There is no significant difference between transperineal and transrectal biopsy infection rates without and with targeted antibiotic prophylaxis, respectively. The cancer detection rates were ...similar. Transperineal biopsy was associated with slightly more pain, but it improves antibiotic stewardship.
The transrectal biopsy approach is traditionally used to detect prostate cancer. An alternative transperineal approach is historically performed under general anesthesia, but recent advances enable transperineal biopsy to be performed under local anesthesia. We sought to compare infectious complications of transperineal biopsy without antibiotic prophylaxis versus transrectal biopsy with targeted prophylaxis.
We assigned biopsy-naïve participants to undergo transperineal biopsy without antibiotic prophylaxis versus transrectal biopsy with targeted prophylaxis (rectal culture screening for fluoroquinolone-resistant bacteria and antibiotic targeting to culture and sensitivity results) through a multicenter, randomized trial. The primary outcome was post-biopsy infection captured by a prospective medical review and patient report on a 7-d survey. The secondary outcomes included cancer detection, noninfectious complications, and a numerical rating scale (0–10) for biopsy-related pain and discomfort during and 7-d after biopsy.
A total of 658 participants were randomized, with zero transperineal versus four (1.4%) transrectal biopsy infections (difference –1.4%; 95% confidence interval CI –3.2%, 0.3%; p = 0.059). The rates of other complications were very low and similar. Importantly, detection of clinically significant cancer was similar (53% transperineal vs 50% transrectal, adjusted difference 2.0%; 95% CI –6.0, 10). Participants in the transperineal arm experienced worse periprocedural pain (0.6 adjusted difference 0–10 scale, 95% CI 0.2, 0.9), but the effect was small and resolved by 7-d.
Office-based transperineal biopsy is tolerable, does not compromise cancer detection, and did not result in infectious complications. Transrectal biopsy with targeted prophylaxis achieved similar infection rates, but requires rectal cultures and careful attention to antibiotic selection and administration. Consideration of these factors and antibiotic stewardship should guide clinical decision-making.
In this multicenter randomized trial, we compare prostate biopsy infectious complications for the transperineal versus transrectal approach. The absence of infectious complications with transperineal biopsy without the use of preventative antibiotics is noteworthy, but not significantly different from transrectal biopsy with targeted antibiotic prophylaxis.
Gene regulatory networks underlie the long-term changes in cell specification, growth of synaptic connections, and adaptation that occur throughout neonatal and postnatal life. Here we show that the ...transcriptional response in neurons is exquisitely sensitive to the temporal nature of action potential firing patterns. Neurons were electrically stimulated with the same number of action potentials, but with different inter-burst intervals. We found that these subtle alterations in the timing of action potential firing differentially regulates hundreds of genes, across many functional categories, through the activation or repression of distinct transcriptional networks. Our results demonstrate that the transcriptional response in neurons to environmental stimuli, coded in the pattern of action potential firing, can be very sensitive to the temporal nature of action potential delivery rather than the intensity of stimulation or the total number of action potentials delivered. These data identify temporal kinetics of action potential firing as critical components regulating intracellular signalling pathways and gene expression in neurons to extracellular cues during early development and throughout life.
Small but timely experiences can have long-term benefits when their psychological effects interact with institutional processes. In a followup of two randomized field experiments, a brief values ...affirmation intervention designed to buffer minority middle schoolers against the threat of negative stereotypes had long-term benefits on collegerelevant outcomes. In study 1, conducted in the Mountain West, the intervention increased Latino Americans’ probability of entering a college readiness track rather than a remedial one near the transition to high school 2 y later. In study 2, conducted in the Northeast, the intervention increased African Americans’ probability of college enrollment 7–9 y later. Among those who enrolled in college, affirmed African Americans attended relatively more selective colleges. Lifting a psychological barrier at a key transition can facilitate students’ access to positive institutional channels, giving rise to accumulative benefits.
Clinicians often risk stratify young febrile infants for invasive bacterial infections (IBIs), defined as bacteremia and/or bacterial meningitis, using complete blood cell count parameters.
To ...estimate the accuracy of individual complete blood cell count parameters to identify febrile infants with IBIs.
Planned secondary analysis of a prospective observational cohort study comprising 26 emergency departments in the Pediatric Emergency Care Applied Research Network from 2008 to 2013. We included febrile (≥38°C), previously healthy, full-term infants younger than 60 days for whom blood cultures were obtained. All infants had either cerebrospinal fluid cultures or 7-day follow-up.
We tested the accuracy of the white blood cell count, absolute neutrophil count, and platelet count at commonly used thresholds for IBIs. We determined optimal thresholds using receiver operating characteristic curves.
Of 4313 enrolled infants, 1340 (31%; 95% CI, 30% to 32%) were aged 0 to 28 days, 2412 were boys (56%), and 2471 were white (57%). Ninety-seven (2.2%; 95% CI, 1.8% to 2.7%) had IBIs. Sensitivities were low for common complete blood cell count parameter thresholds: white blood cell count less than 5000/µL, 10% (95% CI, 4% to 16%) (to convert to 109 per liter, multiply by 0.001); white blood cell count ≥15 000/µL, 27% (95% CI, 18% to 36%); absolute neutrophil count ≥10 000/µL, 18% (95% CI, 10% to 25%) (to convert to × 109 per liter, multiply by 0.001); and platelets <100 × 103/µL, 7% (95% CI, 2% to 12%) (to convert to × 109 per liter, multiply by 1). Optimal thresholds for white blood cell count (11 600/µL), absolute neutrophil count (4100/µL), and platelet count (362 × 103/µL) were identified in models that had areas under the receiver operating characteristic curves of 0.57 (95% CI, 0.50-0.63), 0.70 (95% CI, 0.64-0.76), and 0.61 (95% CI, 0.55-0.67), respectively.
No complete blood cell count parameter at commonly used or optimal thresholds identified febrile infants 60 days or younger with IBIs with high accuracy. Better diagnostic tools are needed to risk stratify young febrile infants for IBIs.
Traumatic brain injury (TBI) is associated with chronic sleep disturbances and cognitive impairment. Our prior preclinical work demonstrated dietary supplementation with branched chain amino acids ...(BCAA: leucine, isoleucine, and valine), precursors to
glutamate production, restored impairments in glutamate, orexin/hypocretin neurons, sleep, and memory in rodent models of TBI. This pilot study assessed the feasibility and preliminary efficacy of dietary supplementation with BCAA on sleep and cognition in Veterans with TBI.
Thirty-two Veterans with TBI were prospectively enrolled in a randomized, double-blinded, placebo-controlled trial comparing BCAA (30 g, b.i.d. for 21-days) with one of two placebo arms (microcrystalline cellulose or rice protein, both 30 g, b.i.d. for 21-days). Pre- and post-intervention outcomes included sleep measures (questionnaires, daily sleep/study diaries, and wrist actigraphy), neuropsychological testing, and blood-based biomarkers related to BCAA consumption.
Six subjects withdrew from the study (2/group), leaving 26 remaining subjects who were highly adherent to the protocol (BCAA, 93%; rice protein, 96%; microcrystalline, 95%; actigraphy 87%). BCAA were well-tolerated with few side effects and no adverse events. BCAA significantly improved subjective insomnia symptoms and objective sleep latency and wake after sleep onset on actigraphy.
Dietary supplementation with BCAA is a mechanism-based, promising intervention that shows feasibility, acceptability, and preliminary efficacy to treat insomnia and objective sleep disruption in Veterans with TBI. A larger scale randomized clinical trial is warranted to further evaluate the efficacy, dosing, and duration of BCAA effects on sleep and other related outcome measures in individuals with TBI.
http://clinicaltrials.gov/, identifier NCT03990909.
High rates of discipline citations predict adverse life outcomes, a harm disproportionately borne by Black and Latino boys. We hypothesized that these citations arise in part from negative cycles of ...interaction between students and teachers, which unfold in contexts of social stereotypes. Can targeted interventions to facilitate identity safety-a sense of belonging, inclusion, and growth-for students help? Experiment 1 combined social-belonging, values-affirmation, and growth-mindset interventions delivered in several class sessions in 2 middle schools with a large Latino population (N = 669). This treatment reduced citations among negatively stereotyped boys in 7th and 8th grades by 57% as compared with a randomized control condition, 95% CI −77%, −20%. A growth-mindset only treatment was also effective (70% reduction, 95% CI −84%, −43%). Experiment 2 tested the social-belonging intervention alone, a grade earlier, at a third school with a large Black population and more overall citations (N = 137 sixth-grade students). In 2 class sessions, students reflected on stories from previous 7th-grade students, which represented worries about belonging and relationships with teachers early in middle school as normal and as improving with time. This exercise reduced citations among Black boys through the end of high school by 65%, 95% CI −85%, −15%, closing the disparity with White boys over 7 years by 75%. Suggesting improved interactions with teachers, longitudinal analyses found that the intervention prevented rises in citations involving subjective judgments (e.g., "insubordination") within 6th and 7th grades. It also forestalled the emergence of worries about being seen stereotypically by the end of 7th grade. Identity threat can give rise to cycles of interaction that are maladaptive for both teachers and students in school; targeted exercises can interrupt these cycles to improve disciplinary outcomes over years.
Ongoing neuronal activity during development and plasticity acts to refine synaptic connections and contributes to the induction of plasticity and ultimately long-term memory storage. ...Activity-dependent, post-transcriptional control of mRNAs occurs through transport to axonal and dendritic compartments, local translation and mRNA stability. We have identified a mechanism that contributes to activity-dependent regulation of mRNA stability during synaptic plasticity in rat hippocampal neurons. In this study, we demonstrate rapid, post-transcriptional control over process-enriched mRNAs by neuronal activity. Systematic analysis of the 3′-UTRs of destabilized transcripts, identifies enrichment in sequence motifs corresponding to microRNA (miRNA)-binding sites. The miRNAs that were identified, miR-326-3p/miR-330-5p, miR-485-5p, miR-666-3p and miR-761 are predicted to regulate networks of genes important in plasticity and development. We find that these miRNAs are developmentally regulated in the hippocampus, many increasing by postnatal day 14. We further find that miR-485-5p controls NGF-induced neurite outgrowth in PC12 cells, tau expression and axonal development in hippocampal neurons. miRNAs can function at the synapse to rapidly control and affect short- and long-term changes at the synapse. These processes likely occur during refinement of synaptic connections and contribute to the induction of plasticity and learning and memory.
Students from lower socioeconomic status (SES) backgrounds can experience stigma in undergraduate educational settings but little research on this topic has been conducted at the PhD level. Lower‐SES ...PhD students may feel lower levels of social integration as they experience incidents of interpersonal disconnection from others inside and outside of academia. Interpersonal disconnection may be a mechanism by which lower‐SES leads to a lower sense of social integration. In this prospective study of first‐year PhD students at three North American universities (N = 608), we assessed students’ perceived social integration and their interpersonal perceptions inside and outside of academia 2–8 times throughout their first year of graduate school. Relative to higher‐SES students, lower‐SES students perceived lower levels of social integration. They had difficulty making academic friends, felt dissimilar to their academic peers, and perceived a lack of understanding about their work in graduate school from non‐academic families and friends. They also lost non‐academic social ties. These interpersonal disconnections prospectively mediated the association between lower SES and lower levels of perceived social integration. Lower‐SES PhD students are at risk of impaired interpersonal relationships. Institutional policies to promote social connections among PhD students may help lower‐SES students integrate into academia.
Purpose
Patients with locally advanced grade 2–3 extremity/truncal soft tissue sarcomas (STS) are at high risk of recurrence. The objective of this study was to assess the efficacy and feasibility of ...neoadjuvant concurrent chemoradiotherapy (cCRT) in selected grade 2–3 patients with limb or trunk wall STS, and to compare this schedule to a sequential approach combining neoadjuvant chemotherapy and adjuvant radiotherapy.
Methods
We retrospectively included patients who underwent neoadjuvant cCRT at two comprehensive cancer centers from 1992–2016. We then compared these results to those of patients treated with preoperative chemotherapy and postoperative radiotherapy from a third comprehensive cancer center with a propensity score matched analysis.
Results
A total of 53 patients were treated by neoadjuvant cCRT; 58 patients could be matched with 29 patients in each treatment group after propensity score matching. Disease-free survival and overall survival at 5 years were 54.9 and 63.5%, respectively with neoadjuvant cCRT, with no significant difference when compared to the sequential treatment group. R0 resection rate was higher (90.9 vs 44.8%,
p
< 0.01) in the cCRT group than in the sequential treatment group during a shorter therapeutic sequence (118 vs 210.5 days,
p
< 0.01), with no impact on the surgical procedure or postoperative complications.
Conclusion
cCRT is feasible with acceptable immediate and late toxicities. It could facilitate surgery by increasing the R0 resection rate and improve patient compliance by shortening the therapeutic sequence.
SLAMF6 is a homotypic receptor of the Ig-superfamily whose exact role in immune modulation has remained elusive. Its constitutive expression on resting and activated T cells precludes it from being a
...exhaustion marker. By breeding Pmel-1 mice with SLAMF6 -/- mice, we generated donors for T cells lacking SLAMF6 and expressing a transgenic TCR for gp100-melanoma antigen. Activated Pmel-1xSLAMF6 -/- CD8+ T cells displayed improved polyfunctionality and strong tumor cytolysis. T-bet was the dominant transcription factor in Pmel-1 x SLAMF6 -/- cells, and upon activation, they acquired an effector-memory phenotype. Adoptive transfer of Pmel-1 x SLAMF6 -/- T cells to melanoma-bearing mice resulted in lasting tumor regression in contrast to temporary responses achieved with Pmel-1 T cells. LAG-3 expression was elevated in the SLAMF6 -/- cells, and the addition of the LAG-3-blocking antibody to the adoptive transfer protocol improved the SLAMF6 -/- T cells and expedited the antitumor response even further. The results from this study support the notion that SLAMF6 is an inhibitory immune receptor whose absence enables powerful CD8+ T cells to eradicate tumors.