Efficacy, tolerability, and bone density outcomes of elagolix with add-back therapy for endometriosis-associated pain: 12 months of an ongoing randomized phase 3 trial.

BACKGROUND: Elagolix, an approved oral treatment for endometriosis-associated pain, has been associated with hypoestrogenic effects when used as monotherapy. Hormonal add-back therapy has the potential to mitigate these effects. OBJECTIVE: To evaluate efficacy, tolerability, and bone density outcomes of elagolix 200 mg twice daily with 1 mg estradiol /0.5 mg norethindrone acetate (add-back) therapy once daily compared with placebo in premenopausal women with moderate-to-severe endometriosis-associated pain. STUDY DESIGN: This ongoing, 48-month, phase 3 study consists of a 12-month, double-blind period, with randomization 4:1:2 to elagolix 200 mg twice daily with add-back therapy, elagolix 200 mg twice daily monotherapy for 6 months followed by elagolix with add-back therapy, or placebo. The co-primary endpoints were proportion of patients with clinical improvement (termed "responders") in dysmenorrhea and nonmenstrual pelvic pain at month 6. We report 12-month results on efficacy of elagolix with add-back therapy versus placebo in reducing dysmenorrhea, nonmenstrual pelvic pain, dyspareunia, and fatigue. Tolerability assessments include adverse events and change from baseline in bone mineral density. RESULTS: A total of 679 patients were randomized to elagolix with add-back therapy (n=389), elagolix monotherapy (n=97), or placebo (n=193). Compared with patients randomized to placebo, a significantly greater proportion of patients randomized to elagolix with add-back therapy responded with clinical improvement in dysmenorrhea (62.8% versus 23.7%; P≤.001) and nonmenstrual pelvic pain (51.3% versus 36.8%; P≤.001) at 6 months. Compared with placebo, elagolix with add-back therapy produced significantly greater improvement from baseline in 7 hierarchically ranked secondary endpoints including dysmenorrhea (months 12, 6, 3), nonmenstrual pelvic pain (months 12, 6, 3), and fatigue (months 6) (all P<.01). Overall, the incidence of adverse events was 73.8% with elagolix plus add-back therapy and 66.8% with placebo. The rate of severe and serious adverse events did not meaningfully differ between treatment groups. Study drug discontinuations associated with adverse events were low in patients receiving elagolix with add-back therapy (12.6%) and those receiving placebo (9.8%). Patients randomized to elagolix monotherapy exhibited decreases from baseline in bone mineral density of -2.43% (lumbar spine), -1.54% (total hip), and -1.78% (femoral neck) at month 6. When add-back therapy was added to elagolix at month 6, the change from baseline in bone mineral density remained in a similar range of -1.58% to -1.83% at month 12. However, patients who received elagolix plus add-back therapy from baseline exhibited little change from baseline in bone mineral density (<1% change) at months 6 and 12. CONCLUSION: Compared with placebo, elagolix with add-back therapy resulted in significant, clinically meaningful improvement in dysmenorrhea, nonmenstrual pelvic pain, and fatigue at 6 months that continued until month 12 for both dysmenorrhea and nonmenstrual pelvic pain. Elagolix with add-back therapy was generally well tolerated. Loss of bone mineral density at 12 months was greater in patients who received elagolix with add-back therapy than those who received placebo. However, the change in bone mineral density with elagolix plus add-back therapy was < 1% and was attenuated compared with bone loss observed with elagolix monotherapy.

Regulatory Framework for Implantable Neurostimulation Devices: Comparison of Systems in the US and European Union.

BACKGROUND: Implantable neurostimulation devices must be authorized before they are placed on the market. For this purpose, requirements, and processes for assessing their fulfillment, have been defined in different jurisdictions. OBJECTIVE: In this study, we aimed to address differences between the US and European Union (EU) regulatory systems and their relationship to innovation. MATERIALS AND METHODS: A literature review and analysis were conducted using legal texts and guidance documents. RESULTS: The US system has one central body, the Food and Drug Administration, whereas the EU system has several bodies with different responsibilities. The devices themselves are divided into risk classes, which are based on the vulnerability of the human body. This risk class determines the intensity of the review by the market authorization body. In addition to the requirements for development, manufacture, and distribution, the device itself must meet technical and clinical requirements. Compliance with technical requirements is indicated by nonclinical laboratory studies. Proof of efficacy is provided by means of clinical investigations. Procedures are defined for reviewing these elements. Once the market authorization process has been completed, the devices can be placed on the market. In the postmarketing phase, the devices must continue to be monitored, and measures must be initiated, if necessary. CONCLUSIONS: Both US and EU systems are intended to ensure that only safe and effective devices find their way to and remain on the market. The basic approaches of the two systems are comparable. In detail, however, there are differences in ways these goals are achieved.

Implications of the Propagation Method for the Phytochemistry of Nepeta cataria L. throughout a Growing Season.

Catnip (Nepeta cataria L.) plants produce a wide array of specialized metabolites with multiple applications for human health. The productivity of such metabolites, including nepetalactones, and natural insect repellents is influenced by the conditions under which the plants are cultivated. In this study, we assessed how field-grown catnip plants, transplanted after being propagated via either single-node stem cuttings or seeds, varied regarding their phytochemical composition throughout a growing season in two distinct environmental conditions (Pittstown and Upper Deerfield) in the state of New Jersey, United States. Iridoid terpenes were quantified in plant tissues via ultra-high-performance liquid chromatography with triple quadrupole mass spectrometry (UHPLC-QqQ-MS), and phenolic compounds (phenolic acids and flavonoids) were analyzed via UHPLC with diode-array detection (UHPLC-DAD). The highest contents of total nepetalactones in Pittstown were found at 6 weeks after transplanting (WAT) for both seedlings and cuttings (1305.4 and 1223.3 mg/100 g, respectively), while in Upper Deerfield, the highest contents for both propagules were at 11 WAT (1247.7 and 997.1 mg/100 g, respectively) for seed-propagated and stem cuttings). The highest concentration of nepetalactones was associated with floral-bud to partial-flowering stages. Because plants in Pittstown accumulated considerably more biomass than plants grown in Upper Deerfield, the difference in nepetalactone production per plant was striking, with peak productivity reaching only 598.9 mg per plant in Upper Deerfield and 1833.1 mg per plant in Pittstown. Phenolic acids accumulated in higher contents towards the end of the season in both locations, after a period of low precipitation, and flavone glycosides had similar accumulation patterns to nepetalactones. In both locations, rooted stem cuttings reached their maximum nepetalactone productivity, on average, four weeks later than seed-propagated plants, suggesting that seedlings have, overall, better agronomic performance.

Elagolix for Heavy Menstrual Bleeding in Women with Uterine Fibroids.

BACKGROUND: Uterine fibroids are hormone-responsive neoplasms that are associated with heavy menstrual bleeding. Elagolix, an oral gonadotropin-releasing hormone antagonist resulting in rapid, reversible suppression of ovarian sex hormones, may reduce fibroid-associated bleeding. METHODS: We conducted two identical, double-blind, randomized, placebo-controlled, 6-month phase 3 trials (Elaris Uterine Fibroids 1 and 2 [UF-1 and UF-2]) to evaluate the efficacy and safety of elagolix at a dose of 300 mg twice daily with hormonal "add-back" therapy (to replace reduced levels of endogenous hormones; in this case, estradiol, 1 mg, and norethindrone acetate, 0.5 mg, once daily) in women with fibroid-associated bleeding. An elagolix-alone group was included to assess the impact of add-back therapy on the hypoestrogenic effects of elagolix. The primary end point was menstrual blood loss of less than 80 ml during the final month of treatment and at least a 50% reduction in menstrual blood loss from baseline to the final month; missing data were imputed with the use of multiple imputation. RESULTS: A total of 412 women in UF-1 and 378 women in UF-2 underwent randomization, received elagolix or placebo, and were included in the analyses. Criteria for the primary end point were met in 68.5% of 206 women in UF-1 and in 76.5% of 189 women in UF-2 who received elagolix plus add-back therapy, as compared with 8.7% of 102 women and 10% of 94 women, respectively, who received placebo (P<0.001 for both trials). Among the women who received elagolix alone, the primary end point was met in 84.1% of 104 women in UF-1 and in 77% of 95 women in UF-2. Hot flushes (in both trials) and metrorrhagia (in UF-1) occurred significantly more commonly with elagolix plus add-back therapy than with placebo. Hypoestrogenic effects of elagolix, especially decreases in bone mineral density, were attenuated with add-back therapy. CONCLUSIONS: Elagolix with add-back therapy was effective in reducing heavy menstrual bleeding in women with uterine fibroids. (Funded by AbbVie; Elaris UF-1 and Elaris UF-2 ClinicalTrials.gov numbers, NCT02654054 and NCT02691494.).

Symptoms and associated impact in pre- and postmenopausal women with sexual arousal disorder: a concept elicitation study.

BACKGROUND: Approximately 26% of adult women in the United States suffer from female sexual arousal disorder (FSAD), yet little has been done to compare the experience of FSAD in pre- and postmenopausal women, which is critical to enhance the current understanding of FSAD and inform the development and assessment of treatment options for these patient populations. AIM: To explore the experience of condition-associated symptoms and the relative importance of FSAD symptoms, including their severity, bother, and impact, on participants' health-related quality of life (HRQoL) in pre- and postmenopausal women with FSAD. METHODS: In-depth, qualitative, semistructured concept elicitation interviews were conducted with premenopausal (n = 23) and postmenopausal (n = 13) women who were clinically diagnosed with FSAD by a trained sexual medicine clinician. All interviews were audio recorded and transcribed verbatim by a professional transcription company. Thematic analysis was performed with the assistance of NVivo qualitative analysis software. OUTCOMES: Outcomes included qualitative interview data about FSAD symptoms and HRQoL, as well as a comparison between pre- and postmenopausal populations. RESULTS: The most frequently reported symptom in both cohorts was "inability or difficulty with orgasm" (premenopausal, n = 21; postmenopausal, n = 13). The symptom that premenopausal women most desired to have treated was lubrication, and for postmenopausal women, it was a lack of lubrication or wetness and loss of feeling/sensation. In total, 21 of 23 premenopausal women and all 13 postmenopausal women reported a lack of feeling or sensation in the genitals. The most frequently reported HRQoL impact in both groups was decreased confidence. CLINICAL IMPLICATIONS: Results from this study suggest that the manifestation and experience of FSAD are similar in pre- and postmenopausal women and that the unmet need for an FSAD treatment in the postmenopausal population is just as great as that of the premenopausal population. STRENGTHS AND LIMITATIONS: This study involved in-depth qualitative interviews with a relatively small group of women (N = 36) recruited from only 5 study sites across the United States. CONCLUSION: The analysis of qualitative data from the concept elicitation interviews revealed a substantial physical and emotional burden of FSAD, underscoring the need for Food and Drug Administration-approved treatment options for pre- and postmenopausal women with FSAD.

Laboratory Comparison of Low-Cost Particulate Matter Sensors to Measure Transient Events of Pollution-Part B-Particle Number Concentrations.

Low-cost Particulate Matter (PM) sensors offer an excellent opportunity to improve our knowledge about this type of pollution. Their size and cost, which support multi-node network deployment, along with their temporal resolution, enable them to report fine spatio-temporal resolution for a given area. These sensors have known issues across performance metrics. Generally, the literature focuses on the PM mass concentration reported by these sensors, but some models of sensors also report Particle Number Concentrations (PNCs) segregated into different PM size ranges. In this study, eight units each of Alphasense OPC-R1, Plantower PMS5003 and Sensirion SPS30 have been exposed, under controlled conditions, to short-lived peaks of PM generated using two different combustion sources of PM, exposing the sensors' to different particle size distributions to quantify and better understand the low-cost sensors performance across a range of relevant environmental ranges. The PNCs reported by the sensors were analysed to characterise sensor-reported particle size distribution, to determine whether sensor-reported PNCs can follow the transient variations of PM observed by the reference instruments and to determine the relative impact of different variables on the performances of the sensors. This study shows that the Alphasense OPC-R1 reported at least five size ranges independently from each other, that the Sensirion SPS30 reported two size ranges independently from each other and that all the size ranges reported by the Plantower PMS5003 were not independent of each other. It demonstrates that all sensors tested here could track the fine temporal variation of PNCs, that the Alphasense OPC-R1 could closely follow the variations of size distribution between the two sources of PM, and it shows that particle size distribution and composition are more impactful on sensor measurements than relative humidity.

Kinkéliba (Combretum micranthum) Leaf Extract Alleviates Skin Inflammation: In Vitro and In Vivo Study.

Kinkéliba (Combretum micranthum, Seh-Haw in Wolof) is a popular bush tea in West African countries. Although the kinkéliba plant's leaves have been widely consumed for its nutritional and medicinal properties, its benefits on skin health potential have been practically untouched. In human epidermal primary keratinocytes, vitexin and isovitexin-rich kinkéliba extract treatment significantly (p < 0.001) enhanced up to 39.6% of the cell survival rate decreased by UV radiation irritation. The treatment of kinkéliba leaf extracts also reduced the production of UV-induced pro-inflammatory cytokines IL-6 and IL-8 by 57.6% and 42.5%, respectively (p < 0.001), which cause skin redness and skin barrier dysfunction, as well as wrinkles and collagen degradation. The anti-inflammation efficacy of kinkéliba leaf extracts might involve significant inhibition on the levels of cellular reactive oxygen species (ROS) (-70.8%, p < 0.001) and nitrotyrosine (-56.9%, p < 0.05). Further topical applications of kinkéliba leaf extract gel were found to reduce sodium lauryl sulfate (SLS)-induced skin inflammation: at D7, the skin trans-epidermal water loss (TEWL) and skin redness (a* value) were both reduced by 59.81% (p < 0.001) and 22.4% (p < 0.001), compared with D0. In vitro and in vivo data support a new topical application of the kinkéliba leaf as an effective active ingredient for the treatment of skin inflammation, as well as subsequent barrier dysfunction and inflammaging.

Primary tumour immune response and lymph node yields in colon cancer.

BACKGROUND: The mechanism underlying improved survival in non-metastatic colon cancer with higher lymph node (LN) yield is unknown. This study aimed to identify whether molecular features in the primary tumour were predictive of LN yield. METHODS: Clinical, genomic, transcriptomic, proteomic and methylation data of non-metastatic, colon cancers studied in The Cancer Genome Atlas were interrogated for associations with LN yield. Based on maximal survival effects, patients were segregated into high (>15) and low (≤15) LN yield. Gene set enrichment analysis was performed on transcriptomic changes to identify biological processes associated with LN yield. Correlations were validated in an independent set of Stage II colon cancers. RESULTS: High LN yield was found predictive of overall and disease-free survival. There was no association of higher LN yield and increasing nodal positivity. High LN yield was strongly linked with gene expression changes associated with the adaptive and dendritic cell immune response. This association was most prominent in node-negative cancers. Analogous findings were reproduced in the validation dataset. CONCLUSION: The study shows a strong association of an activated immune response in tumours with a high LN yield. Immunogenic tumours have a better prognosis, likely explaining the survival benefit with higher LN yields.

Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy.

BACKGROUND: B-cell anomalies play a role in the pathogenesis of membranous nephropathy. B-cell depletion with rituximab may therefore be noninferior to treatment with cyclosporine for inducing and maintaining a complete or partial remission of proteinuria in patients with this condition. METHODS: We randomly assigned patients who had membranous nephropathy, proteinuria of at least 5 g per 24 hours, and a quantified creatinine clearance of at least 40 ml per minute per 1.73 m2 of body-surface area and had been receiving angiotensin-system blockade for at least 3 months to receive intravenous rituximab (two infusions, 1000 mg each, administered 14 days apart; repeated at 6 months in case of partial response) or oral cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months). Patients were followed for 24 months. The primary outcome was a composite of complete or partial remission of proteinuria at 24 months. Laboratory variables and safety were also assessed. RESULTS: A total of 130 patients underwent randomization. At 12 months, 39 of 65 patients (60%) in the rituximab group and 34 of 65 (52%) in the cyclosporine group had a complete or partial remission (risk difference, 8 percentage points; 95% confidence interval [CI], -9 to 25; P = 0.004 for noninferiority). At 24 months, 39 patients (60%) in the rituximab group and 13 (20%) in the cyclosporine group had a complete or partial remission (risk difference, 40 percentage points; 95% CI, 25 to 55; P<0.001 for both noninferiority and superiority). Among patients in remission who tested positive for anti-phospholipase A2 receptor (PLA2R) antibodies, the decline in autoantibodies to anti-PLA2R was faster and of greater magnitude and duration in the rituximab group than in the cyclosporine group. Serious adverse events occurred in 11 patients (17%) in the rituximab group and in 20 (31%) in the cyclosporine group (P = 0.06). CONCLUSIONS: Rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months. (Funded by Genentech and the Fulk Family Foundation; MENTOR ClinicalTrials.gov number, NCT01180036.).

Sexual Dysfunction as a Harbinger of Cardiovascular Disease in Postmenopausal Women: How Far Are We?

BACKGROUND: Female sexual dysfunction (FSD) affects 40-50% of women in the general population, resulting from the interaction among organic, psychological, sociocultural and relational factors; differently from men, in women definitive clinical evidence suggesting a connection between cardiovascular (CV) diseases (CVDs) and female sexual function is still lacking. AIM: To focus on the current scientific support for an association between CV diseases and/or risk factors and FSD, focused primarily on postmenopausal women. METHODS: This is a narrative review based on an extensive literature search of peer-reviewed publications on the associations between CV diseases and/or risk factors and FSD and their underlying mechanisms, which was performed using the PubMed database. OUTCOMES: We present a summary of the evidence from clinical and preclinical studies and discuss the possible mechanisms providing the pathophysiologic bases of vasculogenic FSD. RESULTS: Growing evidence shows that female sexual function, especially arousal, is significantly affected by genital vascular impairment, which can lead to FSD. For many cardiometabolic risk factors and diseases, such as hypertension, diabetes, dyslipidemia and metabolic syndrome, an adverse impact on endothelial function as well as an association with FSD have been recognized. In this scenario, similarly to penile Doppler blood flow studies in men, clitoral Doppler ultrasound can represent an innovative and useful tool to early reveal the presence of CV risk factors and sexual dysfunction. Notably, although the prevalence of CVDs as well as of FSD increases as a function of menopause and aging, middle-aged women have shown a higher prevalence of distressing sexual problems than older and younger women. CLINICAL IMPLICATIONS: It becomes clinically relevant to assess particularly postmenopausal women for FSD and CVDs, since both disorders still remain underdiagnosed and sub-optimally untreated. Clitoral Doppler ultrasound could represent a useful technique to diagnose the presence of underlying CVD, which along with risk factors could predict sexual dysfunction in women. STRENGTHS & LIMITATIONS: This review focuses on a very important and innovative topic, providing a context for describing, elaborating and evaluating the relevant theory that sexual dysfunction could be a harbinger for CVDs also in women. However, its narrative nature as well as the lack of specifically designed studies to assess a definitive association between FSD and CVDs represent the principle limitations of this paper. CONCLUSION: Postmenopausal women, particularly those in the middle-age range, should be assessed for CV risk factors and FSD, so that both CVDs and sexual problems do not persist unnoticed. Cipriani S, Simon JA. Sexual Dysfunction as a Harbinger of Cardiovascular Disease in Postmenopausal Women: How Far Are We? J Sex Med 2022;19:1321-1332.

Review of menopausal hormone therapy with estradiol and progesterone versus other estrogens and progestins.

Objective: The objective of the present document was to review/summarize reported outcomes compared between menopausal hormone therapy (MHT) containing estradiol (E2) versus other estrogens and MHT with progesterone (P4) versus progestins (defined as synthetic progestogens).Methods: PubMed and EMBASE were systematically searched through February 2021 for studies comparing oral E2 versus oral conjugated equine estrogens (CEE) or P4 versus progestins for endometrial outcomes, venous thromboembolism (VTE), cardiovascular outcomes, breast outcomes, cognition, and bone outcomes in postmenopausal women.Results: A total of 74 comparative publications were identified/summarized. Randomized studies suggested that P4 and progestins are likely equally effective in preventing endometrial hyperplasia/cancer when used at adequate doses. E2- versus CEE-based MHT had a similar or possibly better risk profile for VTE and cardiovascular outcomes, and P4- versus progestin-based MHT had a similar or possibly better profile for breast cancer and cardiovascular outcomes. E2 may potentially protect better against age-related cognitive decline and bone fractures versus CEE; P4 was similar or possibly better versus progestins for these outcomes. Limitations are that many studies were observational and some were not adequately powered for the reported outcomes.Conclusions: Evidence suggests a differential effect of MHT containing E2 or P4 and those containing CEE or progestins, with some evidence trending to a potentially better safety profile with E2 and/or P4.

Music-based Intervention for Improving Sleep Quality of Adults without Sleep Disorder: A Systematic Review and Meta-analysis.

BACKGROUND: Listening to music is often used as a self-help intervention to improve sleep quality, but its efficacy among individuals without sleep disorder remains unclear. METHODS: A search was performed on five databases to identify for studies that examined the use of music-based intervention to improve sleep quality among individuals without sleep disorder. Random-effects meta-analysis was performed, and the certainty of evidence was evaluated using GRADE (Grading of Recommendations Assessment, Development and Evaluation). RESULTS: Twenty-two articles which recruited 1,514 participants were included for review. Meta-analysis of six studies including 424 participants did not find an improvement in sleep quality among recipients of music-based intervention compared to those with standard care (mean difference: -0.80; 95% CI: -2.15 to 0.54, low-quality evidence). Subgroup analysis showed a clear improvement in sleep quality when interventions were administered for at least 3 weeks (-2.09; -3.84 to -0.34, n = 3). No difference in terms of sleep onset latency (standardized mean difference (SMD) -0.32; 95% CI -0.88 to 0.25, n = 4, very-low quality evidence) and sleep efficiency (SMD: -0.59; 95% CI -3.15 to 1.97, n = 2, very-low quality evidence) were observed. The effect of music-based intervention on anxiety, depression and quality of life were mixed with suggestions of possible benefits. CONCLUSION: Music-based intervention in addition to standard care appears to be a promising strategy to improve sleep quality when delivered for 3 week or longer. However, effects are inconsistent across studies and larger randomized controlled studies reporting long-term outcomes are needed before it can be recommended for routine use. PROSPERO REGISTRATION: CRD42018081193.

First report of Powdery Mildew Caused by Golovinomyces ambrosiae on Industrial Hemp in New Jersey.

In December 2019, New Jersey became one of the first states to have its industrial hemp (Cannabis sativa L.) plan approved by the U.S. Department of Agriculture (USDA) following enactment of the 2018 Farm Bill that authorized the production of hemp. Following this approval, hemp was legally grown for the first time in 2020. During the growing seasons of 2020 and 2021, powdery mildew-like symptoms were observed during the summer months (Jun to Aug) in greenhouse hemp research and fall months (Aug to Oct) in field production plots on Rutgers Agricultural Experiment Station farms in southern and northern New Jersey. Symptoms were observed on leaves and stems of hemp cultivars 'CB Genius', 'Cherry Wine' and 'Bay Mist'. Symptoms initially appeared as small white patches of mycelia and conidia on the adaxial surface of leaves that gradually spread to entire leaves and stems. Leaf discoloration (e.g., chlorosis) and premature leaf drop were observed. More severe symptoms and damage were observed in the greenhouse than outdoor cultivation. A voucher specimen was deposited in the U.S National Fungus Collections, USDA-ARS, Beltsville, MD (accession number 929187). Morphological examination of the white colonies from the cultivar 'Baymist' was carried out using light microscopy and further characterized by sequencing. This isolate was labelled PMH2. Hyphae were septate, conidiophores were hyaline, unbranched, measuring 130 to 240 µm in length and produced 1 to 4 conidia in chains. Conidia were hyaline, ellipsoid to ovoid in shape and measured 20 to 36 ×10 to 18 µm (n=30). Oil-like drops were present within conidia, although no distinct fibrosin bodies were observed. Chasmothecia were not observed. Morphological observations were consistent with those of Golovinomyces spp. as described by Braun and Cook (2012). Morphological observations (conidiophore and conidial measurements) were also similar to the description of G. ambrosiae on Hemp, as described in Wiseman et al, 2021. Sequencing of internal transcribed spacer (ITS), large ribosomal subunit (28S), intergenic spacer (IGS), beta- tubulin (TUB2) and chitin synthase 1(CHS1) region, were carried out with the primer sets ITS5/ITS4, LSU1/LSU2, IGS-12a/NS1R, TubF1/TubR1 and gCS1a1/gCS1b respectively, as shown by Qiu et al. (2020). Maximum-likelihood phylogenetic analysis confirmed the grouping of the PMH2 isolate within the G. ambrosiae accessions. Each individual gene alignment was treated as a separate partition. Sequences were not concatenated for maximum -likelihood phylogenetic analysis. Sequence data were deposited in GenBank under the accessions OK626453 (ITS), OK626454 (28S), OL456201 (IGS), OL415512 (TUB2) and OL415513(CHS1). To fulfill Koch's postulates, two mature, potted plants of C. sativa cv. 'Alpha Explorer' were inoculated by gently pressing symptomatic hemp leaves onto their leaf surface. They were incubated in an indoor grow room at 23°C and relative humidity of 50%. Non-inoculated healthy plants of C. sativa cv. 'Alpha Explorer' served as control. Inoculated plants developed powdery mildew symptoms within 10 to 12 days, while all control plants were asymptomatic. The powdery mildew on inoculated plants was found to be morphologically similar to the original. G. ambrosiae has been reported on C.sativa in Oregon (Wiseman et al. 2021) and G. ambrosiae (as G. spadiceus) has been reported on Cannabis in Kentucky (Szarka et al. 2019), Ohio (Farinas and Hand 2020) and New York (Weldon et al. 2020). This is the first known report of Golovinomyces ambrosiae causing powdery mildew on hemp in New Jersey. With the recent opening ( Dec15, 2021) of cultivation licensing and retailing of recreational marijuana, the acreage of Hemp production in New Jersey is expected to significantly increase, particularly for greenhouse production. It is important to document the species to develop management strategies to control this disease.

Predictive Accuracy of a Perioperative Laboratory Test-Based Prediction Model for Moderate to Severe Acute Kidney Injury After Cardiac Surgery.

Importance: Effective treatment of acute kidney injury (AKI) is predicated on timely diagnosis; however, the lag in the increase in serum creatinine levels after kidney injury may delay therapy initiation. Objective: To determine the derivation and validation of predictive models for AKI after cardiac surgery. Design, Setting, and Participants: Multivariable prediction models were derived based on a retrospective observational cohort of adult patients undergoing cardiac surgery between January 2000 and December 2019 from a US academic medical center (n = 58 526) and subsequently validated on an external cohort from 3 US community hospitals (n = 4734). The date of final follow-up was January 15, 2020. Exposures: Perioperative change in serum creatinine and postoperative blood urea nitrogen, serum sodium, potassium, bicarbonate, and albumin from the first metabolic panel after cardiac surgery. Main Outcomes and Measures: Area under the receiver-operating characteristic curve (AUC) and calibration measures for moderate to severe AKI, per Kidney Disease: Improving Global Outcomes (KDIGO), and AKI requiring dialysis prediction models within 72 hours and 14 days following surgery. Results: In a derivation cohort of 58 526 patients (median [IQR] age, 66 [56-74] years; 39 173 [67%] men; 51 503 [91%] White participants), the rates of moderate to severe AKI and AKIrequiring dialysis were 2674 (4.6%) and 868 (1.48%) within 72 hours and 3156 (5.4%) and 1018 (1.74%) within 14 days after surgery. The median (IQR) interval to first metabolic panel from conclusion of the surgical procedure was 10 (7-12) hours. In the derivation cohort, the metabolic panel-based models had excellent predictive discrimination for moderate to severe AKI within 72 hours (AUC, 0.876 [95% CI, 0.869-0.883]) and 14 days (AUC, 0.854 [95% CI, 0.850-0.861]) after the surgical procedure and for AKI requiring dialysis within 72 hours (AUC, 0.916 [95% CI, 0.907-0.926]) and 14 days (AUC, 0.900 [95% CI, 0.889-0.909]) after the surgical procedure. In the validation cohort of 4734 patients (median [IQR] age, 67 (60-74) years; 3361 [71%] men; 3977 [87%] White participants), the models for moderate to severe AKI after the surgical procedure showed AUCs of 0.860 (95% CI, 0.838-0.882) within 72 hours and 0.842 (95% CI, 0.820-0.865) within 14 days and the models for AKI requiring dialysis and 14 days had an AUC of 0.879 (95% CI, 0.840-0.918) within 72 hours and 0.873 (95% CI, 0.836-0.910) within 14 days after the surgical procedure. Calibration assessed by Spiegelhalter z test showed P >.05 indicating adequate calibration for both validation and derivation models. Conclusions and Relevance: Among patients undergoing cardiac surgery, a prediction model based on perioperative basic metabolic panel laboratory values demonstrated good predictive accuracy for moderate to severe acute kidney injury within 72 hours and 14 days after the surgical procedure. Further research is needed to determine whether use of the risk prediction tool improves clinical outcomes.

Fifteen-minute consultation: A structured approach to a child with primary spontaneous pneumothorax.

Primary spontaneous pneumothorax (PSP) is an uncommon presentation in children but may occur at any age and occurs in patients with no pre-existing lung disease. Management aims are to re-expand the collapsed lung, relieve pressure in the intrapleural space and avoid a tension pneumothorax. Correct management of PSP will avoid unnecessary intervention, reduce length of hospital stay and also reduce the risk of recurrence. There are no established guidelines for treating PSP in children and there is significant variation in management among centres and clinicians. This article provides a clear, evidence-based and structured approach to assessment and management of PSP in children and young people.

Investigation of Volatile Iridoid Terpenes in Nepeta cataria L. (Catnip) Genotypes.

Catnip (Nepeta cataria L.) is of scientific interest largely due to the production of nepetalactones, volatile iridoid terpenes with strong arthropod repellent activity. However, the plant can also produce other bioactive volatile iridoids, such as nepetalic acid (NA), nepetalactam (NT) and dihydronepetalactone (DHNL) that have not been studied extensively. Germplasm studies on plants that can produce such compounds are scarce. The present study evaluated the chemical diversity of catnip genotypes with a focus on NA, NT and DHNL. A total of 34 genotypes were harvested at different times over two years. The ethanolic extract of the plants was screened for iridoids by ultra-high-performance liquid chromatography/triple quadrupole mass spectrometry. CR9 × CR3 genotype had the highest value for biomass yield, while cultivar CR9 had the highest value for accumulated NA. Genotype UK.2 had the highest value for accumulated NT yield and CR5 had the highest value for accumulated DHNL. Overall, patented cultivars and elite selections performed better than other less studied genotypes. Harvest time influenced the accumulation of secondary metabolites differentially for the genotypes. This is the first germplasm study with a focus on these iridoid compounds, yet more studies are necessary as genotype characterization is essential for breeding and standardization of products for industry.

Modelling dynamics of coronavirus disease 2019 spread for pandemic forecasting based on Simulink.

In this paper, we demonstrate the application of MATLAB to develop a pandemic prediction system based on Simulink. The susceptible-exposed-asymptomatic but infectious-symptomatic and infectious (severe infected population + mild infected population)-recovered-deceased (SEAI(I1+I2)RD) physical model for unsupervised learning and two types of supervised learning, namely, fuzzy proportional-integral-derivative (PID) and wavelet neural-network PID learning, are used to build a predictive-control system model that enables self-learning artificial intelligence (AI)-based control. After parameter setting, the data entering the model are predicted, and the value of the data set at a future moment is calculated. PID controllers are added to ensure that the system does not diverge at the beginning of iterative learning. To adapt to complex system conditions and afford excellent control, a wavelet neural-network PID control strategy is developed that can be adjusted and corrected in real time, according to the output error.

Interleaved electro-optic dual comb generation to expand bandwidth and scan rate for molecular spectroscopy and dynamics studies near 1.6 µm.

A chirped-pulse interleaving method is reported for generation of dual optical frequency combs based on electro-optic phase modulators (EOM) in a free-running all-fiber based system. Methods are discussed to easily modify the linear scan rate and comb resolution by more than three orders of magnitude and to significantly increase the spectral bandwidth coverage. The agility of the technique is shown to both capture complex line shapes and to magnify rapid passage effects in spectroscopic and molecular dynamics studies of CO2. These methods are well-suited for applications in the areas of remote sensing of greenhouse gas emissions, molecular reaction dynamics, and sub-Doppler studies across the wide spectral regions accessible to EOMs.

Microbiota metabolites modulate the T helper 17 to regulatory T cell (Th17/Treg) imbalance promoting resilience to stress-induced anxiety- and depressive-like behaviors.

Chronic stress disrupts immune homeostasis while gut microbiota-derived metabolites attenuate inflammation, thus promoting resilience to stress-induced immune and behavioral abnormalities. There are both peripheral and brain region-specific maladaptations of the immune response to chronic stress that produce interrelated mechanistic considerations required for the design of novel therapeutic strategies for prevention of stress-induced psychological impairment. This study shows that a combination of probiotics and polyphenol-rich prebiotics, a synbiotic, attenuates the chronic-stress induced inflammatory responses in the ileum and the prefrontal cortex promoting resilience to the consequent depressive- and anxiety-like behaviors in male mice. Pharmacokinetic studies revealed that this effect may be attributed to specific synbiotic-produced metabolites including 4-hydroxyphenylpropionic, 4-hydroxyphenylacetic acid and caffeic acid. Using a model of chronic unpredictable stress, behavioral abnormalities were associated to strong immune cell activation and recruitment in the ileum while inflammasome pathways were implicated in the prefrontal cortex and hippocampus. Chronic stress also upregulated the ratio of activated proinflammatory T helper 17 (Th17) to regulatory T cells (Treg) in the liver and ileum and it was predicted with ingenuity pathway analysis that the aryl hydrocarbon receptor (AHR) could be driving the synbiotic's effect on the ileum's inflammatory response to stress. Synbiotic treatment indiscriminately attenuated the stress-induced immune and behavioral aberrations in both the ileum and the brain while in a gut-immune co-culture model, the synbiotic-specific metabolites promoted anti-inflammatory activity through the AHR. Overall, this study characterizes a novel synbiotic treatment for chronic-stress induced behavioral impairments while defining a putative mechanism of gut-microbiota host interaction for modulating the peripheral and brain immune systems.

Critical Point-Finding Methods Reveal Gradient-Flat Regions of Deep Network Losses.

Despite the fact that the loss functions of deep neural networks are highly nonconvex, gradient-based optimization algorithms converge to approximately the same performance from many random initial points. One thread of work has focused on explaining this phenomenon by numerically characterizing the local curvature near critical points of the loss function, where the gradients are near zero. Such studies have reported that neural network losses enjoy a no-bad-local-minima property, in disagreement with more recent theoretical results. We report here that the methods used to find these putative critical points suffer from a bad local minima problem of their own: they often converge to or pass through regions where the gradient norm has a stationary point. We call these gradient-flat regions, since they arise when the gradient is approximately in the kernel of the Hessian, such that the loss is locally approximately linear, or flat, in the direction of the gradient. We describe how the presence of these regions necessitates care in both interpreting past results that claimed to find critical points of neural network losses and in designing second-order methods for optimizing neural networks.