phenotypes affecting the gray matter (pGM) or the white matter (pWM) of sCJD cases with the PrP 129MM genotype (sCJDMM). Prevalence of pGM- and pWM-CJD proved comparable and was estimated to be ~ 0.6% among sporadic prion diseases and ~ 1.1% among the sCJDMM group. Mean age at onset (61 and 68 years) and disease duration (~ 7 months) of pWM- and pGM-CJD did not differ significantly. PrP plaques were mostly confined to the cerebellar cortex in pGM-CJD, but were ubiquitous in pWM-CJD. Typing of resPrPD T1 showed an unglycosylated fragment of ~ 20 kDa (T120) in pGM-CJD and sCJDMM1 patients, while a doublet of ~ 21–20 kDa (T121−20) was a molecular signature of pWM-CJD in subcortical regions. In addition, conformational characteristics of pWM-CJD resPrPD T1 differed from those of pGM-CJD and sCJDMM1. Inoculation of pWM-CJD and sCJDMM1 brain extracts to transgenic mice expressing human PrP reproduced the histotype with PrP plaques only in mice challenged with pWM-CJD. Furthermore, T120 of pWM-CJD, but not T121, was propagated in mice. These data suggest that T121 and T120 of pWM-CJD, and T120 of sCJDMM1 are distinct prion strains. Further studies are required to shed light on the etiology of p-CJD cases, particularly those of T120 of the novel pGM-CJD subtype.

IntroductionThe detection of respiratory syncytial virus (RSV) in upper airway samples does not necessarily infer causality of illness. Calculating the attributable fraction (AF) of RSV in clinical syndromes could refine disease burden estimates.MethodsUsing unconditional logistic regression models, we estimated the AF of RSV-associated influenza-like illness (ILI) and severe-acute respiratory illness (SARI) cases by comparing RSV-detection prevalence among ILI and SARI cases to those of healthy controls in South Africa, 2012-2016. The analysis, stratified by HIV serostatus, was conducted in the age categories ResultsWe included 12,048 individuals: 2,687 controls, 5,449 ILI cases and 5,449 SARI cases. RSV-AFs for ILI were significant in ConclusionHigh RSV-AFs in young children confirm RSV detection is associated severe respiratory illness in South African children, specifically infants. These estimates will assist with refining burden estimates and cost effectiveness models.Key pointThe attributable fraction of illness is key to accurate burden estimates, specifically in the presents of sensitive PCR testing. Burden and cost burden estimates are key to cost-effectiveness model for new prevention technologies in the pipeline for respiratory syncytial virus.