Notes

Topical ointment Management of GLP-1 Receptor Agonists Stops Retinal Neurodegeneration in Experimental Diabetes.
The sample size of 675 participants is based on true sensitivity of 92.5%, null hypothesis sensitivity of 80%, 80% power, and 5% significance. The primary outcome is AF detection ≥30 s duration during 28 days of cardiac rhythm monitoring. Secondary outcomes are AF detection at 1-year, recurrent cardiovascular events, and mortality and will be identified by electronic linkage and telephone follow-up. The results will guide the development of a more personalized care pathway to search for AF after ischaemic stroke or TIA. This could help to reduce cardiac rhythm monitoring for people with a low probability of AF detection and allow more intensive cardiac monitoring to be focused on people who are more likely to have AF and benefit. Participants will be consented for their data to be used in future research studies, providing a rich resource for stroke and cardiovascular research communities.
Quantification of peritoneal protein loss (PPL) may be expressed according to a timely collection (24-h measurement or 4-h PET assessment) and as a concentration. The aim of this study was to compare the quantification methods of 24-h and 4-h collections.

This study included 81 prevalent peritoneal dialysis patients. Demographics and clinical and bioelectrical impedance features were registered. PPL was measured (4-h PET and 24-h results) and peritoneal protein clearance was calculated. A linear regression model was performed.

Age and continuous ambulatory peritoneal dialysis (compared to cycler) were positively associated with greater PPL on 24-h collections. Neither cardiovascular disease, hypertension, diabetes nor the comorbidity Charlson Index was significantly associated with PPL. There was a consistent univariable relationship with D/P creatinine, whichever sampling method was used. Only 24-h measurements of PPL correlated with body composition variables. In multiple linear regression analysis, D/P creatinine association with PPL stands out. On the other hand, 24-h determinations (in grams or clearance) were associated with overhydration. PET protein quantification was associated with peritoneal creatinine clearance.

Different methods sign different pathophysiological pathways. PET protein loss quantification should be regarded as a marker of peritoneal membrane intrinsic permeability. Measurements of a 24-h sample might be closer to patients' clinical status and prognosis, signalizing opportunities for therapy intervention.
Different methods sign different pathophysiological pathways. PET protein loss quantification should be regarded as a marker of peritoneal membrane intrinsic permeability. Measurements of a 24-h sample might be closer to patients' clinical status and prognosis, signalizing opportunities for therapy intervention.
Lipodystrophy (LD) syndromes are rare heterogeneous disorders characterized by reduction or absence of subcutaneous fat, low or nondetectable leptin concentrations in blood and impaired hunger/satiety regulation. Metreleptin treatment reverses metabolic complications and improves eating behavior in LD. Because depression in anorexia nervosa (AN), which is also characterized by hypoleptinemia, improves substantially upon treatment with metreleptin, we hypothesized that metreleptin substitution may be associated with an antidepressant effect in patients with LD, too.

In this ancillary study, 10 adult patients with LD were treated with metreleptin. To assess depressive symptoms, the self-rating questionnaire Beck's Depression Inventory (BDI) was filled in at preestablished time points prior (T1) and after initiation of metreleptin (T2 1 week; T3 4 weeks; T4 12 weeks) dosing. The differences between time points were tested with nonparametric Friedman's analysis of variance. Sensitivity analyses were performedped during the first week of metreleptin treatment. It needs to be noted that by the nature of this observational study without a placebo group, nonspecific treatment expectation affecting mood cannot fully be ruled out.
Cervical cancer (CC) is one of the human immunodeficiency virus (HIV)-related cancers. The objective of this retrospective observational cohort study was to explore the treatment response, survival, and independent prognostic predictors for HIV-positive patients with CC. Design/Participants/Materials/Setting/Methods This is a retrospective case-control study. learn more Patients with primary CC, treated at Xiangyang Central Hospital, Hubei, China, from June 2013 to June 2019, were reviewed. All included patients were divided into the HIV-positive and HIV-negative groups. The primary outcome was overall survival (OS). A Kaplan-Meier curve was used to evaluate the survival condition. Univariate and multivariate Cox proportional hazard regression was used to determine the prognostic predictors for HIV-positive CC patients.

A total of 1,319 patients were included in the study, with 30 in the HIV-positive group and 1,289 in the HIV-negative group. The HIV-negative group had statistically better OS than the HIV-positive gnificantly lower survival and higher recurrence rate in CC patients with HIV infection, compared with those without HIV infection. Furthermore, inoperable HIV-positive CC patients are less likely to benefit from concurrent radiotherapy and chemotherapy than HIV-negative patients. Recurrence and blood CD4 count are independent prognostic factors for HIV-positive CC patients.
There is a significantly lower survival and higher recurrence rate in CC patients with HIV infection, compared with those without HIV infection. Furthermore, inoperable HIV-positive CC patients are less likely to benefit from concurrent radiotherapy and chemotherapy than HIV-negative patients. Recurrence and blood CD4 count are independent prognostic factors for HIV-positive CC patients.
Hyperalgesia frequently occurs after surgery and is associated with adverse effects on surgical outcomes. Thus, we aimed to examine whether the hypothalamus-pituitary-adrenal (HPA) axis function after surgery is involved in the development of postoperative hyperalgesia.

Surgery- and pain-related variables were measured 24 and 48 hours after the first and second total knee arthroplasties (TKAs) in postmenopausal patients undergoing one-week-interval staged bilateral TKA. Two sets of saliva samples were consecutively collected from patients before (pre-T1) and one week after (post-T1) the first TKA (n = 69). HPA axis function was analyzed in a subgroup of 20 patients with a typical cortisol awakening response (CAR) in both sets of saliva samples.

Surgery-related variables were comparable between the first and second TKAs. However, pain-related variables (pain ratings and the amount of opioid analgesics consumed) were greater after the second than the first TKA. Cortisol and dehydroepiandrosterone (DHEA) secretion during the post-awakening period (CARauc and Daucawk, respectively) was higher at post-T1 than at pre-T1, but the molar CARauc/Daucawk ratio was comparable between the time points examined. No relationship was observed between the pre-T1 CARauc and pain ratings after the first TKA. However, post-T1 CARauc showed a positive correlation with pain ratings after the second TKA. Postoperative pain ratings were negatively correlated with Daucawk and positively correlated with the molar CARauc/Daucawk ratio at all examined time points.

The results suggest that adrenocortical steroidogenic activity favoring the production of cortisol over DHEA after surgery may contribute to the development of hyperalgesia during the early postoperative period.
The results suggest that adrenocortical steroidogenic activity favoring the production of cortisol over DHEA after surgery may contribute to the development of hyperalgesia during the early postoperative period.
We conducted a systematic literature review to identify evidence for cabozantinib activity in patients with solid tumors after prior checkpoint inhibitor (CPI) therapy.

The review was conducted according to PRISMA guidelines and registered with PROSPERO (CRD42021259873). MEDLINE®, Embase, and the Cochrane Library were searched on 19 May 2021 to identify publications reporting the efficacy/effectiveness and safety/tolerability of cabozantinib in patients with solid tumors who had received prior CPI-based therapy. Publications were screened by one reviewer with uncertainties resolved by a second and/or the full author group. Risk of bias was assessed using Gradingof Recommendations Assessment, Development and Evaluation (GRADE) for clinical trials and the Newcastle-Ottawa Scale (NOS) for observational studies.

Of 669 publications screened, 21 were eligible 18 reported data on renal cell carcinoma, and one each for hepatocellular carcinoma, metastatic urothelial carcinoma, and non-small cell lung cancer. Of six trial publications, three reported moderate-quality evidence and three low-quality evidence. Of 15 observational studies, NOS scores ranged from 3 to 6, suggesting a high potential for uncertainty. The studies consistently reported clinical activity for cabozantinib after CPI therapy, across treatment lines and tumor types, with no new safety signals. The findings were limited by the quality and quantity of available data.

Cabozantinib appears to have anti-tumor activity after prior CPI therapy in patients with solid tumors. Our results are driven largely by studies in renal cell carcinoma. Evidence from ongoing phase 3 trials is required to establish further the role of cabozantinib after CPI therapy.
Cabozantinib appears to have anti-tumor activity after prior CPI therapy in patients with solid tumors. Our results are driven largely by studies in renal cell carcinoma. Evidence from ongoing phase 3 trials is required to establish further the role of cabozantinib after CPI therapy.A clinically significant mechanism of tuberculosis resistance to the aminoglycoside kanamycin (KAN) is its acetylation catalyzed by upregulated Mycobacterium tuberculosis (Mtb) acetyltransferase Eis. In search for inhibitors of Eis, we discovered an inhibitor with a substituted benzyloxy-benzylamine scaffold. A structure-activity relationship study of 38 compounds in this structural family yielded highly potent (IC50 ∼ 1 μM) Eis inhibitors, which did not inhibit other acetyltransferases. Crystal structures of Eis in complexes with three of the inhibitors showed that the inhibitors were bound in the aminoglycoside binding site of Eis, consistent with the competitive mode of inhibition, as established by kinetics measurements. When tested in Mtb cultures, two inhibitors (47 and 55) completely abolished resistance to KAN of the highly KAN-resistant strain Mtb mc2 6230 K204, likely due to Eis inhibition as a major mechanism. Thirteen of the compounds were toxic even in the absence of KAN to Mtb and other mycobacteria, but not to non-mycobacteria or to mammalian cells. This, yet unidentified mechanism of toxicity, distinct from Eis inhibition, will merit future studies along with further development of these molecules as anti-mycobacterial agents.Liver fibrosis is characterized by the excessive deposition of extracellular matrix components and results from chronic liver injury. At present, there is no approved drug for the treatment of liver fibrosis by the Food and Drug Administration. Here, we have reported a series of novel compounds with phenacrylanilide scaffolds that potently inhibit the transfer growth factor β1 (TGF-β1)-induced activation of LX-2, a hepatic stellate cell (HSC) line. Among them, compound 42 suppressed TGF-β1-induced upregulation of fibrotic markers (α-SMA and fibronectin) and showed excellent safety in vitro. Furthermore, in a carbon tetrachloride (CCl4) -induced liver fibrosis model, 42 at a dose of 30 mg/kg/day through oral administration for 3 weeks effectively improved liver function, restored damaged liver structures, and reduced collagen deposition, with a greater effect than Tranilast. In addition, epithelial-mesenchymal transition (EMT) is inhibited by compound 42 in the process of fibrosis. Meanwhile, the imbalanced immune microenvironment could also be effectively reversed.
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