Mapping the genetic landscape establishing a tumor immune microenvironment favorable for anti-PD-1 response in mice and humans.

Identifying host genetic factors modulating immune checkpoint inhibitor (ICI) efficacy has been experimentally challenging because of variations in both host and tumor genomes, differences in the microbiome, and patient life exposures. Utilizing the Collaborative Cross (CC) multi-parent mouse genetic resource population, we developed an approach that fixes the tumor genomic configuration while varying host genetics. With this approach, we discovered that response to anti-PD-1 (aPD1) immunotherapy was significantly heritable in four distinct murine tumor models (H2 between 0.18-0.40). For the MC38 colorectal carcinoma system (H2 = 0.40), we mapped four significant ICI response quantitative trait loci (QTL) localized to mouse chromosomes (mChr) 5, 9, 15 and 17, and identified significant epistatic interactions between specific QTL pairs. Differentially expressed genes within these QTL were highly enriched for immune genes and pathways mediating allograft rejection and graft vs host disease. Using a cross species analytical approach, we found a core network of 48 genes within the four QTLs that showed significant prognostic value for overall survival in aPD1 treated human cohorts that outperformed all other existing validated immunotherapy biomarkers, especially in human tumors of the previously defined immune subtype 4. Functional blockade of two top candidate immune targets within the 48 gene network, GM-CSF and high affinity IL-2/IL-15 signaling, completely abrogated the MC38 tumor transcriptional response to aPD1 therapy in vivo. Thus, we have established a powerful cross species in vivo platform capable of uncovering host genetic factors that establish the tumor immune microenvironment configuration propitious for ICI response.

Transperineal Versus Transrectal Magnetic Resonance Imaging-targeted and Systematic Prostate Biopsy to Prevent Infectious Complications: The PREVENT Randomized Trial.

BACKGROUND AND OBJECTIVE: 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. METHODS: 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. KEY FINDINGS AND LIMITATIONS: 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. CONCLUSIONS AND CLINICAL IMPLICATIONS: 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. PATIENT SUMMARY: 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.

Evaluating the Proportion of Low-Value Blood Cultures Obtained in a Pediatric Emergency Department.

BACKGROUND: Existing literature suggests that for some pediatric conditions, blood cultures may be of low value in specific clinical circumstances. The goals of our study were to: 1) identify common pediatric illnesses and define criteria for low-value blood cultures in children aged from 91 days to 19 years, 2) apply these criteria retrospectively to identify the patients in our emergency department (ED) who had low-value blood cultures obtained, and 3) describe this cohort and assess the proportion of true bacteremia in low-value blood cultures. METHOD: The study team reviewed the literature and developed consensus criteria to identify conditions in which blood cultures were of low value for our study population. The criteria were applied retrospectively to well-appearing patients aged from 91 days to 19 years, without a central venous catheter, and evaluated in our ED with a peripheral blood culture from June 2018 to April 2020. Children admitted to the intensive care/hematology-oncology/cardiology/pulmonary units, those transferred from our ED to an outside facility, who transferred to our ED due to a positive blood culture from an outside facility, and repeat visits of a patient within 30 days from a previous visit were excluded from the study. After chart review, children with fever for 7 days or more, who were unvaccinated, immunosuppressed, had implanted devices, had a complex medical history, or had provider concerns for bacteremia/sepsis were excluded. RESULTS: The study population consisted of 1436 children. Children at risk for bacteremia (n = 718) were excluded. Four hundred twenty-four children had discharge diagnoses not included in our study. There were 294 (20.5%) patients who had low-value cultures per our study criteria. Nine children (9/294, 3.1%) had false-positive blood cultures, and three (3/294, 1.0%) had true-positive blood cultures. CONCLUSIONS: We identified a cohort of patients in our ED with blood cultures obtained when available literature indicates they were of low value.

Characterization of the prenatal renal phenotype associated with 17q12, HNF1B, microdeletions.

OBJECTIVE: Recurrent deletions involving 17q12 are associated with a variety of clinical phenotypes, including congenital abnormalities of the kidney and urinary tract (CAKUT), maturity onset diabetes of the young, type 5, and neurodevelopmental disorders. Structural and/or functional renal disease is the most common phenotypic feature, although the prenatal renal phenotypes and the postnatal correlates have not been well characterized. METHOD: We reviewed pre- and postnatal medical records of 26 cases with prenatally or postnatally identified 17q12/HNF1B microdeletions (by chromosomal microarray or targeted gene sequencing), obtained through a multicenter collaboration. We specifically evaluated 17 of these cases (65%) with reported prenatal renal ultrasound findings. RESULTS: Heterogeneous prenatal renal phenotypes were noted, most commonly renal cysts (41%, n = 7/17) and echogenic kidneys (41%), although nonspecific dysplasia, enlarged kidneys, hydronephrosis, pelvic kidney with hydroureter, and lower urinary tract obstruction were also reported. Postnatally, most individuals developed renal cysts (73%, 11/15 live births), and there were no cases of end-stage renal disease during childhood or the follow-up period. CONCLUSION: Our findings demonstrate that copy number variant analysis to assess for 17q12 microdeletion should be considered for a variety of prenatally detected renal anomalies. It is important to distinguish 17q12 microdeletion from other etiologies of CAKUT as the prognosis for renal function and presence of associated findings are distinct and may influence pregnancy and postnatal management.

Microbiome modulates immunotherapy response in cutaneous squamous cell carcinoma.

The gut microbiome is increasingly recognized to alter cancer risk, progression and response to treatments such as immunotherapy, especially in cutaneous melanoma. However, whether the microbiome influences immune checkpoint inhibitor (ICI) immunotherapy response to non-melanoma skin cancer has not yet been defined. As squamous cell carcinomas (SCC) are in closest proximity to the skin microbiome, we hypothesized that the skin microbiome, which regulates cutaneous immunity, might affect SCC-associated anti-PD1 immunotherapy treatment response. We used ultraviolet radiation to induce SCC in SKH1 hairless mice. We then treated the mice with broad-band antibiotics to deplete the microbiome, followed by colonisation by candidate skin and gut bacteria or persistent antibiotic treatment, all in parallel with ICI treatment. We longitudinally monitored skin and gut microbiome dynamics by 16S rRNA gene sequencing and tumour burden by periodic tumour measurements and histologic assessment. Our study revealed that antibiotics-induced abrogation of the microbiome reduced the tumour burden, suggesting a functional role of the microbiome in non-melanoma skin cancer therapy response.

Protocol of a multicentre randomised controlled trial assessing transperineal prostate biopsy to reduce infectiouscomplications.

INTRODUCTION: Approximately one million prostate biopsies are performed annually in the USA, and most are performed using a transrectal approach under local anaesthesia. The risk of postbiopsy infection is increasing due to increasing antibiotic resistance of rectal flora. Single-centre studies suggest that a clean, percutaneous transperineal approach to prostate biopsy may have a lower risk of infection. To date, there is no high-level evidence comparing transperineal versus transrectal prostate biopsy. We hypothesise that transperineal versus transrectal prostate biopsy under local anaesthesia has a significantly lower risk of infection, similar pain/discomfort levels and comparable detection of non-low-grade prostate cancer. METHODS AND ANALYSIS: We will perform a multicentre, prospective randomised clinical trial to compare transperineal versus transrectal prostate biopsy for elevated prostate-specific antigen in the first biopsy, prior negative biopsy and active surveillance biopsy setting. Prostate MRI will be performed prior to biopsy, and targeted biopsy will be conducted for suspicious MRI lesions in addition to systematic biopsy (12 cores). Approximately 1700 men will be recruited and randomised in a 1:1 ratio to transperineal versus transrectal biopsy. A streamlined design to collect data and to determine trial eligibility along with the two-stage consent process will be used to facilitate subject recruitment and retention. The primary outcome is postbiopsy infection, and secondary outcomes include other adverse events (bleeding, urinary retention), pain/discomfort/anxiety and critically, detection of non-low-grade (grade group ≥2) prostate cancer. ETHICS AND DISSEMINATION: The Institutional Review Board of the Biomedical Research Alliance of New York approved the research protocol (protocol number #18-02-365, approved 20 April 2020). The results of the trial will be presented at scientific conferences and published in peer-reviewed medical journals. TRIAL REGISTRATION NUMBER: NCT04815876.

Microbiome modulates immunotherapy response in cutaneous squamous cell carcinoma.

The gut microbiome is increasingly recognized to alter cancer risk, progression, and response to treatments such as immunotherapy, especially in cutaneous melanoma. However, whether the microbiome influences immune checkpoint inhibitor (ICI) immunotherapy response to non-melanoma skin cancer has not yet been defined. As squamous cell carcinomas (SCC) are in closest proximity to the skin microbiome, we hypothesized that the skin microbiome, which regulates cutaneous immunity, might affect SCC-associated anti-PD1 immunotherapy treatment response. We used ultraviolet radiation to induce SCC in SKH1 hairless mice. We then treated the mice with broad-band antibiotics to deplete the microbiome, followed by colonization by candidate skin and gut bacteria or persistent antibiotic treatment, all in parallel with ICI treatment. We longitudinally monitored skin and gut microbiome dynamics by 16S rRNA gene sequencing, and tumor burden by periodic tumor measurements and histologic assessment. Our study revealed that antibiotics-induced abrogation of the microbiome reduced tumor burden, suggesting a functional role of the microbiome in non-melanoma skin cancer therapy response.

Safety and Efficacy of CYP2C19 Genotype-Guided Escalation of P2Y12 Inhibitor Therapy After Percutaneous Coronary Intervention in Chronic Kidney Disease: a Post Hoc Analysis of the TAILOR-PCI Study.

PURPOSE: Chronic kidney disease (CKD) is a risk factor for ischemic and bleeding events with dual antiplatelet therapy after percutaneous coronary intervention (PCI). Whether the presence of CYP2C19 loss of function (LOF) alleles modifies this risk, and whether a genotype-guided (GG) escalation of P2Y12 inhibitor therapy post PCI is safe in this population is unclear. METHODS: This was a post hoc analysis of randomized patients in TAILOR PCI. Patients were divided into two groups based on estimated glomerular filtration rate (eGFR) threshold of < 60 ml/min/1.73 m2 for CKD (n = 539) and non-CKD (n = 4276). The aggregate of cardiovascular death, stroke, myocardial infarction, stent thrombosis, and severe recurrent coronary ischemia at 12-months post-PCI was assessed as the primary endpoint. Secondary endpoint was major or minor bleeding. RESULTS: Mean (standard deviation) eGFR among patients with CKD was 49.5 (8.4) ml/min/1.72 m2. Among all patients, there was no significant interaction between randomized strategy and CKD status for any endpoint. Among LOF carriers, the interaction between randomized strategy and CKD status on composite ischemic outcome was not significant (p = 0.2). GG strategy was not associated with an increased risk of bleeding in either CKD group. CONCLUSIONS: In this exploratory analysis, escalation of P2Y12 inhibitor therapy following a GG strategy did not reduce the primary outcome in CKD. However, P2Y12 inhibitor escalation following a GG strategy was not associated with increased bleeding risk in CKD. Larger studies in CKD are needed. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01742117?term=TAILOR-PCI&draw=2&rank=1 . NCT01742117.

Canadian Spontaneous Coronary Artery Dissection Cohort Study: 3-Year Outcomes.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) is an important cause of myocardial infarction (MI) in young to middle-aged women. OBJECTIVES: We aim to define the long-term natural history of SCAD. METHODS: We performed a multicenter, prospective, observational study of patients with nonatherosclerotic SCAD presenting acutely from 22 North American centers. We recorded baseline demographics, in-hospital characteristics, precipitating and predisposing conditions, angiographic features (adjudicated), in-hospital and 3-year major adverse cardiovascular events (MACE). Cox regression multivariable analysis was performed. RESULTS: We prospectively enrolled 750 consecutive patients with SCAD from June 2014 to June 2018. Mean age was 51.7 ± 10.5 years, 88.5% were women (55.0% postmenopausal); 31.3% presented with ST-segment elevation myocardial infarction, and 68.3% with non-ST-segment elevation myocardial infarction. Precipitating emotional stressor was reported in 50.3%, and physical stressor in 28.9%. Predisposing conditions included fibromuscular dysplasia in 42.9% (56.4% in those with complete screening), peripartum state 4.5%, and genetic disorders 1.6%. Most patients were treated conservatively (84.3%); 14.1% underwent percutaneous coronary intervention (PCI), 0.7% coronary artery bypass graft. At 3.0-year median follow-up, mortality was 0.8%, recurrent MI 9.9% (extension of previous SCAD 3.5%, de novo recurrent SCAD 2.4%, iatrogenic dissection 1.9%), with overall MACE 14.0%. Presence of genetic disorders, peripartum SCAD, and extracoronary fibromuscular dysplasia were independent predictors of 3-year MACE. Patients who underwent PCI at index hospitalization had similar postdischarge MACE compared with no PCI. At 3 years, 80.0% remained on aspirin and 73.5% on beta-blockade. CONCLUSIONS: Long-term mortality and de novo recurrent SCAD was low in our contemporary large SCAD cohort that included low revascularization rate and high use of beta-blockade and aspirin. Genetic disorders, extracoronary fibromuscular dysplasia, and peripartum SCAD were independent predictors of long-term MACE.

Synthesis of metal anthranilate complexes: catalytic and antipathogenic studies.

BACKGROUND: Anthranilic acid is an active compound with diverse biological activities such as anti-inflammatory, antineoplastic, anti-malarial and α-glucosidase inhibitory properties. It can also chelate transition metals to form complexes with applications as antipathogens, photoluminescent materials, corrosion inhibitors, and catalysts. RESULTS: Anthranilic acid complexes (1-10) of Zn(II), Bi(III), Ag(I), Fe(II), Co(II), Cu(II), Mn(II), Al, Ni(II), and Cr(III) were synthesized and characterized using thermogravimetric (TGA), elemental analysis, FT-IR, UV-vis spectrometry, mass spectrometry and magnetic susceptibility. The morphology and size of metal complex (1-10) particles were determined by scanning electron microscope (SEM) and the surface area was determined by BET analysis. TGA and CHN analysis data indicated that the stoichiometries of complexes were 1:2 metal/ligand except for Ag(I), Al and Bi. Furthermore, DFT study was performed to optimize the structure of selected complexes. The complexes (1-10) were evaluated for their catalytic activity in the reduction of 4-nitrophenol (4-NP), antibacterial activity against S. aureus, P. aeroginosa and E. coli as well as their antifungal activity against F. solani and A. niger. The complexes were also tested against the second-stage juveniles (J2) root-knot nematodes. CONCLUSION: Co(II) complex 5 and Cu(II) complex 6 showed high catalytic activity for the reduction of 4-NP to 4-aminophenol (4-AP). Ag(I) complex 3 showed the best activity against the pathogens that were tested namely clinically important bacteria S. aureus, P. aeroginosa and E. coli, commercially important fungi F. solani and A. niger and J2 root-knot nematodes M. javanica.

Observation versus screening spinal MRI and pre-emptive treatment for spinal cord compression in patients with castration-resistant prostate cancer and spinal metastases in the UK (PROMPTS): an open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Early diagnosis of malignant spinal cord compression (SCC) is crucial because pretreatment neurological status is the major determinant of outcome. In metastatic castration-resistant prostate cancer, SCC is a clinically significant cause of disease-related morbidity and mortality. We investigated whether screening for SCC with spinal MRI, and pre-emptive treatment if radiological SCC (rSCC) was detected, reduced the incidence of clinical SCC (cSCC) in asymptomatic patients with metastatic castration-resistant prostate cancer and spinal metastasis. METHODS: We did a parallel-group, open-label, randomised, controlled, phase 3, superiority trial. Patients with metastatic castration-resistant prostate cancer were recruited from 45 National Health Service hospitals in the UK. Eligible patients were aged at least 18 years, with an Eastern Co-operative Oncology Group performance status of 0-2, asymptomatic spinal metastasis, no previous SCC, and no spinal MRI in the past 12 months. Participants were randomly assigned (1:1), using a minimisation algorithm with a random element (balancing factors were treatment centre, alkaline phosphatase [normal vs raised, with the upper limit of normal being defined at each participating laboratory], number of previous systemic treatments [first-line vs second-line or later], previous spinal treatment, and imaging of thorax and abdomen), to no MRI (control group) or screening spinal MRI (intervention group). Serious adverse events were monitored in the 24 h after screening MRI in the intervention group. Participants with screen-detected rSCC were offered pre-emptive treatment (radiotherapy or surgical decompression was recommended per treating physician's recommendation) and 6-monthly spinal MRI. All patients were followed up every 3 months, and then at month 30 and 36. The primary endpoint was time to and incidence of confirmed cSCC in the intention-to-treat population (defined as all patients randomly assigned), with the primary timepoint of interest being 1 year after randomisation. The study is registered with ISRCTN, ISRCTN74112318, and is now complete. FINDINGS: Between Feb 26, 2013, and April 25, 2017, 420 patients were randomly assigned to the control (n=210) or screening MRI (n=210) groups. Median age was 74 years (IQR 68 to 79), 222 (53%) of 420 patients had normal alkaline phosphatase, and median prostate-specific antigen concentration was 48 ng/mL (IQR 17 to 162). Screening MRI detected rSCC in 61 (31%) of 200 patients with assessable scans in the intervention group. As of data cutoff (April 23, 2020), at a median follow-up of 22 months (IQR 13 to 31), time to cSCC was not significantly improved with screening (hazard ratio 0·64 [95% CI 0·37 to 1·11]; Gray's test p=0·12). 1-year cSCC rates were 6·7% (95% CI 3·8-10·6; 14 of 210 patients) for the control group and 4·3% (2·1-7·7; nine of 210 patients) for the intervention group (difference -2·4% [95% CI -4·2 to 0·1]). Median time to cSCC was not reached in either group. No serious adverse events were reported within 24 h of screening. INTERPRETATION: Despite the substantial incidence of rSCC detected in the intervention group, the rate of cSCC in both groups was low at a median of 22 months of follow-up. Routine use of screening MRI and pre-emptive treatment to prevent cSCC is not warranted in patients with asymptomatic castration-resistant prostate cancer with spinal metastasis. FUNDING: Cancer Research UK.

An Enhanced Recovery After Surgery protocol for robotic-assisted laparoscopic nephrectomies utilizing a quadratus lumborum block.

Enhanced Recovery After Surgery (ERAS) protocols have been developed in several fields to reduce hospitalization lengths and overall costs. There have also been developments in multimodal analgesia methods to curtail opioid usage after surgery. Herein, we present the results of our initiation of an ERAS protocol for robotic-assisted laparoscopic partial and radical nephrectomies, employing a quadratus lumborum (QL) regional anesthetic block. We retrospectively reviewed 614 patients in our Institutional Review Board approved database who underwent robotic-assisted laparoscopic partial or radical nephrectomies from January 2017 to February 2020. An ERAS protocol utilizing multimodal analgesia (acetaminophen and gabapentin) and a QL block was developed and introduced in February 2019. We then compared the opioid consumption and perioperative outcomes of patients before and after ERAS protocol initiation. 192 ERAS patients (February 2019 to February 2020) were compared to 422 non-ERAS patients (January 2017 to January 2019). Baseline characteristics and the proportion of preoperative opioids users were similar between the two groups. There were no statistically significant differences in surgery length, hospitalization length, or complication rates. There were statistically significant differences in our primary endpoint, opioid consumption, on post-operative days 0 (p < 0.001), 1 (p < 0.001), and 2 (p < 0.001). The total opioid requirements over the course of admission were lower in the ERAS group compared to the non-ERAS group (p = 0.03). The initiation of an ERAS protocol employing multimodal analgesia and a QL block, for patients undergoing robotic-assisted laparoscopic partial or radical nephrectomies, can decrease opioid requirements without compromising perioperative outcomes.

Nonrandomized Comparison of Efficacy and Side Effects of Bicalutamide Compared With Luteinizing Hormone-Releasing Hormone (LHRH) Analogs in Combination With Radiation Therapy in the CHHiP Trial.

PURPOSE: CHHiP is a randomized trial evaluating moderately hypofractionated radiation therapy for treatment of localized prostate cancer. Of all participants, 97% of them had concurrent short-course hormone therapy (HT), either luteinizing hormone-releasing hormone analog (LHRHa) or 150 mg of bicalutamide daily. This exploratory analysis compares efficacy and side effects in a nonrandomized comparison. METHODS AND MATERIALS: In our study, 2700 patients received LHRHa and 403 received bicalutamide. The primary endpoint was biochemical/clinical failure. Groups were compared with Cox regression adjusted for various prognostic factors and stratified by radiation therapy dose. A key secondary endpoint was erectile dysfunction (ED) assessed by clinicians (using scores from Late Effects on Normal Tissues: Subjective/Objective/Management [LENT-SOM] subjective erectile function for vaginal penetration) and patients (single items within the University of California-Los Angeles Prostate Cancer Index [UCLA PCI] and Expanded Prostate Cancer Index Composite [EPIC]-50 questionnaires) at 2 years and compared between HT regimens by χ2 trend test. RESULTS: Bicalutamide patients were significantly younger (median 67 vs 69 years LHRHa). Median follow-up was 9.3 years. There was no difference in biochemical or clinical failure with an adjusted hazard ratio or 0.97 (95% confidence interval, 0.77-1.23; P = .8). At 2 years, grade ≥2 LENT-SOM ED was reported in significantly more LHRHa patients (313 out of 590; 53%) versus bicalutamide (17 out of 68; 25%) (P < .0001). There were no differences in ED seen with UCLA-PCI and EPIC-50 questionnaires. CONCLUSIONS: In this nonrandomized comparison, there was no evidence of a difference in efficacy according to type of HT received. Bicalutamide preserved clinician assessed (LENT-SOM) erectile function at 2 years but patient-reported outcomes were similar between groups.

Implementation of a multimodal opioid-sparing enhanced recovery pathway for robotic-assisted radical prostatectomy.

The purpose of the study is to evaluate the impact of a multimodal Enhanced Recovery After Surgery (ERAS) protocol on perioperative opioid consumption and hospital length of stay (LOS) after robotic-assisted radical prostatectomy (RARP). We compared the first 176 patients enrolled in the protocol (ERAS group) with the previous 176 patients (non-ERAS group) at a single quaternary institution from December 2017 to June 2019. The ERAS protocol included a multimodal opioid-sparing regimen utilizing acetaminophen, gabapentin, celecoxib, and liposomal bupivacaine. Demographic data, co-morbidities, post-operative pain scores, post-operative opiate consumption measured by morphine milligram equivalents (MME), operating time, and LOS were collected. The two groups were compared using chi-squared, Fisher exact, or Student t tests as appropriate. Multivariable logistic regression analysis was performed to identify predictors of prolonged LOS (> 1 day). The ERAS and non-ERAS groups were equivalent in terms of baseline characteristics and pathological data. The ERAS group had lower post-operative pain scores, post-operative opiate consumption (MME 15 vs. 46, p < 0.01), and LOS (1.2 vs. 1.7 days, p < 0.01) compared to the non-ERAS group. Only 22% in the ERAS cohort had a prolonged LOS compared to 39% of the non-ERAS group (p < 0.01). The ERAS protocol was a negative predictor of prolonged LOS on multivariable logistic regression analysis (odds ratio 0.39, 95% confidence interval 0.22-0.70, p < 0.01). A limitation of this study is its single-center retrospective design. The implementation of a multimodal opioid-sparing ERAS protocol was associated with improved pain control, reduced perioperative opioid usage, and shorter LOS after RARP.

Impact of Hypofractionated Radiotherapy on Patient-reported Outcomes in Prostate Cancer: Results up to 5 yr in the CHHiP trial (CRUK/06/016).

BACKGROUND: Moderate hypofractionation is the recommended standard of care for localised prostate cancer following the results of trials including Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy in Prostate Cancer (CHHiP). Evaluation of long-term patient-reported outcomes (PROs) is important to confirm safety and enhance patient information. OBJECTIVE: To determine whether 5-yr PROs from the CHHiP quality of life (QoL) substudy confirm 2-yr findings and assess patterns over follow-up. DESIGN, SETTING, AND PARTICIPANTS: A phase III randomised controlled trial recruited from 2002 to 2011. The QoL substudy completed accrual in 2009; participants were followed up to 5 yr after radiotherapy. Analyses used data snapshot taken on August 26, 2016. A total of 71 radiotherapy centres were included in the study (UK, Republic of Ireland, Switzerland, and New Zealand); all 57 UK centres participated in the QoL substudy. CHHiP recruited 3216 men with localised prostate cancer (cT1b-T3aN0M0). INTERVENTION: Conventional (74 Gy/37 fractions/7.4 wk) or hypofractionated radiotherapy (60 Gy/20 fractions/4 wk or 57 Gy/19 fractions/3.8 wk) was delivered with intensity-modulated techniques. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: University of California Los Angeles Prostate Cancer Index, Short Form 36 and Functional Assessment of Cancer Therapy-Prostate, or Expanded Prostate Cancer Index Composite and Short Form 12 questionnaires were administered at baseline, before radiotherapy, at 10 wk, and at 6, 12, 18, 24, 36, 48, and 60 mo after radiotherapy. The QoL primary endpoint was overall bowel bother. RESULTS AND LIMITATIONS: The QoL substudy recruited 2100 patients; 1141 5-yr forms were available from 1957 patients still alive (58%). There were no statistically significant differences in 5-yr prevalence of overall "moderate or big" bowel bother: 19/349 (5.4%), 29/381 (7.6%), and 21/393 (5.3%) for 74, 60, and 57 Gy, respectively; overall urinary or sexual bother at 5 yr was similar between schedules. Bowel and urinary symptoms remained stable from 2 to 5 yr for all schedules. Some evidence of worsening overall sexual bother from baseline to 5 yr was less likely in the hypofractionated schedules compared with 74 Gy (odds ratios for increase in bother score vs 74 Gy: 0.55 [0.30-0.99], p = 0.009 for 60 Gy, and 0.52 [0.29-0.94], p = 0.004 for 57 Gy). General QoL scores were similar between schedules at 5 yr. CONCLUSIONS: Longer follow-up confirms earlier findings, with similar patient-reported bowel, urinary, and sexual problems between schedules overall. The continued low incidence of moderate or high bother confirms that moderate hypofractionation should be the standard of care for intermediate-risk localised prostate cancer. PATIENT SUMMARY: We looked at patient-reported outcomes up to 5 yr after treatment in a trial of different radiotherapy schedules for prostate cancer. The findings confirmed that shorter radiotherapy schedules were as safe as standard radiotherapy in terms of bowel, urinary, and sexual problems. TAKE HOME MESSAGE: Bowel, urinary, and sexual symptoms were similar between schedules up to 5 yr. The continued low incidence of moderate/high bother confirms that moderate hypofractionated radiotherapy should be considered the standard of care for men with intermediate-risk prostate cancer.

Impact of a Large Fire and Subsequent Pollution Control Failure at a Coke Works on Acute Asthma Exacerbations in Nearby Adult Residents.

Clairton, Pennsylvania, is home to the largest coke works facility in the United States (US). On 24 December 2018, a large fire occurred at this facility and damaged pollution control equipment. Although repairs were not completed for several months, production continued at pre-fire capacity and daily emissions increased by 24 to 35 times, with multiple exceedances of monitored levels of outdoor air pollution (OAP). The aim of this study was to objectively evaluate the impact of this industrial incident and resultant OAP exceedances on asthma morbidity. We assessed pre-fire and post-fire rate ratios (RR) of outpatient and emergency department (ED) visits for asthma exacerbations among nearby adult residents. Pre-fire versus post-fire RRs increased for both visit types: RR = 1.82 (95% CI: 1.30, 2.53; p < 0.001) and 1.84 (95% CI: 1.05, 3.22; p = 0.032) for outpatient and ED visits, respectively. Additionally, total visit rates increased on days with OAP exceedances: RR = 2.47 (95% CI: 1.52, 4.01; p < 0.0001), 1.58 (95% CI: 1.00, 2.48; p = 0.048) and 1.79 (95% CI: 1.27, 2.54; p = 0.001) for PM2.5, SO2, and H2S exceedance days, respectively. These results show a near doubling of acute visits for asthma exacerbations in nearby adult residents during this industrial incident and underscore the need for prompt remediation and public notification of OAP exceedances to prevent adverse health impacts.

Effectiveness of a central line associated blood stream infection protocol in a pediatric population.

BACKGROUND: Central line associated bloodstream infections are a common cause of bacteremia and sepsis in pediatric patients with intestinal failure, secondary to long-term CVC use. METHODS: An IRB approved retrospective chart review was conducted on TPN-dependent patients with IF who had an identified CLABSI and presented to Children's of Alabama's emergency department (ED) and were admitted to the hospital. RESULTS: Forty-four patients were included in the study, 28 in the first 18-month period and 26 in the second, with 10 in both populations. After implementation, mean time from ED presentation to antibiotic ordered and ED admission to antibiotic administered were lower. Mean time between antibiotic administration and admission to the floor was greater, and number of infectious disease consultations was greater. Floor-ICU transfers were lower, readmissions within 30 days was similar, and mean length of stay was similar. CONCLUSION: A collaborative, multidiscipline-supported protocol for the care of patients with IF presenting to the ED enhances efficiency of antibiotic ordering/administration, as well as reduces the number of unplanned floor-ICU transfers.

Further delineation of van den Ende-Gupta syndrome: Genetic heterogeneity and overlap with congenital heart defects and skeletal malformations syndrome.

Van den Ende-Gupta syndrome (VDEGS) is a rare autosomal recessive condition characterized by distinctive facial and skeletal features, and in most affected persons, by biallelic pathogenic variants in SCARF2. We review the type and frequency of the clinical features in 36 reported individuals with features of VDEGS, 15 (42%) of whom had known pathogenic variants in SCARF2, 6 (16%) with negative SCARF2 testing, and 15 (42%) not tested. We also report three new individuals with pathogenic variants in SCARF2 and clinical features of VDEGS. Of the six persons without known pathogenic variants in SCARF2, three remain unsolved despite extensive genetic testing. Three were found to have pathogenic ABL1 variants using whole exome sequencing (WES) or whole genome sequencing (WGS). Their phenotype was consistent with the congenital heart disease and skeletal malformations syndrome (CHDSKM), which has been associated with ABL1 variants. Of the three unsolved cases, two were brothers who underwent WGS and targeted long-range sequencing of both SCARF2 and ABL1, and the third person who underwent WES and RNA sequencing for SCARF2. Because these affected individuals with classical features of VDEGS lacked a detectable pathogenic SCARF2 variant, genetic heterogeneity is likely. Our study shows the importance of performing genetic testing on individuals with the VDEGS "phenotype," either as a targeted gene analysis (SCARF2, ABL1) or WES/WGS. Additionally, individuals with the combination of arachnodactyly and blepharophimosis should undergo echocardiography while awaiting results of molecular testing due to the overlapping physical features of VDEGS and CHDSKM.

Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome.

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.

[Unstable injuries of the deltoid ligament complex in ankle fractures : How to diagnose, how to treat?] / Instabile Verletzungen des Deltabandkomplexes bei Sprunggelenkfrakturen : Wie erkennen, wie behandeln?

Unstable injuries of the deltoid ligament complex can have a substantial negative effect on the prognosis and treatment of ankle injuries. Lesions of the deltoid ligament are often overlooked at the initial presentation, both as isolated ruptures and in combination with more complex injuries of the ankle. Neglected unstable injuries of medial ankle ligaments may result in chronic instability, especially following correct treatment of fractures and lateral ligament injuries. These are accompanied by reduced ankle mobility, persisting pain, reduced load bearing and osteoarthritis. Despite the possible subsequent damage, the need for surgical repair of the deltoid ligament in patients with ankle fractures is controversially discussed. Although in most cases of ligament injuries of the upper ankle joint conservative treatment leads to very good results, there is increased interest in acute surgical treatment particularly for unstable injuries in order to avoid secondary instability and the associated sequelae. When surgical treatment should be given priority over conservative treatment has not yet been sufficiently clarified. This article gives an overview of the diagnosis and treatment of injuries of the deltoid ligament complex in patients with ankle fractures based on the current literature.