The polymycovirus-mediated growth enhancement of the entomopathogenic fungus Beauveria bassiana is dependent on carbon and nitrogen metabolism

Polymycoviridae is a growing family of mycoviruses whose members typically have non-conventional capsids and multi-segmented, double-stranded (ds) RNA genomes. Beauveria bassiana polymycovirus (BbPmV) 1 is known to enhance the growth and virulence of its fungal host, the entomopathogenic ascomycete and popular biological control agent B. bassiana. Here we report the complete sequence of BbPmV-3, which has six genomic dsRNA segments. Phylogenetic analysis of RNA-dependent RNA polymerase (RdRp) protein sequences revealed that BbPmV-3 is closely related to the partially sequenced BbPmV-2 but not BbPmV-1. Nevertheless, both BbPmV-3 and BbPmV-1 have similar effects on their respective host isolates ATHUM 4946 and EABb 92/11-Dm, affecting pigmentation, sporulation, and radial growth. Production of conidia and radial growth are significantly enhanced in virus-infected isolates as compared to virus-free isogenic lines on Czapek-Dox complete and minimal media that contain sucrose and sodium nitrate. However, this polymycovirus-mediated effect on growth is dependent on the carbon and nitrogen sources available to the host fungus. Both BbPmV-3 and BbPmV-1 increase growth of ATHUM 4946 and EABb 92/11-Dm when sucrose is replaced by lactose, trehalose, glucose, or glycerol, while the effect is reversed on maltose and fructose. Similarly, both BbPmV-3 and BbPmV-1 decrease growth of ATHUM 4946 and EABb 92/11-Dm when sodium nitrate is replaced by sodium nitrite, potassium nitrate, or ammonium nitrate. In conclusion, the effects of polymycoviruses on B. bassiana are at least partially mediated via its metabolic pathways

Functional Impact of a Cancer-Related Variant in Human Δ\u3csup\u3e1\u3c/sup\u3e‑Pyrroline-5-Carboxylate Reductase 1

Pyrroline-5-carboxylate reductase (PYCR) is a proline biosynthetic enzyme that catalyzes the NAD(P)H-dependent reduction of Δ1-pyrroline-5-carboxylate (P5C) to proline. Humans have three PYCR isoforms, with PYCR1 often upregulated in different types of cancers. Here, we studied the biochemical and structural properties of the Thr171Met variant of PYCR1, which is found in patients with malignant melanoma and lung adenocarcinoma. Although PYCR1 is strongly associated with cancer progression, characterization of a PYCR1 variant in cancer patients has not yet been reported. Thr171 is conserved in all three PYCR isozymes and is located near the P5C substrate binding site. We found that the amino acid replacement does not affect thermostability but has a profound effect on PYCR1 catalytic activity. The kcat of the PYCR1 variant T171M is 100- to 200-fold lower than wild-type PYCR1 when P5C is the variable substrate, and 10- to 25-fold lower when NAD(P)H is varied. A 1.84 Å resolution X-ray crystal structure of T171M reveals that the Met side chain invades the P5C substrate binding site, suggesting that the catalytic defect is due to steric clash preventing P5C from achieving the optimal pose for hydride transfer from NAD(P)H. These results suggest that any impact on PYCR1 function associated with T171M in cancer does not derive from increased catalytic activity

Supportive care of patients diagnosed with high grade glioma and their carers in Australia.

PURPOSE: This study aimed to: determine the supportive care available for Australian patients with High Grade Glioma (HGG) and their carers; identify service gaps; and inform changes needed to implement guidelines and Optimal Care Pathways. METHODS: This cross-sectional online survey recruited multidisciplinary health professionals (HPs) who were members of the Cooperative Trials Group for Neuro-Oncology involved in management of patients diagnosed with HGG in Australian hospitals. Descriptive statistics were calculated. Fisher's exact test was used to explore differences between groups. RESULTS: 42 complete responses were received. A majority of MDT meetings were attended by a: neurosurgeon, radiation oncologist, medical oncologist, radiologist, and care coordinator. Less than 10% reported attendance by a palliative care nurse; physiotherapist; neuropsychologist; or speech therapist. Most could access referral pathways to a cancer care coordinator (76%), neuropsychologist (78%), radiation oncology nurse (77%), or psycho-oncologist (73%), palliative care (93-100%) and mental health professionals (60-85%). However, few routinely referred to an exercise physiologist (10%), rehabilitation physician (22%), dietitian (22%) or speech therapist (28%). Similarly, routine referrals to specialist mental health services were not standard practice. Nearly all HPs (94%) reported HGG patients were advised to present to their GP for pre-existing conditions/comorbidities; however, most HPs took responsibility (≤ 36% referred to GP) for social issues, mental health, symptoms, cancer complications, and treatment side-effects. CONCLUSIONS: While certain services are accessible to HGG patients nationally, improvements are needed. Psychosocial support, specialist allied health, and primary care providers are not yet routinely integrated into the care of HGG patients and their carers despite these services being considered essential in clinical practice guidelines and optimal care pathways

Intraperitoneal drain placement and outcomes after elective colorectal surgery: international matched, prospective, cohort study

Despite current guidelines, intraperitoneal drain placement after elective colorectal surgery remains widespread. Drains were not associated with earlier detection of intraperitoneal collections, but were associated with prolonged hospital stay and increased risk of surgical-site infections.Background Many surgeons routinely place intraperitoneal drains after elective colorectal surgery. However, enhanced recovery after surgery guidelines recommend against their routine use owing to a lack of clear clinical benefit. This study aimed to describe international variation in intraperitoneal drain placement and the safety of this practice. Methods COMPASS (COMPlicAted intra-abdominal collectionS after colorectal Surgery) was a prospective, international, cohort study which enrolled consecutive adults undergoing elective colorectal surgery (February to March 2020). The primary outcome was the rate of intraperitoneal drain placement. Secondary outcomes included: rate and time to diagnosis of postoperative intraperitoneal collections; rate of surgical site infections (SSIs); time to discharge; and 30-day major postoperative complications (Clavien-Dindo grade at least III). After propensity score matching, multivariable logistic regression and Cox proportional hazards regression were used to estimate the independent association of the secondary outcomes with drain placement. Results Overall, 1805 patients from 22 countries were included (798 women, 44.2 per cent; median age 67.0 years). The drain insertion rate was 51.9 per cent (937 patients). After matching, drains were not associated with reduced rates (odds ratio (OR) 1.33, 95 per cent c.i. 0.79 to 2.23; P = 0.287) or earlier detection (hazard ratio (HR) 0.87, 0.33 to 2.31; P = 0.780) of collections. Although not associated with worse major postoperative complications (OR 1.09, 0.68 to 1.75; P = 0.709), drains were associated with delayed hospital discharge (HR 0.58, 0.52 to 0.66; P < 0.001) and an increased risk of SSIs (OR 2.47, 1.50 to 4.05; P < 0.001). Conclusion Intraperitoneal drain placement after elective colorectal surgery is not associated with earlier detection of postoperative collections, but prolongs hospital stay and increases SSI risk

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely