The psychotomimetic ketamine disrupts the transfer of late sensory information in the corticothalamic network.

In prodromal and early schizophrenia, disorders of attention and perception are associated with structural and chemical brain abnormalities and with dysfunctional corticothalamic networks exhibiting disturbed brain rhythms. The underlying mechanisms are elusive. The non-competitive NMDA receptor antagonist ketamine simulates the symptoms of prodromal and early schizophrenia, including disturbances in ongoing and task & sensory-related broadband beta-/gamma-frequency (17-29 Hz/30-80 Hz) oscillations in corticothalamic networks. In normal healthy subjects and rodents, complex integration processes, like sensory perception, induce transient, large-scale synchronised beta/gamma oscillations in a time window of a few hundred ms (200-700 ms) after the presentation of the object of attention (e.g., sensory stimulation). Our goal was to use an electrophysiological multisite network approach to investigate, in lightly anesthetised rats, the effects of a single psychotomimetic dose (2.5 mg/kg, subcutaneous) of ketamine on sensory stimulus-induced oscillations. Ketamine transiently increased the power of baseline beta/gamma oscillations and decreased sensory-induced beta/gamma oscillations. In addition, it disrupted information transferability in both the somatosensory thalamus and the related cortex and decreased the sensory-induced thalamocortical connectivity in the broadband gamma range. The present findings support the hypothesis that NMDA receptor antagonism disrupts the transfer of perceptual information in the somatosensory cortico-thalamo-cortical system.

Microbial Poly-γ-Glutamic Acid (γ-PGA) as an Effective Tooth Enamel Protectant.

Poly-γ-glutamic acid (γ-PGA) is a bio-derived water-soluble, edible, non-immunogenic nylon-like polymer with the biochemical characteristics of a polypeptide. This Bacillus-derived material has great potential for a wide range of applications, from bioremediation to tunable drug delivery systems. In the context of oral care, γ-PGA holds great promise in enamel demineralisation prevention. The salivary protein statherin has previously been shown to protect tooth enamel from acid dissolution and act as a reservoir for free calcium ions within oral cavities. Its superb enamel-binding capacity is attributed to the L-glutamic acid residues of this 5380 Da protein. In this study, γ-PGA was successfully synthesised from Bacillus subtilis natto cultivated on supplemented algae media and standard commercial media. The polymers obtained were tested for their potential to inhibit demineralisation of hydroxyapatite (HAp) when exposed to caries simulating acidic conditions. Formulations presenting 0.1, 0.25, 0.5, 0.75, 1, 2, 3 and 4% (w/v) γ-PGA concentration were assessed to determine the optimal conditions. Our data suggests that both the concentration and the molar mass of the γ-PGA were significant in enamel protection (p = 0.028 and p < 0.01 respectively). Ion Selective Electrode, combined with Fourier Transform Infra-Red studies, were employed to quantify enamel protection capacity of γ-PGA. All concentrations tested showed an inhibitory effect on the dissolution rate of calcium ions from hydroxyapatite, with 1% (wt) and 2% (wt) concentrations being the most effective. The impact of the average molar mass (M) on enamel dissolution was also investigated by employing commercial 66 kDa, 166 kDa, 440 kDa and 520 kDa γ-PGA fractions. All γ-PGA solutions adhered to the surface of HAp with evidence that this remained after 60 min of continuous acidic challenge. Inductively Coupled Plasma analysis showed a significant abundance of calcium ions associated with γ-PGA, which suggests that this material could also act as a responsive calcium delivery system. We have concluded that all γ-PGA samples tested (commercial and algae derived) display enamel protection capacity regardless of their concentration or average molar mass. However, we believe that γ-PGA D/L ratios might affect the binding more than its molar mass.

WATER vs WATER II 3-Year Update: Comparing Aquablation Therapy for Benign Prostatic Hyperplasia in 30-80 cc and 80-150 cc Prostates.

OBJECTIVE: To compare the outcomes of Aquablation for small-to-moderate (30-80cc) prostates with the outcomes for large (80-150 cc) prostates at 3-year follow up. METHODS: WATER is a prospective, double-blind, multicenter, international clinical trial comparing the safety and efficacy of Aquablation and TURP in the treatment of LUTS/BPH in men 45-80 year with a prostate of 30cc-80cc. WATER II is a prospective, multicenter, single-arm international clinical trial of Aquablation in men with a prostate of 80cc-150cc. We compare 36-mo outcomes amongst 116 WATER and 101 WATER II study subjects undergoing Aquablation. RESULTS: International Prostate Symptom Score (IPSS) scores improved from 22.9 and 23.2 at baseline in WATER and WATER II, respectively, to 8.0 and 6.5 at 36-month, with 36-mo reductions of 14.4 and 16.3 points, respectively (P = .247). At baseline, urinary flow rate (Qmax) was 9.4 and 8.7 cc/sec in WATER and WATER II, improving to 20.6 and 18.5 cc/sec, respectively (P = .552) at 36-mo. Improvements in both IPSS and Qmax were immediate and sustained throughout follow-up. At 3 year, 98% and 94% of treated patients were BPH medication-free in WATER and WATER II, respectively (P = .038). At 3yr, 96% and 97% of treated patients were free from surgical retreatment in WATER and WATER II, respectively (P = .613). CONCLUSIONS: Three-year follow-up demonstrates that Aquablation therapy leads to sustained outcomes, few irreversible complications, and low retreatment rates for the treatment of LUTS/BPH independently of prostate volume.

Five-year outcomes for Aquablation therapy compared to TURP: results from a double-blind, randomized trial in men with LUTS due to BPH.

INTRODUCTION: To determine if Aquablation therapy can maintain long term effectiveness in treating men with moderate to severe lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) with a baseline prostate volume between 30 and 80 mL at 5 years compared to TURP. MATERIALS AND METHODS: In a double-blinded, multicenter prospective randomized controlled trial, 181 patients with moderate to severe LUTS secondary to BPH underwent TURP or Aquablation. The primary efficacy endpoint was reduction in International Prostate Symptom Score (IPSS) at 6 months. The primary safety endpoint was the occurrence of Clavien-Dindo persistent Grade 1 or Grade 2 or higher operative complications at 3 months. The assessments included IPSS, Male Sexual Health Questionnaire (MSHQ), International Index of Erectile Function (IIEF) and uroflow (Qmax). The patients were followed for 5 years. RESULTS: The primary safety endpoint was successfully achieved at 3 months where the Aquablation group had a lower event rate than TURP (26% vs. 42%, p = .0149 for superiority). Procedure-related ejaculatory dysfunction was lower for Aquablation (7% vs. 25%, p = .0004). The primary efficacy endpoint was successfully achieved at 6 months, where the mean IPSS decreased from baseline by 16.9 points for Aquablation and 15.1 points for TURP; the mean difference in change score at 6 months was 1.8 points larger for Aquablation (p < .0001 for non-inferiority, p = .1346 for superiority). At 5 years, IPSS scores improved by 15.1 points in the Aquablation group and 13.2 points in TURP (p = .2764). However, for men with larger prostates (≥ 50 mL), IPSS reduction was 3.5 points greater across all follow up visits in the Aquablation group compared to the TURP group (p = .0123). Improvement in peak urinary flow rate was 125% and 89% compared to baseline for Aquablation and TURP, respectively. The risk of patients needing a secondary BPH therapy, defined as needing BPH medication or surgical intervention, up to 5 years due to recurrent LUTS was 51% less in the Aquablation arm compared to the TURP arm. CONCLUSIONS: The improvement in net health outcomes from Aquablation therapy outweigh those offered by a TURP when considering the efficacy benefit along with the lower risk of needing a secondary BPH therapy and avoiding retrograde ejaculation. Following Aquablation therapy, symptom reduction and uroflow improvement at 5 years have shown to be durable and consistent across all years of follow up compared to TURP. Larger prostates (≥ 50 mL) demonstrated a larger safety and efficacy benefit for Aquablation over TURP.

Acute C-Terminal Crosslinking Telopeptide of Type I Collagen (CTX-1) Suppression with Milk Calcium or Calcium Carbonate Is Independent of Visceral Fat in a Randomized Crossover Study in Lean and Overweight Postmenopausal Women.

BACKGROUND: Postmenopausal women with higher visceral adipose tissue (VAT) present with suppressed bone resorption (lower C-terminal crosslinking telopeptide of type I collagen; CTX-1) and turnover (lower osteocalcin) but whether this blunts the effect of calcium is unknown. OBJECTIVES: The primary outcome of this study was the effect of VAT on changes in CTX-1 after intake of 2 forms of calcium. Secondary outcomes included changes in parathyroid hormone (PTH), serum calcium, phosphorus, and alkaline phosphatase (ALP). METHODS: Randomized open three period crossover trial conducted between 2017 and 2019 at the University of South Australia among 77 lean and overweight postmenopausal women (53-79 y) with BMI <25 kg/m2 and >27 kg/m2, respectively. Participants received a single dose of milk (1000 mg calcium), calcium carbonate tablet (1000 mg calcium), and fruit juice (no calcium) in random order with a 7-d washout period. Blood samples were collected at baseline and hourly for 5 h. Data was analyzed by repeated measures ANOVA of log-transformed data. RESULTS: At baseline, women with higher VAT had significantly lower CTX-1 and higher PTH (44% lower and 30% higher, respectively, between Q4 and Q1, P < 0.0001). VAT had no influence on the acute changes in CTX-1 or PTH with calcium or juice. A suppression of 44% in CTX-1 was seen with calcium carbonate and milk and a suppression of 18% with juice. PTH was suppressed more with calcium carbonate (47%) compared to milk (22%). Milk calcium reduced PTH and CTX-1 at 2 h, whereas calcium carbonate reduced PTH in 1 h. The suppression in CTX-1 was slower with lowest concentrations at 4-5 h. CONCLUSIONS: Intake of 1000 mg calcium from milk or from calcium carbonate is effective in acutely suppressing bone resorption in postmenopausal women irrespective of visceral fat. This trial is registered at http://www.ANZCTR.org.au/ACTRN12617000779370.aspx as ACTRN 12617000779370).

Acute C-Terminal Crosslinking Telopeptide of Type I Collagen (CTX-1) Suppression with Milk Calcium or Calcium Carbonate Is Independent of Visceral Fat in a Randomized Crossover Study in Lean and Overweight Postmenopausal Women.

BACKGROUND: Postmenopausal women with higher visceral adipose tissue (VAT) present with suppressed bone resorption (lower C-terminal crosslinking telopeptide of type I collagen; CTX-1) and turnover (lower osteocalcin) but whether this blunts the effect of calcium is unknown. OBJECTIVES: The primary outcome of this study was the effect of VAT on changes in CTX-1 after intake of 2 forms of calcium. Secondary outcomes included changes in parathyroid hormone (PTH), serum calcium, phosphorus, and alkaline phosphatase (ALP). METHODS: Randomized open three period crossover trial conducted between 2017 and 2019 at the University of South Australia among 77 lean and overweight postmenopausal women (53-79 y) with BMI <25 kg/m2 and >27 kg/m2, respectively. Participants received a single dose of milk (1000 mg calcium), calcium carbonate tablet (1000 mg calcium), and fruit juice (no calcium) in random order with a 7-d washout period. Blood samples were collected at baseline and hourly for 5 h. Data was analyzed by repeated measures ANOVA of log-transformed data. RESULTS: At baseline, women with higher VAT had significantly lower CTX-1 and higher PTH (44% lower and 30% higher, respectively, between Q4 and Q1, P < 0.0001). VAT had no influence on the acute changes in CTX-1 or PTH with calcium or juice. A suppression of 44% in CTX-1 was seen with calcium carbonate and milk and a suppression of 18% with juice. PTH was suppressed more with calcium carbonate (47%) compared to milk (22%). Milk calcium reduced PTH and CTX-1 at 2 h, whereas calcium carbonate reduced PTH in 1 h. The suppression in CTX-1 was slower with lowest concentrations at 4-5 h. CONCLUSIONS: Intake of 1000 mg calcium from milk or from calcium carbonate is effective in acutely suppressing bone resorption in postmenopausal women irrespective of visceral fat. This trial is registered at http://www.ANZCTR.org.au/ACTRN12617000779370.aspx as ACTRN 12617000779370).

Vitamin D receptor expression in mature osteoclasts reduces bone loss due to low dietary calcium intake in male mice.

Mature osteoclasts express the vitamin D receptor (VDR) and are able to respond to active vitamin D (1α, 25-dihydroxyvitamin D3; 1,25(OH)2D3) by regulating cell maturation and activity. However, the in vivo consequences of vitamin D signalling directly within functionally mature osteoclasts is only partially understood. To investigate the in vivo role of VDR in mature osteoclasts, conditional deletion of the VDR under control of the cathepsin K promoter (CtskCre/Vdr-/-), was assessed in 6 and 12-week-old mice, either under normal dietary conditions (NormCaP) or when fed a low calcium (0.03 %), low phosphorous (0.08 %) diet (LowCaP). Splenocytes from CtskCre/Vdr-/- mice were co-cultured with MLO-Y4 osteocyte-like cells to assess the effect on osteoclastogenesis. Six-week-old CtskCre/Vdr-/- mice demonstrated a 10 % decrease in vertebral bone volume (p < 0.05), which was associated with increased osteoclast size (p < 0.05) when compared to Vdrfl/fl control mice. Control mice fed a LowCaP diet exhibited extensive trabecular bone loss associated with increased osteoclast surface, number and size (p < 0.0001). Interestingly, CtskCre/Vdr-/- mice fed a LowCaP diet showed exacerbated loss of bone volume fraction (BV/TV%) and trabecular number (Tb.N), by a further 22 % and 21 %, respectively (p < 0.05), suggesting increased osteoclastic bone resorption activity with the loss of VDR in mature osteoclasts under these conditions. Co-culture of CtskCre/Vdr-/- splenocytes with MLO-Y4 cells increased resulting osteoclast numbers 2.5-fold, which were greater in nuclei density and exhibited increased resorption of dentine compared to osteoclasts derived from Vdrfl/fl splenocyte cultures. These data suggest that in addition to RANKL-mediated osteoclastogenesis, intact VDR signalling is required for the direct regulation of the differentiation and activity of osteoclasts in both in vivo and ex vivo settings.

Rationale for Bone Health Optimization in Patients Undergoing Orthopaedic Surgery.

Osteoporosis is common, affecting more than 40 million people, and is associated with increased fracture risk, loss of independence, chronic pain, and disability. Osteoporosis is underdiagnosed and undertreated even after fracture where secondary fracture prevention has been shown to be cost effective in reducing further fracture risk and mortality. Osteoporosis is also undiagnosed in patients undergoing orthopaedic and spine surgery in up to one-third of cases and negatively affects outcomes, need for revision surgery, and risk of complications. The diagnosis of osteoporosis was previously based on bone mineral density; however, recent clinical definitions include T-scores less than -2.5, the presence of hip and spine fractures, and high fracture risk. Surgeons should adopt bone health optimization for elective surgery. This program screens patients to determine whether a bone mineral density test is indicated and provides counseling for nutritional supplements, elimination of toxins, fall risk assessment, and education regarding bone health. Following assessment, patients meeting the criteria for osteoporosis are referred to a bone health specialist or a fracture liaison program. Both antiresorptive and anabolic antiosteoporotic medications appear effective at improving outcomes and reducing complications of orthopaedic and spine surgery, although a delay in surgery may be required.

The Basics of Bone Physiology, Healing, and Osteoporosis.

Osteoporosis is a skeletal condition characterized by decreased bone mineral density and poor bone quality with resultant greater fracture risk. There has been a focus on bone mineral density deficiency, which is easily measured with dual-energy x-ray absorptiometry and managed with pharmaceutic medications. More recently, impaired bone quality independent of bone mineral density has been recognized as a potential cause of fragility fracture and poor bone healing. Many conditions lead to poor bone quality; the most common is vitamin D deficiency and others are genetic causes and other nutritional deficits. In addition, the cellular and molecular changes associated with osteoporosis are being investigated and are potential targets for treatment. Treatment of patients with poor bone health include nutritional supplementation with vitamin D and calcium, weight-bearing exercises, and antiosteoporotic medications when warranted. Antiosteoporotic medications include antiresorptive drugs such as diphosphonate and denosumab that inhibit osteoclastic bone resorption. Anabolic agents such as teriparatide, abaloparatide, and romosozumab stimulate osteoblastic differentiation and bone formation. All these agents are effective in reducing fracture risk.

Vitamin D supplementation improves bone mineralisation independent of dietary phosphate in male X-linked hypophosphatemic (Hyp) mice.

The disorder of X-linked hypophosphatemia (XLH), results in the supressed renal production of active 1α,25-dihydroxyvitamin D (1,25(OH)2D) due to elevated fibroblast growth factor-23 (FGF23) levels. While adequate 25(OH)D levels are generally associated with improved mineralisation of the skeleton independent of circulating 1,25(OH)2D levels, it is unclear whether raising 25(OH)D to sufficiently high levels through dietary vitamin D3 administration contributes to improving bone mineralisation in the murine homolog for XLH, Hyp mice. Three-week-old male Hyp mice were fed one of four diets containing either 1000 IU (C) or 20,000 IU (D) vitamin D3/kg diet with either 0.35% phosphate or 1.25% phosphate (P) until 12 weeks of age (n = 12/group). When compared to C-fed mice, D-fed mice significantly elevated serum 25(OH)D levels to 72.8 ± 4.9 nmol/L (2-fold, p < 0.001) and increased both cortical bone mineral density (15%, p < 0.01), and vertebral trabecular BV/TV% (80%, p < 0.001), despite persistent hypophosphatemia and normocalcemia. The increase in bone volume was associated with improved Tb.Th (12%, p < 0.01) and Tb.N (63%, p < 0.001). Unlike with D-diet, P-fed mice resulted in increased femoral (15%, p < 0.001) and vertebral (12%, p < 0.001) length, and a 34% increase in vertebral trabecular BV/TV% when compared to control fed animals (p < 0.001). However, the addition of the high P diet to the high D diet did not result in additive effects on bone mineralisation when compared to the effects of D diet alone, despite serum 25(OH)D levels elevated to 118.8 ± 8.6 nmol/L. In D-fed mice, the increase in bone mineral density and volume was associated with reduced osteoid volume, reduced ObS/BS, and a trend for reduced serum PTH levels, suggesting reduced bone turnover in these animals. Thus, elevating serum 25(OH)D levels independently improves bone mineralisation in Hyp mice without causing hypercalcemia, suggesting that further studies are required in XLH patients to establish the role of increasing 25(OH)D levels in improving bone mineralisation.

Interventions for sexual dysfunction following stroke.

BACKGROUND: Sexual dysfunction following stroke is common but often is poorly managed. As awareness of sexual dysfunction following stroke increases as an important issue, a clearer evidence base for interventions for sexual dysfunction is needed to optimise management. OBJECTIVES: To evaluate the effectiveness of interventions to reduce sexual dysfunction following stroke, and to assess adverse events associated with interventions for sexual dysfunction following stroke. SEARCH METHODS: We conducted the search on 27 November 2019. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; from June 2014), in the Cochrane Library; MEDLINE (from 1950); Embase (from 1980); the Cumulative Index to Nursing and Allied Health Literature (CINAHL; from 1982); the Allied and Complementary Medicine Database (AMED; from 1985); PsycINFO (from 1806); the Physiotherapy Evidence Database (PEDro; from 1999); and 10 additional bibliographic databases and ongoing trial registers. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared pharmacological treatments, mechanical devices, or complementary medicine interventions versus placebo. We also included other non-pharmacological interventions (such as education or therapy), which were compared against usual care or different forms of intervention (such as different intensities) for treating sexual dysfunction in stroke survivors. DATA COLLECTION AND ANALYSIS: Two review authors independently selected eligible studies, extracted data, and assessed study quality. We determined the risk of bias for each study and performed a 'best evidence' synthesis using the GRADE approach. MAIN RESULTS: We identified three RCTs with a total of 212 participants. We noted significant heterogeneity in interventions (one pharmacological, one physiotherapy-based, and one psycho-educational), and all RCTs were small and of 'low' or 'very low' quality. Based on these RCTs, data are insufficient to provide any reliable indication of benefit or risk to guide clinical practice in terms of the use of sertraline, specific pelvic floor muscle training, or individualised sexual rehabilitation. AUTHORS' CONCLUSIONS: Use of sertraline to treat premature ejaculation needs to be tested in further RCTs. The lack of benefit with structured sexual rehabilitation and pelvic floor physiotherapy should not be interpreted as proof of ineffectiveness. Well-designed, randomised, double-blinded, placebo-controlled trials of long-term duration are needed to determine the effectiveness of various types of interventions for sexual dysfunction. It should be noted, however, that it may not be possible to double-blind trials of complex interventions.

Three-year outcomes after Aquablation therapy compared to TURP: results from a blinded randomized trial.

INTRODUCTION: To compare 3-year efficacy and safety after prostate resection with Aquablation therapy or transurethral resection of the prostate (TURP) for the treatment of lower urinary tract symptoms related to benign prostate hyperplasia (BPH). MATERIALS AND METHODS: One hundred and eighty-one patients assigned to either Aquablation therapy or TURP were followed for 3 years postoperatively. Patients and follow up assessors were blinded to treatment. Assessments included International Prostate Symptom Score (IPSS), Male Sexual Health Questionnaire (MSHQ-EjD), International Index of Erectile Function (IIEF) and uroflow. RESULTS: Over 3 years of treatment, improvements in IPSS scores were statistically similar across groups. Mean 3-year improvements were 14.4 and 13.9 points in the Aquablation and TURP groups, respectively (difference of 0.6 points, 95% CI -3.3-2.2, p = .6848). Similarly, 3-year improvements in Qmax were 11.6 and 8.2 cc/sec (difference of 3.3 [95% CI -0.5-7.1] cc/sec, p = .0848). At 3 years, PSA was reduced significantly in both groups by 0.9 and 1.1 ng/mL, respectively; the reduction was similar across groups (p = .5983). There were no surgical retreatments for BPH beyond 20 months for either Aquablation or TURP. CONCLUSIONS: Three-year BPH symptom reduction and urinary flow rate improvement were similar after TURP and Aquablation therapy. No subjects required surgical retreatment beyond 20 months postoperatively. (ClinicalTrials.gov number, NCT02505919).

Elevated Serum 25-Hydroxyvitamin D Levels Are Associated with Improved Bone Formation and Micro-Structural Measures in Elderly Hip Fracture Patients.

Vitamin D, along with calcium, is generally considered necessary for bone health and reduction of fractures. However, he effects of improving vitamin D status have not always been observed to improve bone mineral density (BMD). We have investigated whether varying vitamin D status in humans, as measured by serum 25(OH)D levels, relate to micro-structural and histomorphetric measures of bone quality and quantity, rather than density. Intertrochanteric trabecular bone biopsies and serum samples were collected from patients undergoing hip arthroplasty (65 females, 38 males, mean age 84.8 ± 8.3 years) at Royal Adelaide Hospital. Estimated GFR, serum ionized calcium, alkaline phosphatase, albumin, supplement and medication intake prior to surgery were taken from patient case records. Serum 25(OH)D, 1,25(OH)2D, and parathyroid hormone (PTH) levels were measured by immunoassays. Trabecular bone structural indices were determined by high-resolution micro-CT. Mean wall thickness (MWT) was measured on toluidine blue-stained histological sections. Bone mRNA levels for vitamin D metabolising enzymes CYP27B1 and CYP24A1 were measured by qRT-PCR. While serum 25(OH)D levels did not associate with bone volume/tissue volume (BV/TV%), serum 25(OH)D levels were strongly and independently associated with MWT (r = 0.81 p < 0.0001) with values significantly greater in patients with higher serum 25(OH)D levels. Furthermore, serum 25(OH)D levels were negatively associated with Bone Surface/Bone Volume (BS/BV) (r = -0.206, p < 0.05) and together with bone CYP27B1 and CYP24A1 mRNA accounted for 10% of the variability of BS/BV (p = 0.001). These data demonstrate that serum 25(OH)D is an independent positive predictor of micro-structural and bone formation measures and may be dependent, in part, on its metabolism within the bone.

Two-Year Outcomes After Aquablation Compared to TURP: Efficacy and Ejaculatory Improvements Sustained.

INTRODUCTION: To compare 2-year safety and efficacy outcomes after Aquablation or transurethral resection of the prostate (TURP) for the treatment of lower urinary tract symptoms related to benign prostate hyperplasia (BPH). METHODS: One hundred eighty-one patients with BPH were assigned at random (2:1 ratio) to either Aquablation or TURP. Patients and follow-up assessors were blinded to treatment. Assessments included the International Prostate Symptom Score (IPSS), Male Sexual Health Questionnaire (MSHQ), International Index of Erectile Function and uroflow. The focus of analysis was 2-year outcomes. RESULTS: At 2 years, IPSS scores improved by 14.7 points in the Aquablation group and 14.9 points in TURP (p = .8304, 95% CI for difference - 2.1 to 2.6 points). Two-year improvements in maximum flow rate (Qmax) were large in both groups at 11.2 and 8.6 cc/s for Aquablation and TURP, respectively (p = 0.1880, 95% CI for difference - 1.3 to 6.4). Sexual function as assessed by MSHQ was stable in the Aquablation group and decreased slightly in the TURP group. At 2 years, PSA was reduced significantly in both groups by 0.7 and 1.2 points, respectively; the reduction was similar across groups (p = 0.1816). Surgical retreatment rates after 12 months for Aquablation were 1.7% and 0% for TURP. Over 2 years, surgical BPH retreatment rates were 4.3% and 1.5% (p = 0.4219), respectively. CONCLUSION: Two-year efficacy outcomes after TURP and Aquablation were similar, and the rate of surgical retreatment was low and similar to TURP. TRIAL REGISTRATION: ClinicalTrials.gov no. NCT02505919. FUNDING: PROCEPT BioRobotics.

Randomized Controlled Trial of Aquablation versus Transurethral Resection of the Prostate in Benign Prostatic Hyperplasia: One-year Outcomes.

OBJECTIVE: To report 1-year safety and efficacy outcomes after either Aquablation or transurethral resection of the prostate (TURP) for the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia (BPH) METHODS: This double-blinded, multicenter prospective randomized controlled trial assigned 181 patients with BPH-related moderate-to-severe lower urinary tract symptoms to either electrocautery-based prostate resection (TURP) or Aquablation. Efficacy endpoints included reduction in International Prostate Symptom Score and improvement in uroflow parameters. The primary safety endpoint was the occurrence of Clavien-Dindo persistent grade 1 or grade 2 or higher complications. RESULTS: BPH symptom score improvements were similar across groups with 12-month reduction of 15.1 points after TURP or Aquablation. In both groups, mean maximum urinary flow rates increased markedly postoperatively, with mean improvements of 10.3 cc/s for Aquablation versus 10.6 cc/s for TURP (P = .8632). At 1 year, Prostate-specific antigen (PSA) was reduced significantly (P < .01) in both groups by 1 point; the reduction was similar across groups (P = .9125). Surgical retreatment for BPH rates for TURP were 1.5% and Aquablation 2.6% within 1 year from the study procedure (P = not significant (NS)). The rate of late complications was low, with no procedure-related adverse events after month 6. CONCLUSION: The 1-year outcomes after TURP and Aquablation were similar and the rate of late procedure-related complications was low. (ClinicalTrials.gov number, NCT02505919).

Symptom relief and anejaculation after aquablation or transurethral resection of the prostate: subgroup analysis from a blinded randomized trial.

OBJECTIVE: To test the hypothesis that benign prostatic hyperplasia (BPH) robotic surgery with aquablation would have a more pronounced benefit in certain patient subgroups, such as men with more challenging anatomies (e.g. large prostates, large middle lobes) and men with moderate BPH. METHODS: We conducted prespecified and post hoc exploratory subgroup analyses from a double-blind, multicentre prospective randomized controlled trial that compared transurethral resection of the prostate (TURP) using either standard electrocautery vs surgery using robotic waterjet (aquablation) to determine whether certain baseline factors predicted more marked responses after aquablation as compared with TURP. The primary efficacy endpoint was reduction in International Prostate Symptom Score (IPSS) at 6 months. The primary safety endpoint was the occurrence of Clavien-Dindo persistent grade 1 or grade ≥2 surgical complications. RESULTS: For men with larger prostates (50-80 g), the mean IPSS reduction was four points greater after aquablation than after TURP (P = 0.001), a larger difference than the overall result (1.8 points; P = 0.135). Similarly, the primary safety endpoint difference (20% vs 46% [26% difference]; P = 0.008) was greater for men with large prostate compared with the overall result (26% vs 42% [16% difference]; P = 0.015). Postoperative anejaculation was also less common after aquablation compared with TURP in sexually active men with large prostates (2% vs 41%; P < 0.001) vs the overall results (10% vs 36%; P < 0.001). Exploratory analysis showed larger IPSS changes after aquablation in men with enlarged middle lobes, men with severe middle lobe obstruction, men with a low baseline maximum urinary flow rate, and men with elevated (>100) post-void residual urine volume. CONCLUSIONS: In men with moderate-to-severe lower urinary tract symptoms attributable to BPH and larger, more complex prostates, aquablation was associated with both superior symptom score improvements and a superior safety profile, with a significantly lower rate of postoperative anejaculation. The standardized, robotically executed, surgical approach with aquablation may overcome the increased outcome variability in more complex anatomy, resulting in superior symptom score reduction.

A Fully Automated High-Throughput Flow Cytometry Screening System Enabling Phenotypic Drug Discovery.

The goal of high-throughput screening is to enable screening of compound libraries in an automated manner to identify quality starting points for optimization. This often involves screening a large diversity of compounds in an assay that preserves a connection to the disease pathology. Phenotypic screening is a powerful tool for drug identification, in that assays can be run without prior understanding of the target and with primary cells that closely mimic the therapeutic setting. Advanced automation and high-content imaging have enabled many complex assays, but these are still relatively slow and low throughput. To address this limitation, we have developed an automated workflow that is dedicated to processing complex phenotypic assays for flow cytometry. The system can achieve a throughput of 50,000 wells per day, resulting in a fully automated platform that enables robust phenotypic drug discovery. Over the past 5 years, this screening system has been used for a variety of drug discovery programs, across many disease areas, with many molecules advancing quickly into preclinical development and into the clinic. This report will highlight a diversity of approaches that automated flow cytometry has enabled for phenotypic drug discovery.

WATER: A Double-Blind, Randomized, Controlled Trial of Aquablation® vs Transurethral Resection of the Prostate in Benign Prostatic Hyperplasia.

PURPOSE: We compared the safety and efficacy of Aquablation and transurethral prostate resection for the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia. MATERIALS AND METHODS: In a double-blind, multicenter, prospective, randomized, controlled trial 181 patients with moderate to severe lower urinary tract symptoms related to benign prostatic hyperplasia underwent transurethral prostate resection or Aquablation. The primary efficacy end point was the reduction in International Prostate Symptom Score at 6 months. The primary safety end point was the development of Clavien-Dindo persistent grade 1, or 2 or higher operative complications. RESULTS: Mean total operative time was similar for Aquablation and transurethral prostate resection (33 vs 36 minutes, p = 0.2752) but resection time was lower for Aquablation (4 vs 27 minutes, p <0.0001). At month 6 patients treated with Aquablation and transurethral prostate resection experienced large I-PSS improvements. The prespecified study noninferiority hypothesis was satisfied (p <0.0001). Of the patients who underwent Aquablation and transurethral prostate resection 26% and 42%, respectively, experienced a primary safety end point, which met the study primary noninferiority safety hypothesis and subsequently demonstrated superiority (p = 0.0149). Among sexually active men the rate of anejaculation was lower in those treated with Aquablation (10% vs 36%, p = 0.0003). CONCLUSIONS: Surgical prostate resection using Aquablation showed noninferior symptom relief compared to transurethral prostate resection but with a lower risk of sexual dysfunction. Larger prostates (50 to 80 ml) demonstrated a more pronounced superior safety and efficacy benefit. Longer term followup would help assess the clinical value of Aquablation.

Provitamin A biofortification of cassava enhances shelf life but reduces dry matter content of storage roots due to altered carbon partitioning into starch.

Storage roots of cassava (Manihot esculenta Crantz), a major subsistence crop of sub-Saharan Africa, are calorie rich but deficient in essential micronutrients, including provitamin A ß-carotene. In this study, ß-carotene concentrations in cassava storage roots were enhanced by co-expression of transgenes for deoxy-d-xylulose-5-phosphate synthase (DXS) and bacterial phytoene synthase (crtB), mediated by the patatin-type 1 promoter. Storage roots harvested from field-grown plants accumulated carotenoids to ≤50 µg/g DW, 15- to 20-fold increases relative to roots from nontransgenic plants. Approximately 85%-90% of these carotenoids accumulated as all-trans-ß-carotene, the most nutritionally efficacious carotenoid. ß-Carotene-accumulating storage roots displayed delayed onset of postharvest physiological deterioration, a major constraint limiting utilization of cassava products. Large metabolite changes were detected in ß-carotene-enhanced storage roots. Most significantly, an inverse correlation was observed between ß-carotene and dry matter content, with reductions of 50%-60% of dry matter content in the highest carotenoid-accumulating storage roots of different cultivars. Further analysis confirmed a concomitant reduction in starch content and increased levels of total fatty acids, triacylglycerols, soluble sugars and abscisic acid. Potato engineered to co-express DXS and crtB displayed a similar correlation between ß-carotene accumulation, reduced dry matter and starch content and elevated oil and soluble sugars in tubers. Transcriptome analyses revealed a reduced expression of genes involved in starch biosynthesis including ADP-glucose pyrophosphorylase genes in transgenic, carotene-accumulating cassava roots relative to nontransgenic roots. These findings highlight unintended metabolic consequences of provitamin A biofortification of starch-rich organs and point to strategies for redirecting metabolic flux to restore starch production.

The N-Methyl d-Aspartate Glutamate Receptor Antagonist Ketamine Disrupts the Functional State of the Corticothalamic Pathway.

The non-competitive N-methyl d-aspartate glutamate receptor (NMDAR) antagonist ketamine elicits a brain state resembling high-risk states for developing psychosis and early stages of schizophrenia characterized by sensory and cognitive deficits and aberrant ongoing gamma (30-80 Hz) oscillations in cortical and subcortical structures, including the thalamus. The underlying mechanisms are unknown. The goal of the present study was to determine whether a ketamine-induced psychotic-relevant state disturbs the functional state of the corticothalamic (CT) pathway. Multisite field recordings were performed in the somatosensory CT system of the sedated rat. Baseline activity was challenged by activation of vibrissa-related prethalamic inputs. The sensory-evoked thalamic response was characterized by a short-latency (∼4 ms) prethalamic-mediated negative sharp potential and a longer latency (∼10 ms) CT-mediated negative potential. Following a single subcutaneous injection of ketamine (2.5 mg/kg), spontaneously occurring and sensory-evoked thalamic gamma oscillations increased and decreased in power, respectively. The power of the sensory-related gamma oscillations was positively correlated with both the amplitude and the area under the curve of the corresponding CT potential but not with the prethalamic potential. The present results show that the layer VI CT pathway significantly contributes in thalamic gamma oscillations, and they support the hypothesis that reduced NMDAR activation disturbs the functional state of CT and corticocortical networks.