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Every research study that includes volunteer participants requires safety assurances in proportion to the risks of the study. Investigator-initiated clinical research can present unique regulatory challenges particularly for studies with a risk profile that warrants more oversight than minimal risk but less than for large, commercial, or high-risk research. The use of an independent safety officer (ISO) offers a middle way of right-sizing oversight to match the risk. ISOs are clinicians or researchers with relevant expertise who are independent of the investigator and the research study. Their relationship to the study is defined by a formal charter which is aligned with the protocol and Data and Safety Monitoring Plan to address the oversight process, responsibilities of the ISO, and clearly describe the variables to be monitored. The ISO responsibilities include reviewing safety data, adverse events, recruitment, demographics, study progress, data quality, protocol changes, and any new scientific information that pertains to the trial. Finally, the ISO reports in their review on any significant findings may propose modifications to the study or a need to stop the trial.
Antimicrobial stewardship programs typically use days of therapy to assess antimicrobial use. However, this metric does not account for the antimicrobial spectrum of activity. We applied an antibiotic spectrum index to a population of very-low-birth-weight infants to assess its utility to evaluate the impact of antimicrobial stewardship interventions.
To assess the safety of, and subsequent allergy documentation associated with, an antimicrobial stewardship intervention consisting of test-dose challenge procedures prompted by an electronic guideline for hospitalized patients with reported β-lactam allergies.
Retrospective cohort study.
Large healthcare system consisting of 2 academic and 3 community acute-care hospitals between April 2016 and December 2017.
We evaluated β-lactam antibiotic test-dose outcomes, including adverse drug reactions (ADRs), hypersensitivity reactions (HSRs), and electronic health record (EHR) allergy record updates. HSR predictors were examined using a multivariable logistic regression model. Modification of the EHR allergy record after test doses considered relevant allergy entries added, deleted, and/or specified.
We identified 1,046 test-doses: 809 (77%) to cephalosporins, 148 (14%) to penicillins, and 89 (9%) to carbapenems. Overall, 78 patients (7.5%; 95% confidence interval [CI], 5.9%–9.2%) had signs or symptoms of an ADR, and 40 (3.8%; 95% CI, 2.8%–5.2%) had confirmed HSRs. Most HSRs occurred at the second (ie, full-dose) step (68%) and required no treatment beyond drug discontinuation (58%); 3 HSR patients were treated with intramuscular epinephrine. Reported cephalosporin allergy history was associated with an increased odds of HSR (odds ratio [OR], 2.96; 95% CI, 1.34–6.58). Allergies were updated for 474 patients (45%), with records specified (82%), deleted (16%), and added (8%).
This antimicrobial stewardship intervention using β-lactam test-dose procedures was safe. Overall, 3.8% of patients with β-lactam allergy histories had an HSR; cephalosporin allergy histories conferred a 3-fold increased risk. Encouraging EHR documentation might improve this safe, effective, and practical acute-care antibiotic stewardship tool.
Prior research has established associations between neighbourhood poverty and cumulative biological risk (CBR). CBR is conceptualized as indicative of the effects of stress on biological functioning, and is linked with increased morbidity and mortality. Studies suggest that supportive social relationships may be health protective, and may erode under conditions of poverty. This study examines whether social relationships are inversely associated with CBR and whether associations between neighbourhood poverty and CBR are mediated through social relationships. Data were from a stratified probability sample community survey (n=919) of residents of Detroit, Michigan, USA (2002–2003) and from the 2000 US Census. The outcome variable, CBR, included anthropometric and clinical measures. Independent variables included four indicators of social relationships: social support, neighbourhood satisfaction, social cohesion and neighbourhood participation. Multilevel models were used to test both research questions, with neighbourhood poverty and social relationships included at the block group level, and social relationships also included at the individual level, to disentangle individual from neighbourhood effects. Findings suggest some associations between social relationships and CBR after accounting for neighbourhood poverty and individual characteristics. In models that accounted for all indicators of social relationships, individual-level social support was associated with greater CBR (β=0.12, p=0.04), while neighbourhood-level social support was marginally significantly protective of CBR (within-neighbourhood: β=−0.36, p=0.06; between-neighbourhood: β=−0.24, p=0.06). In contrast, individual-level neighbourhood satisfaction was protective of CBR (β=−0.10, p=0.02), with no within-neighbourhood (β=0.06, p=0.54) or between-neighbourhood association (β=−0.04, p=0.38). Results indicate no significant association between either social cohesion or neighbourhood participation and CBR. Associations between neighbourhood poverty and CBR were not mediated by social relationships. These findings suggest that neighbourhood-level social support and individual-level neighbourhood satisfaction may be health protective and that neighbourhood poverty, social support and neighbourhood satisfaction are associated with CBR through independent pathways.
A major challenge for scholars seeking new directions in sociolegal research is the persistence of old paradigms and assumptions about law. The challenge for the new is not to be cast as part of the old by efforts that assimilate its methods, goals, and results to earlier approaches. Such efforts, aimed at comparison and clarification, tend to “domesticate” the new, or in Boa Santos's words “doubly institutionalize” a developing project by reading the order of a conventional analysis into the emergent order appearing in the interstices of new scholarly work. In this essay we focus on interpretivism as a developing project in sociolegal research. In particular, we discuss three aspects of interpretive research that are at the center of current debates in sociolegal theory: meaning construction and the dynamics of power, legal ideology, and knowledge as politics. Our discussion focuses on different readings of ideology, on different understandings of power, and on the politics of interpretive research connected with these readings. To illuminate the struggles over these points and at the same time illustrate the process of domestication, we begin with a recent paper by David Trubek and John Esser, “‘Critical Empiricism’ in American Legal Studies.” Their paper lays out a treatment of ideology and politics that provides a basis for our broader discussion of interpretive work in the second half of this essay.
Born in 1960 with the publication of Philippe Ariès's L'enfant et la vie familiale, family history as we know it has been tremendously fertile. Although the succession is disputed, its progeny are legion. It is not my intention here to trace the complex genealogy of Ariès's descendants or to separate dutiful heirs from rebels who have renounced their patrimony. The family tree is too prolific, its internal divisions too complex. I hope rather to focus on two main themes in the history of the family, themes which seem to me particularly fruitful where our understanding of the Renaissance is concerned. The first theme involves the fundamental structures of family life— ties of kinship and patterns of residence. The second is marriage and the role of women in the family. In both cases, I am particularly interested in the cultural values represented by these structures and behaviors.
Determining the predictors of serum retinol at mid-pregnancy is relevant for planning interventions aimed at improving vitamin A status of pregnant women and their offspring. This prospective study assessed predictors of serum retinol at the beginning of the third trimester of pregnancy. We enrolled 442 pregnant women living in the urban area of Cruzeiro do Sul, Western Brazilian Amazon. Demographic, socio-economic, environmental and clinical characteristics as well as obstetric history, anthropometric, dietary and biochemical data, including serum retinol, were gathered between 16 and 20 gestational weeks. Serum retinol also measured at the beginning of the third trimester of pregnancy (approximately 28 gestational weeks) was the outcome of interest. Multiple linear regression models were used to evaluate associations with the outcome. Overall, the following variables explained serum retinol at the beginning of the third trimester of pregnancy in the adjusted model (R2 = 11·1 %): seasonality (winter season – November to April; β=0·134; 95 % CI 0·063, 0·206), weekly consumption of Amazonian fruits (β=0·087; 95 % CI 0·012, 0·162) and retinol concentrations between 16 and 20 gestational weeks (β=0·045; 95 % CI 0·016, 0·074) were positively associated, whereas having a smoker in the house was negatively associated (β=–0·087; 95 % CI: –0·166, –0·009). Consumption of pro-vitamin A-rich fruits by pregnant women should be encouraged. Passive smoking may play a role in decreasing vitamin A status as a proxy of smoking exposure during pregnancy.
During vocalization, efference copy/corollary discharge mechanisms suppress the auditory cortical response to self-generated sounds. Previously, we found attenuated vocalization-related auditory cortical suppression in psychosis and a similar trend in the psychosis risk syndrome. Here, we report data from the final sample of early illness schizophrenia patients (ESZ), individuals at clinical high risk for psychosis (CHR), and healthy controls (HC).
Event-related potentials (ERP) were recorded from ESZ (n = 84), CHR (n = 71), and HC (n = 103) participants during a vocalization paradigm. The N1 ERP component was elicited during production (Talk) and playback (Listen) of vocalization. Age effects on N1 suppression (Talk–Listen), Talk N1, and Listen N1 were compared across groups. N1 measures were adjusted for normal aging before testing for group differences.
Both ESZ and CHR groups showed reduced Talk–Listen N1 suppression relative to HC, but did not differ from each other. Listen N1 was reduced in ESZ, but not in CHR, relative to HC. Deficient Talk–Listen N1 suppression was associated with greater unusual thought content in CHR individuals. N1 suppression increased with age in HC (12–36 years), and while CHR individuals showed a similar age-related increase, no such relationship was evident in ESZ.
Putative efference copy/corollary discharge-mediated auditory cortical suppression during vocalization is deficient in ESZ and precedes psychosis onset, particularly in CHR individuals with greater unusual thought content. Furthermore, this suppression increases from adolescence through early adulthood, likely reflecting the effects of normal brain maturation. This maturation effect is disrupted in ESZ, presumably due to countervailing illness effects.
Attention-deficit hyperactivity disorder (ADHD) and anxiety disorders have been proposed as precursors of bipolar disorder, but their joint and relative roles in the development of bipolar disorder are unknown.
To test the prospective relationship of ADHD and anxiety with onset of bipolar disorder.
We examined the relationship between ADHD, anxiety disorders and bipolar disorder in a birth cohort of 2 409 236 individuals born in Denmark between 1955 and 1991. Individuals were followed from their sixteenth birthday or from January 1995 to their first clinical contact for bipolar disorder or until December 2012. We calculated incidence rates per 10 000 person-years and tested the effects of prior diagnoses on the risk of bipolar disorder in survival models.
Over 37 394 865 person-years follow-up, 9250 onsets of bipolar disorder occurred. The incidence rate of bipolar disorder was 2.17 (95% CI 2.12–2.19) in individuals with no prior diagnosis of ADHD or anxiety, 23.86 (95% CI 19.98–27.75) in individuals with a prior diagnosis of ADHD only, 26.05 (95% CI 24.47–27.62) in individuals with a prior diagnosis of anxiety only and 66.16 (95% CI 44.83–87.47) in those with prior diagnoses of both ADHD and anxiety. The combination of ADHD and anxiety increased the risk of bipolar disorder 30-fold (95% CI 21.66–41.40) compared with those with no prior ADHD or anxiety.
Early manifestations of both internalising and externalising psychopathology indicate liability to bipolar disorder. The combination of ADHD and anxiety is associated with a very high risk of bipolar disorder.
Purpose: We identified key clinicopathologic features of brain metastasis (BM) patients who are long-term survivors (LTS). Methods: We screened a prospective database of 1892 patients (treated 2006-2017), identified 92 (5%) who lived > 3 years following BM diagnosis, and performed per patient analyses. Results: Median age at diagnosis of BM was 57 years (range 19-77), 77% were women. The most common tumors were lung (50%), breast (26%), thyroid (7%) and skin (5%). 42% had tumors with drug-targetable oncoproteins (e.g. EGFR mutant) and 15% expressed hormonal receptors. ECOG was <2 in 70%. 47% had stage IV disease at diagnosis (75% with brain as the first site). 55% had controlled extracranial disease at the time of BM diagnosis. Median BM diameter was 1.5 cm (range 0.2-7) and 62% had a single lesion. Treatment was with surgery, radiosurgery, whole brain radiation (WBRT), or systemic therapy alone in 38%, 62%, 52%, and 4%, respectively. 53% received targeted- or immuno-therapy. Median follow up was 63 months (range 36-113). 61% failed intracranially at a median 24 months (range 1-99). 5 and 10- year survival (from BM diagnosis) was 82%, and 34%, respectively. Neither upfront WBRT nor other variables tested correlated with improved survival. In patients who died, an MRI was available within 3 months from death in 57%; of those 55% had no active intracranial disease, suggesting that the majority of deaths were non-neurologic. Conclusion: In general, LTS of BM had a limited number of BM, inactive extracranial disease, and drug targetable mutations.
Objectives: Glioblastoma is a lethal disease in the elderly population. We aimed to evaluate disease and treatment outcomes in the oldest-old patients. Methods: Patients >80 years old with histologically confirmed glioblastoma treated between 2004 and 2009 were identified. We included patients managed with best supportive care (BSC), temozolomide (TMZ) alone, radiotherapy (RT) alone, or concomitantly with TMZ (CRT). Survival outcomes were analyzed using the Kaplan–Meier method. Results: Ultimately, 48 patients were analyzed. Median age and Eastern Cooperative Oncology Group (ECOG) Performance Status were 82 years and 2, respectively. The median Age-Adjusted Charlson Index (AAC) was 6. Gross total and subtotal resections were performed in 16.7% and 18.8% of patients, respectively. Biopsy followed by RT alone was the treatment modality for 23/48 (47.9%), while 17/48 (35.4%) received surgery followed by RT alone or CRT. A total of 8 (16.7%) were managed with BSC after biopsy. Median overall survival (OS) and progression-free survival (PFS) were 4.1 (95% confidence interval [95% CI] 3.3-4.9) and 2.7 (95% CI 1.5-3.9) months, respectively. Improved median OS was observed in those treated with surgical resection followed by RT alone or CRT (7.1 months), compared to biopsy followed by RT alone (4.2 months) or BSC (2.0 months; p=0.002). Surgical resection, age≤85, and AAC<6 were associated with better OS (p=0.032, p=0.031, and p=0.02, respectively). Cause of death was neurological progression in 56% of cases. RT was well-tolerated. Conclusions: PFS and OS outcomes remain poor in the oldest-old patients (>80 years old). Younger age, lower AAC, surgical resection, and adjuvant treatment were associated with improved OS.