Longitudinal Electrocochleography as an Objective Measure of Serial Behavioral Audiometry in Electro-Acoustic Stimulation Patients.

OBJECTIVE: Minimally traumatic surgical techniques and advances in cochlear implant (CI) electrode array designs have allowed acoustic hearing present in a CI candidate prior to surgery to be preserved postoperatively. As a result, these patients benefit from combined electric-acoustic stimulation (EAS) postoperatively. However, 30% to 40% of EAS CI users experience a partial loss of hearing up to 30 dB after surgery. This additional hearing loss is generally not severe enough to preclude use of acoustic amplification; however, it can still impact EAS benefits. The use of electrocochleography (ECoG) measures of peripheral hair cell and neural auditory function have shed insight into the pathophysiology of postimplant loss of residual acoustic hearing. The present study aims to assess the long-term stability of ECoG measures and to establish ECoG as an objective method of monitoring residual hearing over the course of EAS CI use. We hypothesize that repeated measures of ECoG should remain stable over time for EAS CI users with stable postoperative hearing preservation. We also hypothesize that changes in behavioral audiometry for EAS CI users with loss of residual hearing should also be reflected in changes in ECoG measures. DESIGN: A pool of 40 subjects implanted under hearing preservation protocol was included in the study. Subjects were seen at postoperative visits for behavioral audiometry and ECoG recordings. Test sessions occurred 0.5, 1, 3, 6, 12 months, and annually after 12 months postoperatively. Changes in pure-tone behavioral audiometric thresholds relative to baseline were used to classify subjects into two groups: one group with stable acoustic hearing and another group with loss of acoustic hearing. At each test session, ECoG amplitude growth functions for several low-frequency stimuli were obtained. The threshold, slope, and suprathreshold amplitude at a fixed stimulation level was obtained from each growth function at each time point. Longitudinal linear mixed effects models were used to study trends in ECoG thresholds, slopes, and amplitudes for subjects with stable hearing and subjects with hearing loss. RESULTS: Preoperative, behavioral audiometry indicated that subjects had an average low-frequency pure-tone average (125 to 500 Hz) of 40.88 ± 13.12 dB HL. Postoperatively, results showed that ECoG thresholds and amplitudes were stable in EAS CI users with preserved residual hearing. ECoG thresholds increased (worsened) while ECoG amplitudes decreased (worsened) for those with delayed hearing loss. The slope did not distinguish between EAS CI users with stable hearing and subjects with delayed loss of hearing. CONCLUSIONS: These results provide a new application of postoperative ECoG as an objective tool to monitor residual hearing and understand the pathophysiology of delayed hearing loss. While our measures were conducted with custom-designed in-house equipment, CI companies are also designing and implementing hardware and software adaptations to conduct ECoG recordings. Thus, postoperative ECoG recordings can potentially be integrated into clinical practice.

Presence of cells in the polyaneuploid cancer cell (PACC) state predicts the risk of recurrence in prostate cancer.

BACKGROUND: The nonproliferating polyaneuploid cancer cell (PACC) state is associated with therapeutic resistance in cancer. A subset of cancer cells enters the PACC state by polyploidization and acts as cancer stem cells by undergoing depolyploidization and repopulating the tumor cell population after the therapeutic stress is relieved. Our aim was to systematically assess the presence and importance of this entity in men who underwent radical prostatectomy with curative intent to treat their presumed localized prostate cancer (PCa). MATERIALS AND METHODS: Men with National Comprehensive Cancer Network intermediate- or high-risk PCa who underwent radical prostatectomy l from 2007 to 2015 and who did not receive neoadjuvant treatment were included. From the cohort of 2159 patients, the analysis focused on a subcohort of 209 patients and 38 cases. Prostate tissue microarrays (TMAs) were prepared from formalin-fixed, paraffin-embedded blocks of the radical prostatectomy specimens. A total of 2807 tissue samples of matched normal/benign and cancer were arrayed in nine TMA blocks. The presence of PACCs and the number of PACCs on each core were noted. RESULTS: The total number of cells in the PACC state and the total number of cores with PACCs were significantly correlated with increasing Gleason score (p = 0.0004) and increasing Cancer of the Prostate Risk Assessment Postsurgical (CAPRA-S) (p = 0.004), but no other variables. In univariate proportional hazards models of metastasis-free survival, year of surgery, Gleason score (9-10 vs. 7-8), pathology stage, CAPRA-S, total PACCs, and cores positive for PACCs were all statistically significant. The multivariable models with PACCs that gave the best fit included CAPRA-S. Adding either total PACCs or cores positive for PACCs to CAPRA-S both significantly improved model fit compared to CAPRA-S alone. CONCLUSION: Our findings show that the number of PACCs and the number of cores positive for PACCs are statistically significant prognostic factors for metastasis-free survival, after adjusting for CAPRA-S, in a case-cohort of intermediate- or high-risk men who underwent radical prostatectomy. In addition, despite the small number of men with complete data to evaluate time to metastatic castration-resistant PCa (mCRPC), the total number of PACCs was a statistically significant predictor of mCRPC in univariate analysis and suggested a prognostic effect even after adjusting for CAPRA-S.

Effects of Spiritual Care on Well-Being of Intensive Care Family Surrogates: A Clinical Trial.

CONTEXT: Critical illness of a family member is associated with high emotional and spiritual distress and difficult medical decisions. OBJECTIVES: To determine if a semistructured spiritual care intervention improves the well-being of family surrogate decision makers in intensive care (ICU) settings. METHODS: This study is a randomized, allocation-concealed, parallel group, usual care-controlled, single-blind trial of patient/surrogate dyads in five ICUs in one Midwest, academic medical center. Patients were 18 and older admitted to the ICU and unable to make medical decisions. The intervention involved proactive contact from the chaplain, scheduled, semi-structured visits, weekly follow-up, and bereavement calls. The control group received usual care. The primary endpoint was the surrogate's anxiety (Generalized Anxiety Disorders-7 scale), six to eight weeks after discharge. RESULTS: Of 192 patient/surrogate dyads enrolled, 128 completed outcome assessments. At follow-up, anxiety in the intervention group was lower than control (median score 1 (interquartile range 0,6) vs. 4 (1,9), P = 0.0057). The proportion of patients with a minimal clinically important difference (MCID) in anxiety of 2+ was 65.2% in the intervention group vs. 49.2% in control. The odds of an MCID remained higher in adjusted analysis (Odds Ratio 3.11, 95% confidence interval 1.18, 8.21; P = 0.0218) The adjusted odds of an MCID were higher for spiritual well-being (OR 3.79, CI 1.41,10.17; P = 0.0081). Satisfaction with spiritual care was also higher (adjusted mean 3.5 ± 0.4 vs. 2.9 ± 0.1); P < .0001). CONCLUSIONS: Proactive, semistructured spiritual care delivered by chaplains improves well-being for ICU surrogates. Results provide evidence for inclusion of chaplains in palliative and intensive care teams.

Cell Cycle Progression Score, but Not Phosphatase and Tensin Homolog Loss, Is an Independent Prognostic Factor for Metastasis in Intermediate- and High-risk Prostate Cancer in Men Treated With and Without Salvage Radiotherapy.

PURPOSE: The prognostic value for metastasis of the cell-cycle progression score and phosphatase and tensin homolog haven't been evaluated jointly in contemporary men with exclusively intermediate- or high-risk prostate cancer. We evaluated associations of cell-cycle progression and phosphatase and tensin homolog with metastasis-free survival in contemporary intermediate/high-risk prostate cancer patients overall, and intermediate/high-risk men receiving salvage radiotherapy. MATERIALS AND METHODS: In a case-cohort of 209 prostatectomy patients with intermediate/high-risk prostate cancer, and a cohort of 172 such men who received salvage radiotherapy, cell-cycle progression score was calculated from RNA expression, and phosphatase and tensin homolog was analyzed by immunohistochemistry. Proportional hazards regression, weighted for case-cohort design or unweighted for the salvage radiotherapy cohort, was used to evaluate associations of cell-cycle progression, phosphatase and tensin homolog with metastasis-free survival. Improvement in model discrimination was evaluated with the concordance index. RESULTS: In the case-cohort 41 men had metastasis, and 17 developed metastasis in the salvage radiotherapy cohort, at median follow-up of 3 and 4 years, respectively. For both case-cohort and salvage radiotherapy cohort, cell-cycle progression was independently associated with metastasis-free survival after adjustment for Cancer of the Prostate Risk Assessment Post-Surgical: hazard ratio (95% confidence interval) = 3.11 (1.70-5.69) and 1.85 (1.19-2.85), respectively. Adding cell-cycle progression to Cancer of the Prostate Risk Assessment Post-Surgical increased the concordance index from 0.861 to 0.899 (case-cohort), and 0.745 to 0.819 (salvage radiotherapy cohort). Although statistically significant in univariate analyses, phosphatase and tensin homolog was no longer significant after adjustment for Cancer of the Prostate Risk Assessment Post-Surgical. Analysis of interaction with National Comprehensive Cancer Network risk group showed that cell-cycle progression had the strongest effect among unfavorable intermediate-risk men. CONCLUSIONS: In the first study to evaluate metastasis risk associated with cell-cycle progression and phosphatase and tensin homolog in exclusively intermediate/high-risk prostate cancer, and in such men with salvage radiotherapy, cell-cycle progression but not phosphatase and tensin homolog was associated with significantly increased 2- to 3-fold risk of metastasis after Cancer of the Prostate Risk Assessment Post-Surgical adjustment.

Clinical perspective on hearing preservation in cochlear implantation, the University of Iowa experience.

Preservation of residual acoustic hearing has emerged as an important concept for those individuals undergoing cochlear implantation with residual low frequency hearing. Acoustic plus electric speech processing improves hearing outcomes in quiet, enables melody recognition, preserves spatial hearing if there is acoustic hearing in both ears and significantly improves hearing in noise. The development of our experience with acoustic plus electric processing is reviewed along with clinical trials and patient outcomes that our team has documented over the past twenty years.

Access and Polarization Electrode Impedance Changes in Electric-Acoustic Stimulation Cochlear Implant Users with Delayed Loss of Acoustic Hearing.

Acoustic hearing can be preserved after cochlear implant (CI) surgery, allowing for combined electric-acoustic stimulation (EAS) and superior speech understanding compared to electric-only hearing. Among patients who initially retain useful acoustic hearing, 30-40 % experience a delayed hearing loss that occurs 3 or more months after CI activation. Increases in electrode impedances have been associated with delayed loss of residual acoustic hearing, suggesting a possible role of intracochlear inflammation/fibrosis as reported by Scheperle et al. (Hear Res 350:45-57, 2017) and Shaul et al. (Otol Neurotol 40(5):e518-e526, 2019). These studies measured only total impedance. Total impedance consists of a composite of access resistance, which reflects resistance of the intracochlear environment, and polarization impedance, which reflects resistive and capacitive properties of the electrode-electrolyte interface as described by Dymond (IEEE Trans Biomed Eng 23(4):274-280, 1976) and Tykocinski et al. (Otol Neurotol 26(5):948-956, 2005). To explore the role of access and polarization impedance components in loss of residual acoustic hearing, these measures were collected from Nucleus EAS CI users with stable acoustic hearing and subsequent precipitous loss of hearing. For the hearing loss group, total impedance and access resistance increased over time while polarization impedance remained stable. For the stable hearing group, total impedance and access resistance were stable while polarization impedance declined. Increased access resistance rather than polarization impedance appears to drive the increase in total impedances seen with loss of hearing. Moreover, access resistance has been correlated with intracochlear fibrosis/inflammation in animal studies as observed by Xu et al. (Hear Res 105(1-2):1-29, 1997) and Tykocinski et al. (Hear Res 159(1-2):53-68, 2001). These findings thus support intracochlear inflammation as one contributor to loss of acoustic hearing in our EAS CI population.

Comparison of Multimodal Therapies and Outcomes Among Patients With High-Risk Prostate Cancer With Adverse Clinicopathologic Features.

Importance: The optimal management strategy for high-risk prostate cancer and additional adverse clinicopathologic features remains unknown. Objective: To compare clinical outcomes among patients with high-risk prostate cancer after definitive treatment. Design, Setting, and Participants: This retrospective cohort study included patients with high-risk prostate cancer (as defined by the National Comprehensive Cancer Network [NCCN]) and at least 1 adverse clinicopathologic feature (defined as any primary Gleason pattern 5 on biopsy, clinical T3b-4 disease, ≥50% cores with biopsy results positive for prostate cancer, or NCCN ≥2 high-risk features) treated between 2000 and 2014 at 16 tertiary centers. Data were analyzed in November 2020. Exposures: Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy (ADT), or EBRT plus brachytherapy boost (BT) with ADT. Guideline-concordant multimodal treatment was defined as RP with appropriate use of multimodal therapy (optimal RP), EBRT with at least 2 years of ADT (optimal EBRT), or EBRT with BT with at least 1 year ADT (optimal EBRT with BT). Main Outcomes and Measures: The primary outcome was prostate cancer-specific mortality; distant metastasis was a secondary outcome. Differences were evaluated using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression models. Results: A total of 6004 men (median [interquartile range] age, 66.4 [60.9-71.8] years) with high-risk prostate cancer were analyzed, including 3175 patients (52.9%) who underwent RP, 1830 patients (30.5%) who underwent EBRT alone, and 999 patients (16.6%) who underwent EBRT with BT. Compared with RP, treatment with EBRT with BT (subdistribution hazard ratio [sHR] 0.78, [95% CI, 0.63-0.97]; P = .03) or with EBRT alone (sHR, 0.70 [95% CI, 0.53-0.92]; P = .01) was associated with significantly improved prostate cancer-specific mortality; there was no difference in prostate cancer-specific mortality between EBRT with BT and EBRT alone (sHR, 0.89 [95% CI, 0.67-1.18]; P = .43). No significant differences in prostate cancer-specific mortality were found across treatment cohorts among 2940 patients who received guideline-concordant multimodality treatment (eg, optimal EBRT alone vs optimal RP: sHR, 0.76 [95% CI, 0.52-1.09]; P = .14). However, treatment with EBRT alone or EBRT with BT was consistently associated with lower rates of distant metastasis compared with treatment with RP (eg, EBRT vs RP: sHR, 0.50 [95% CI, 0.44-0.58]; P < .001). Conclusions and Relevance: These findings suggest that among patients with high-risk prostate cancer and additional unfavorable clinicopathologic features receiving guideline-concordant multimodal therapy, prostate cancer-specific mortality outcomes were equivalent among those treated with RP, EBRT, and EBRT with BT, although distant metastasis outcomes were more favorable among patients treated with EBRT and EBRT with BT. Optimal multimodality treatment is critical for improving outcomes in patients with high-risk prostate cancer.

Residual Hair Cell Responses in Electric-Acoustic Stimulation Cochlear Implant Users with Complete Loss of Acoustic Hearing After Implantation.

Changes in cochlear implant (CI) design and surgical techniques have enabled the preservation of residual acoustic hearing in the implanted ear. While most Nucleus Hybrid L24 CI users retain significant acoustic hearing years after surgery, 6-17 % experience a complete loss of acoustic hearing (Roland et al. Laryngoscope. 126(1):175-81. (2016), Laryngoscope. 128(8):1939-1945 (2018); Scheperle et al. Hear Res. 350:45-57 (2017)). Electrocochleography (ECoG) enables non-invasive monitoring of peripheral auditory function and may provide insight into the pathophysiology of hearing loss. The ECoG response is evoked using an acoustic stimulus and includes contributions from the hair cells (cochlear microphonic-CM) as well as the auditory nerve (auditory nerve neurophonic-ANN). Seven Hybrid L24 CI users with complete loss of residual hearing months after surgery underwent ECoG measures before and after loss of hearing. While significant reductions in CMs were evident after hearing loss, all participants had measurable CMs despite having no measurable acoustic hearing. None retained measurable ANNs. Given histological data suggesting stable hair cell and neural counts after hearing loss (e.g., Quesnel et al. Hear Res. 333:225-234. (2016)), the loss of ECoG and audiometric hearing may reflect reduced synaptic input. This is consistent with the theory that residual CM responses coupled with little to no ANN responses reflect a "disconnect" between hair cells and auditory nerve fibers (Fontenot et al. Ear Hear. 40(3):577-591. 2019). This "disconnection" may prevent proper encoding of auditory stimulation at higher auditory pathways, leading to a lack of audiometric responses, even in the presence of viable cochlear hair cells.

Limited effects of long-term daily cranberry consumption on the gut microbiome in a placebo-controlled study of women with recurrent urinary tract infections.

BACKGROUND: Urinary tract infections (UTIs) affect 15 million women each year in the United States, with > 20% experiencing frequent recurrent UTIs. A recent placebo-controlled clinical trial found a 39% reduction in UTI symptoms among recurrent UTI sufferers who consumed a daily cranberry beverage for 24 weeks. Using metagenomic sequencing of stool from a subset of these trial participants, we assessed the impact of cranberry consumption on the gut microbiota, a reservoir for UTI-causing pathogens such as Escherichia coli, which causes > 80% of UTIs. RESULTS: The overall taxonomic composition, community diversity, carriage of functional pathways and gene families, and relative abundances of the vast majority of observed bacterial taxa, including E. coli, were not changed significantly by cranberry consumption. However, one unnamed Flavonifractor species (OTU41), which represented ≤1% of the overall metagenome, was significantly less abundant in cranberry consumers compared to placebo at trial completion. Given Flavonifractor's association with negative human health effects, we sought to determine OTU41 characteristic genes that may explain its differential abundance and/or relationship to key host functions. Using comparative genomic and metagenomic techniques, we identified genes in OTU41 related to transport and metabolism of various compounds, including tryptophan and cobalamin, which have been shown to play roles in host-microbe interactions. CONCLUSION: While our results indicated that cranberry juice consumption had little impact on global measures of the microbiome, we found one unnamed Flavonifractor species differed significantly between study arms. This suggests further studies are needed to assess the role of cranberry consumption and Flavonifractor in health and wellbeing in the context of recurrent UTI. TRIAL REGISTRATION: Clinical trial registration number: ClinicalTrials.gov NCT01776021 .

Influence of Zinc on the Acute Changes in Erythropoietin and Proinflammatory Cytokines with Hypoxia.

Baranauskas, Marissa N., Joseph Powell, Alyce D. Fly, Bruce J. Martin, Timothy D. Mickleborough, Hunter L. Paris, and Robert F. Chapman. Influence of zinc on the acute changes in erythropoietin and proinflammatory cytokines with hypoxia. High Alt Med Biol. 22: 148-156, 2021. Background: Considerable, unexplained, interindividual variability characterizes the erythropoietin (EPO) response to hypoxia, which can impact hematological acclimatization for individuals sojourning to altitude. Zinc supplementation has the potential to alter EPO by attenuating increases in inflammation and oxidative stress. Yet, the application of such an intervention has not been evaluated in humans. In this proof-of-concept study, we aimed to evaluate the EPO and inflammatory responses to acute hypoxia in human participants following chronic zinc supplementation. Methods: Nine physically active participants (men n = 5, women n = 4, age 28 ± 4 years, height 176 ± 11 cm, mass 77 ± 21 kg) were exposed to 12 hours of normobaric hypoxia simulating an altitude of 3,000 m (FiO2 = 0.14) before and after 8 weeks of supplementation with 40 mg/day of elemental zinc from picolinate. Blood samples for subsequent analysis of serum zinc, EPO, superoxide dismutase (extracellular superoxide dismutase [EC-SOD]), C-reactive protein (CRP), and proinflammatory cytokines were obtained pre- and postsupplementation and exposure to hypoxia. Results: After zinc supplementation, EPO increased by 64.9 ± 36.0% (mean ± standard deviation) following 12 hours of hypoxia, but this response was not different from presupplementation (70.8 ± 46.1%). Considerable interindividual (range: -1% to +208%) variability was apparent in the acute EPO response. While most markers of inflammation did not change with hypoxia, interleukin-6 concentrations increased from 1.17 ± 0.05 to 1.97 ± 0.32 pg/ml during the final 6 hours. The acute EPO response at 12 hours was not related to changes in serum zinc, EC-SOD, CRP, or proinflammatory cytokines. Conclusions: Zinc supplementation does not influence the acute EPO or inflammatory response with short-term exposure to moderate levels of normobaric hypoxia (3,000 m) in apparently healthy young adults.

Performance of clinicopathologic models in men with high risk localized prostate cancer: impact of a 22-gene genomic classifier.

BACKGROUND: Prostate cancer exhibits biological and clinical heterogeneity even within established clinico-pathologic risk groups. The Decipher genomic classifier (GC) is a validated method to further risk-stratify disease in patients with prostate cancer, but its performance solely within National Comprehensive Cancer Network (NCCN) high-risk disease has not been undertaken to date. METHODS: A multi-institutional retrospective study of 405 men with high-risk prostate cancer who underwent primary treatment with radical prostatectomy (RP) or radiation therapy (RT) with androgen-deprivation therapy (ADT) at 11 centers from 1995 to 2005 was performed. Cox proportional hazards models were used to determine the hazard ratios (HR) for the development of metastatic disease based on clinico-pathologic variables, risk groups, and GC score. The area under the receiver operating characteristic curve (AUC) was determined for regression models without and with the GC score. RESULTS: Over a median follow-up of 82 months, 104 patients (26%) developed metastatic disease. On univariable analysis, increasing GC score was significantly associated with metastatic disease ([HR]: 1.34 per 0.1 unit increase, 95% confidence interval [CI]: 1.19-1.50, p < 0.001), while age, serum PSA, biopsy GG, and clinical T-stage were not (all p > 0.05). On multivariable analysis, GC score (HR: 1.33 per 0.1 unit increase, 95% CI: 1.19-1.48, p < 0.001) and GC high-risk (vs low-risk, HR: 2.95, 95% CI: 1.79-4.87, p < 0.001) were significantly associated with metastasis. The addition of GC score to regression models based on NCCN risk group improved model AUC from 0.46 to 0.67, and CAPRA from 0.59 to 0.71. CONCLUSIONS: Among men with high-risk prostate cancer, conventional clinico-pathologic data had poor discrimination to risk stratify development of metastatic disease. GC score was a significant and independent predictor of metastasis and may help identify men best suited for treatment intensification/de-escalation.

Intergroup Randomized Phase III Study of Postoperative Oxaliplatin, 5-Fluorouracil, and Leucovorin Versus Oxaliplatin, 5-Fluorouracil, Leucovorin, and Bevacizumab for Patients with Stage II or III Rectal Cancer Receiving Preoperative Chemoradiation: A Trial of the ECOG-ACRIN Research Group (E5204).

BACKGROUND: The addition of bevacizumab to chemotherapy improved outcomes for patients with metastatic colon cancer. E5204 was designed to test whether the addition of bevacizumab to mFOLFOX6, following neoadjuvant chemoradiation and definitive surgery, could improve overall survival (OS) in patients with stage II/III adenocarcinoma of the rectum. SUBJECTS, MATERIALS, AND METHODS: Patients with stage II/III rectal cancer who had completed neoadjuvant 5-fluorouracil-based chemoradiation and had undergone complete resection were enrolled. Patients were randomized to mFOLFOX6 (Arm A) or mFOLFOX6 with bevacizumab (Arm B) administered every 2 weeks for 12 cycles. RESULTS: E5204 registered only 355 patients (17% of planned accrual goal) as it was terminated prematurely owing to poor accrual. At a median follow-up of 72 months, there was no difference in 5-year overall survival (88.3% vs. 83.7%) or 5-year disease-free survival (71.2% vs. 76.5%) between the two arms. The rate of treatment-related grade ≥ 3 adverse events (AEs) was 68.8% on Arm A and 70.7% on Arm B. Arm B had a higher proportion of patients who discontinued therapy early as a result of AEs and patient withdrawal than did Arm A (32.4% vs. 21.5%, p = .029).The most common grade 3-4 treatment-related AEs were neutropenia, leukopenia, neuropathy, diarrhea (without prior colostomy), and fatigue. CONCLUSION: At 17% of its planned accrual, E5204 did not meet its primary endpoint. The addition of bevacizumab to FOLFOX6 in the adjuvant setting did not significantly improve OS in patients with stage II/III rectal cancer. IMPLICATIONS FOR PRACTICE: At 17% of its planned accrual, E5204 was terminated early owing to poor accrual. At a median follow-up of 72 months, there was no significant difference in 5-year overall survival (88.3% vs. 83.7%) or in 5-year disease-free survival (71.2% vs. 76.5%) between the two arms. Despite significant advances in the treatment of rectal cancer, especially in improving local control rates, the risk of distant metastases and the need to further improve quality of life remain a challenge. Strategies combining novel agents with chemoradiation to improve both distant and local control are needed.

Quantifying the burden of trauma imaging on the CT scan service at a major trauma centre in South Africa.

BACKGROUND: Imaging is an integral part of trauma management and the huge burden of trauma in South Africa places substantial pressures on radiology resources. This study aims to provide a holistic overview of the burden of trauma imaging and the cost of trauma to a busy CT scanning facility at a tertiary hospital in South Africa. METHOD: We set out to describe and quantify the impact of blunt poly-trauma on CT scanning services at Grey's Hospital in Pietermaritzburg. We aimed to provide a holistic assessment in terms of use of equipment and staff, cost to the hospital and overall usage of CT scanning. RESULTS: Over the four-year study period, 1572 patients required a CT scan following blunt torso trauma (mean age: 30 years, 81% males). Of the 1572 patients, 625 had a chest radiograph (40%), 383 a cervical spine X-ray (24%), 347 a pelvic X-ray (22%), 292 a skull X-ray (18%), 193 a limb X-ray (12%), 133 an abdominal radiograph (8%), and 86 a FAST scan (5%). The 1572 CT included: 967 head, 568 neck, 65 chest, 241 abdominal, 228 pelvic, 12 upper limb, 38 lower limb and 394 had full body (Pan) CT scan. The mean total cost of the CT scanning for blunt poly-trauma is ZAR 12 000. The total cost of CT scanning for blunt poly-trauma is 0.92% of the total hospital expenditure. Roughly 7.8% of the total hours worked by the CT scanner over the time period under review was dedicated to blunt poly-trauma. CONCLUSION: Blunt poly-trauma is a preventable disease, which has a major financial impact on the healthcare system in general. This study has documented the tremendous burden it places on an already stretched CT scanning service.

Development of a target-free high-throughput screening platform for the discovery of antileishmanial compounds.

Leishmania parasites are the causative agents of a wide spectrum of human diseases. The clinical manifestations of leishmaniasis range from self-healing skin lesions to fatality. The World Health Organization has classed leishmaniasis as a category 1 neglected tropical disease. Leishmaniasis represents a major international health challenge, affecting 12 million people per year and with nearly 310 million people at risk. The first-line chemotherapies used to treat leishmaniasis are intravenous pentavalent antimonials; however, these drugs are highly toxic. As the use of oral treatment options such as paromomycin and miltefosine has increased, the incidence of disease relapse has increased and drug resistance to antimonials has developed, emphasizing the importance of identifying new chemotherapies. A novel, target-free fluorometric high-throughput screen with an average Z-score of 0.73 +/- 0.13 has been developed to identify small molecules with antileishmanial activity. Screening of 10,000 small molecules from the ChemBridge DIVER-set™ library cassette #5 yielded 210 compounds that killed 80% of parasites, resulting in a hit rate of 2.1%. One hundred and nine molecular scaffolds were represented within the hit compounds, and one scaffold that exhibited potent antileishmanial activity was 2,4-diaminoquinazoline. Host cell toxicity was determined prior to in-vitro infection of human THP-1 macrophages with Leishmania donovani mCherry expressing promastigotes; successful drug treatment was considered when the half maximal inhibitory concentration was <10 µM. BALB/c mice were infected with Leishmania major mCherry promastigotes and treated with small molecules that were successful during in-vitro infections. Several small molecules tested were as efficacious at resolving cutaneous leishmaniasis lesions in mice as known antimonial treatments.

Validation of the Decipher Test for predicting adverse pathology in candidates for prostate cancer active surveillance.

ABSTACT: BACKGROUND: Many men diagnosed with prostate cancer are active surveillance (AS) candidates. However, AS may be associated with increased risk of disease progression and metastasis due to delayed therapy. Genomic classifiers, e.g., Decipher, may allow better risk-stratify newly diagnosed prostate cancers for AS. METHODS: Decipher was initially assessed in a prospective cohort of prostatectomies to explore the correlation with clinically meaningful biologic characteristics and then assessed in diagnostic biopsies from a retrospective multicenter cohort of 266 men with National Comprehensive Cancer Network (NCCN) very low/low and favorable-intermediate risk prostate cancer. Decipher and Cancer of the Prostate Risk Assessment (CAPRA) were compared as predictors of adverse pathology (AP) for which there is universal agreement that patients with long life-expectancy are not suitable candidates for AS (primary pattern 4 or 5, advanced local stage [pT3b or greater] or lymph node involvement). RESULTS: Decipher from prostatectomies was significantly associated with adverse pathologic features (p-values < 0.001). Decipher from the 266 diagnostic biopsies (64.7% NCCN-very-low/low and 35.3% favorable-intermediate) was an independent predictor of AP (odds ratio 1.29 per 10% increase, 95% confidence interval [CI] 1.03-1.61, p-value 0.025) when adjusting for CAPRA. CAPRA area under curve (AUC) was 0.57, (95% CI 0.47-0.68). Adding Decipher to CAPRA increased the AUC to 0.65 (95% CI 0.58-0.70). NPV, which determines the degree of confidence in the absence of AP for patients, was 91% (95% CI 87-94%) and 96% (95% CI 90-99%) for Decipher thresholds of 0.45 and 0.2, respectively. Using a threshold of 0.2, Decipher was a significant predictor of AP when adjusting for CAPRA (p-value 0.016). CONCLUSION: Decipher can be applied to prostate biopsies from NCCN-very-low/low and favorable-intermediate risk patients to predict absence of adverse pathologic features. These patients are predicted to be good candidates for active surveillance.

Low Tristetraprolin Expression Is Associated with Lethal Prostate Cancer.

BACKGROUND: Inflammation is linked to prostate cancer progression and is mediated by NF-κB. Tristetraprolin is a key node of NF-κB activation and we investigated its biological and prognostic role in lethal prostate cancer. METHODS: In vitro assays assessed the function of tristetraprolin and the association between low mRNA tristetraprolin levels and lethal prostate cancer (metastatic disease or death) was assessed across independent prostatectomy cohorts: (i) nested case-control studies from Health Professionals Follow-up Study and Physicians' Health Study, and (ii) prostatectomy samples from Cleveland Clinic, Mayo Clinic, Johns Hopkins and Memorial Sloan Kettering Cancer Center. Tristetraprolin expression levels in prostatectomy samples from patients with localized disease and biopsies of metastatic castration-resistant prostate cancer (mCRPC) were assessed in a Cornell University cohort. RESULTS: In vitro tristetraprolin expression was inversely associated with NF-κB-controlled genes, proliferation, and enzalutamide sensitivity. Men with localized prostate cancer and lower quartile of tumor tristetraprolin expression had a significant, nearly two-fold higher risk of lethal prostate cancer after adjusting for known clinical and histologic prognostic features (age, RP Gleason score, T-stage). Tristetraprolin expression was also significantly lower in mCRPC compared with localized prostate cancer. CONCLUSIONS: Lower levels of tristetraprolin in human prostate cancer prostatectomy tissue are associated with more aggressive prostate cancer and may serve as an actionable prognostic and predictive biomarker. IMPACT: There is a clear need for improved biomarkers to identify patients with localized prostate cancer in need of treatment intensification, such as adjuvant testosterone suppression, or treatment de-intensification, such as active surveillance. Tristetraprolin levels may serve as informative biomarkers in localized prostate cancer.

Older Age Predicts Biopsy and Radical Prostatectomy Grade Reclassification to Aggressive Prostate Cancer in Men on Active Surveillance.

PURPOSE: Age at prostate cancer diagnosis has been positively associated with prostate cancer specific mortality and in men on active surveillance with a higher risk of biopsy grade reclassification to Gleason score 3 + 4 or greater (Grade Group 2 or greater). However, to our knowledge the association between age and biopsy grade reclassification to an aggressive phenotype (Gleason score 4 + 3 or greater [Grade Group 3 or greater]) has not been explored. MATERIALS AND METHODS: From 1995 to 2016 we followed 1,625 men 41 to 81 years old with NCCN® (National Comprehensive Cancer Network®) very low (68%) or low (32%) risk prostate cancer on active surveillance. We determined the rate of biopsy grade reclassification to Grade Group 3 or greater. Competing risk analysis was applied to evaluate the association between age at enrollment and the risk of biopsy grade reclassification. Additionally, in men who underwent radical prostatectomy after biopsy grade reclassification we assessed the rate of radical prostatectomy grade reclassification (ie radical prostatectomy Grade Group greater than biopsy Grade Group). RESULTS: The 5-year incidence of biopsy grade reclassification to Grade Group 3 or greater was 4%, 7% and 14% in men younger than 60, 60 to 69 and 70 years old or older, respectively (p <0.001). On univariate analysis older age was associated with biopsy grade reclassification to Grade Group 3 or greater (per 10-year increase HR 2.43, p <0.001). On multivariable analysis adjusting for year of diagnosis, race, prostate specific antigen density and cancer volume at diagnosis older age remained associated with biopsy grade reclassification to Grade Group 3 or greater (per 10-year increase HR 2.19, p <0.001). In men who underwent radical prostatectomy after biopsy grade reclassification those who were older had a higher rate of radical prostatectomy grade reclassification (p <0.05). CONCLUSIONS: In men on active surveillance older age at diagnosis was positively associated with biopsy grade reclassification to Grade Group 3 or greater and radical prostatectomy grade reclassification. These observations imply that for many older men, active surveillance as opposed to watchful waiting remains a more appropriate management strategy.

In Vivo Electrocochleography in Hybrid Cochlear Implant Users Implicates TMPRSS3 in Spiral Ganglion Function.

Cochlear implantation, a surgical method to bypass cochlear hair cells and directly stimulate the spiral ganglion, is the standard treatment for severe-to-profound hearing loss. Changes in cochlear implant electrode array design and surgical approach now allow for preservation of acoustic hearing in the implanted ear. Electrocochleography (ECochG) was performed in eight hearing preservation subjects to assess hair cell and neural function and elucidate underlying genetic hearing loss. Three subjects had pathogenic variants in TMPRSS3 and five had pathogenic variants in genes known to affect the cochlear sensory partition. The mechanism by which variants in TMPRSS3 cause genetic hearing loss is unknown. We used a 500-Hz tone burst to record ECochG responses from an intracochlear electrode. Responses consist of a cochlear microphonic (hair cell) and an auditory nerve neurophonic. Cochlear microphonics did not differ between groups. Auditory nerve neurophonics were smaller, on average, in subjects with TMPRSS3 deafness. Results of this proof-of-concept study provide evidence that pathogenic variants in TMPRSS3 may impact function of the spiral ganglion. While ECochG as a clinical and research tool has been around for decades, this study illustrates a new application of ECochG in the study of genetic hearing and deafness in vivo.

Linking permafrost thaw to shifting biogeochemistry and food web resources in an arctic river.

Rapidly, increasing air temperatures across the Arctic are thawing permafrost and exposing vast quantities of organic carbon, nitrogen, and phosphorus to microbial processing. Shifts in the absolute and relative supplies of these elements will likely alter patterns of ecosystem productivity and change the way carbon and nutrients are delivered from upland areas to surface waters such as rivers and lakes. The ultra-oligotrophic nature of surface waters across the Arctic renders these ecosystems particularly susceptible to changes in productivity and food web dynamics as permafrost thaw alters terrestrial-aquatic linkages. The objectives of this study were to evaluate decadal-scale patterns in surface water chemistry and assess potential implications of changing water chemistry to benthic organic matter and aquatic food webs. Data were collected from the upper Kuparuk River on the North Slope of Alaska by the U.S. National Science Foundation's Long-Term Ecological Research program during 1978-2014. Analyses of these data show increases in stream water alkalinity and cation concentrations consistent with signatures of permafrost thaw. Changes are also documented for discharge-corrected nitrate concentrations (+), discharge-corrected dissolved organic carbon concentrations (-), total phosphorus concentrations (-), and δ13 C isotope values of aquatic invertebrate consumers (-). These changes show that warming temperatures and thawing permafrost in the upland environment are leading to shifts in the supply of carbon and nutrients available to surface waters and consequently changing resources that support aquatic food webs. This demonstrates that physical, geochemical, and biological changes associated with warming permafrost are fundamentally altering linkages between upland and aquatic ecosystems in rapidly changing arctic environments.

Meditation-Induced Coherence and Crucial Events.

In this paper we emphasize that 1/f noise has two different origins, one compatible with Laplace determinism and one determined by unpredictable crucial events. The dynamics of heartbeats, manifest as heart rate variability (HRV) time series, are determined by the joint action of these different memory sources with meditation turning the Laplace memory into a strongly coherent process while exerting an action on the crucial events favoring the transition from the condition of ideal 1/f noise to the Gaussian basin of attraction. This theoretical development affords a method of statistical analysis that establishes a quantitative approach to the evaluation of the stress reduction realized by the practice of Chi meditation and Kundalini Yoga.