Dose-related cardiac outcomes in response to postnatal dexamethasone treatment in premature lambs.

BACKGROUND: Postnatal corticosteroids are used in the critical care of preterm infants for the prevention and treatment of bronchopulmonary dysplasia. We aimed to investigate the effects of early postnatal dexamethasone therapy and dose on cardiac maturation and morphology in preterm lambs. METHODS: Lambs were delivered prematurely at ~128 days of gestational age and managed postnatally according to best clinical practice. Preterm lambs were administered dexamethasone daily at either a low-dose (n = 9) or a high-dose (n = 7), or were naïve to steroid treatment and administered saline (n = 9), over a 7-day time-course. Hearts were studied at postnatal Day 7 for gene expression and assessment of myocardial structure. RESULTS: High-dose dexamethasone treatment in the early postnatal period led to marked differences in cardiac gene expression, altered cardiomyocyte maturation and reduced cardiomyocyte endowment in the right ventricle, as well as increased inflammatory infiltrates into the left ventricle. Low-dose exposure had minimal effects on the preterm heart. CONCLUSION: Neonatal dexamethasone treatment led to adverse effects in the preterm heart in a dose-dependent manner within the first week of life. The observed cardiac changes associated with high-dose postnatal dexamethasone treatment may influence postnatal growth and remodeling of the preterm heart and subsequent long-term cardiac function.

Long-term Health-related Quality of Life in Patients on Active Surveillance for Prostate Cancer: A Systematic Review.

CONTEXT: Active surveillance (AS) represents the preferred treatment option in patients with low-risk prostate cancer. Optimised patient selection has enabled more patients to be managed with AS for a longer time. Thus, there is growing interest in its effect on long-term quality of life compared with interventional management. OBJECTIVE: To perform a systematic review evaluating the long-term patient-reported outcomes regarding mental health, and sexual and urinary function in patients on AS. EVIDENCE ACQUISITION: We performed a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. We included series assessing validated patient-reported outcomes of health-related quality of life, and sexual and urinary function in AS patients followed up for at least 5 yr. EVIDENCE SYNTHESIS: Our search yielded 1854 citations, including 19 papers involving 3643 patients on AS, 14 651 patients receiving surgery or radiotherapy, and 2478 controls without prostate cancer. In ten studies, major differences were observed in sexual and urinary symptoms between groups, such as better sexual function and fewer irritative urinary symptoms in patients on AS, though overall functional outcomes were comparable. In all studies, health-related quality of life for patients on AS was better than, or similar to, that for patients who had undergone surgery or radiotherapy and comparable with that for individuals without cancer. CONCLUSIONS: We observed differences in specific functional outcomes between patients on AS and surgery or radiotherapy, ≥5 yr after treatment. Patients on AS reported good quality of life, similar to that in individuals without prostate cancer. AS should continue to be a recommended management strategy for appropriately selected patients. PATIENT SUMMARY: Active surveillance is an accepted pathway for patients with low-risk localised prostate cancer. Previous literature has shown that it did not negatively affect short-term quality of life. This review finds that long-term quality of life for these patients is similar to that for people without prostate cancer.

A decade of declining prostatectomy margin positivity within a prostate cancer clinical quality registry.

CONTEXT: Positive surgical margin (PSM) on radical prostatectomy (RP) is associated with an increased risk of biochemical recurrence and use of salvage therapies. Given these adverse consequences, exploration of time trends and predictors of PSM will improve the patient outcomes following surgery for prostate cancer. METHODS: Pathological data from RP patients treated from 2011 to 2020 was extracted from the Victorian Prostate Cancer Outcomes Registry. This is a clinical quality registry that regularly benchmarks and reports back to individual clinicians the PSM percentage for their patients. Trends in PSM over time were visualized with separate running mean plots for both pT2 and pT3/4 disease. Predictors of PSM were explored with multivariable regression with date of surgery, surgical method, and hospital type, public or private, entered as covariates. RESULTS: In total, 12,394 patients formed the sample with PSM recorded in 25% (n = 3,141) of patients, 12% (777/6,640) in pT2 disease and 41% (2,364/5,754) in pT3/4 disease. Comparing 2011-12 to 2019-20, the pT3/4 PSM proportion declined from 50% to 38% while pT2 percentages were steady at 13%. In "high volume" institutions, pT2 PSM fell from 12% to 6.5%. Independent predictors of lower PSM were robotic vs. open method and being treated at a private vs. public institution. CONCLUSION: A clear decline in the proportion of pT3 PSM was observed in a large prostate cancer registry. Proposed explanatory factors include improved technical proficiency with robotic surgery and participation in a registry-based quality improvement initiative.

How Prostate Cancer Patients are Surveyed may Influence Self-Reported Sexual Function Responses.

BACKGROUND: The side effects of prostate cancer treatment include decreases in sexual function, hence, the way patient reported outcomes are collected may affect the quantity and quality of responses. AIM: To determine the effect that different survey modes (email, telephone, or mail) had on the quantity of missing data and self-reported function following treatment. METHODS: Men newly diagnosed with prostate cancer and enrolled in the Victorian Prostate Cancer Outcomes Registry formed the study population. The Expanded Prostate Cancer Index Composite (EPIC-26) survey instrument was administered approximately 1 year after their initial treatment. EPIC-26 measures self-reported function in the sexual, urinary, bowel, and hormonal domains. Multivariable regression models were used to examine effects of survey mode, adjusting for age, residence, socioeconomic status, diagnosing institute type, risk group and primary treatment modality. OUTCOMES: The percentage of patients for whom a domain score could not be calculated due to missing responses and the functional score within each domain. RESULTS: Registry staff attempted to reach 8,586 men eligible to complete the EPIC-26. Of these, 4,301 (50%) returned the survey via email, 1,882 (22%) completed by telephone, and 197 (2.3%) by mail. 2,206 (26%) were uncontactable or did not respond. Email responders had the highest proportion answering all 26 questions (95% vs 87% by phone and 67% by mail). The sexual function score was unable to be calculated due to missing responses for 1.3% of email responders, 8.8% by phone, and 8.1% by mail. After adjustment for patient and disease factors, phone responders were almost 6 times more likely than email responders to have a missing score in this domain, odds ratio = 5.84 (95% confidence interval: 4.06-8.40). The adjusted mean functional score (out of 100) was higher for those responding by phone than email or mail across all domains. The largest adjusted difference between phone and email was observed in the hormonal domain (mean difference 4.5, 95% confidence interval: 3.5-5.4), exceeding the published minimally important difference for this score. CLINICAL IMPLICATIONS: Studies that ask questions regarding sexual health and use multi-modal data collection methods should be aware that this potentially affects their data and consider adjusting for this factor in their analyses. STRENGTHS AND LIMITATIONS: A large study sample utilizing a widely available survey instrument. Patient specific reasons for non-response were not explored. CONCLUSION: Completion mode effects should be considered when analyzing responses to sexual function questions in an older, male population. Papa N, Bensley JG, Perera M, et al. How Prostate Cancer Patients are Surveyed may Influence Self-Reported Sexual Function Responses. J Sex Med 2022;19:1442-1450.

Self-reported lack of energy or feeling depressed 12 months after treatment in men diagnosed with prostate cancer within a population-based registry.

OBJECTIVE: Feeling depressed and lethargic are common side effects of prostate cancer (PCa) and its treatments. We examined the incidence and severity of feeling depressed and lack of energy in patients in a population based PCa registry. METHODS: We included men diagnosed with PCa between 2015 and 2019 in Victoria, Australia, and enrolled in the Prostate Cancer Outcomes Registry. The primary outcome measures were responses to two questions on the Expanded Prostate Cancer Index Composite (EPIC-26) patient reported instrument: problems with feeling depressed and problems with lack of energy 12 months following treatment. We evaluated associations between these and age, cancer risk category, treatment type, and urinary, bowel, and sexual function. RESULTS: Both outcome questions were answered by 9712 out of 12,628 (77%) men. 981 patients (10%) reported at least moderate problems with feeling depressed; 1563 (16%) had at least moderate problems with lack of energy and 586 (6.0%) with both. Younger men reported feeling depressed more frequently than older men. Lack of energy was more common for treatments that included androgen deprivation therapy than not (moderate/big problems: 31% vs. 13%), irrespective of disease risk category. Both outcomes were associated with poorer urinary, bowel, and sexual functional domain scores. CONCLUSIONS: Self-reported depressive feelings and lack of energy were frequent in this population-based registry. Problems with feeling depressed were more common in younger men and lack of energy more common in men having hormonal treatment. Clinicians should be aware of the incidence of these symptoms in these at-risk groups and be able to screen for them.

Substantial Increases Occur in Serum Activins and Follistatin during Lung Transplantation.

BACKGROUND: Lung transplantation exposes the donated lung to a period of anoxia. Re-establishing the circulation after ischemia stimulates inflammation causing organ damage. Since our published data established that activin A is a key pro-inflammatory cytokine, we assessed the roles of activin A and B, and their binding protein, follistatin, in patients undergoing lung transplantation. METHODS: Sera from 46 patients participating in a published study of remote ischemia conditioning in lung transplantation were used. Serum activin A and B, follistatin and 11 other cytokines were measured in samples taken immediately after anaesthesia induction, after remote ischemia conditioning or sham treatment undertaken just prior to allograft reperfusion and during the subsequent 24 hours. RESULTS: Substantial increases in serum activin A, B and follistatin occurred after the baseline sample, taken before anaesthesia induction and peaked immediately after the remote ischemia conditioning/sham treatment. The levels remained elevated 15 minutes after lung transplantation declining thereafter reaching baseline 2 hours post-transplant. Activin B and follistatin concentrations were lower in patients receiving remote ischemia conditioning compared to sham treated patients but the magnitude of the decrease did not correlate with early transplant outcomes. CONCLUSIONS: We propose that the increases in the serum activin A, B and follistatin result from a combination of factors; the acute phase response, the reperfusion response and the use of heparin-based anti-coagulants.

Alcohol exposure during late ovine gestation alters fetal liver iron homeostasis without apparent dysmorphology.

High levels of alcohol (ethanol) exposure during fetal life can affect liver development and can increase susceptibility to infection after birth. Our aim was to determine the effects of a moderate level of ethanol exposure in late gestation on the morphology, iron status, and inflammatory status of the ovine fetal liver. Pregnant ewes were chronically catheterized at 91 days of gestation (DG; term ~145 DG) for daily intravenous infusion of ethanol (0.75 g/kg maternal body wt; n = 8) or saline (n = 7) over 1 h from 95 to 133 DG. At necropsy (134 DG), fetal livers were collected for analysis. Liver weight, general liver morphology, hepatic cell proliferation and apoptosis, perivascular collagen deposition, and interleukin (IL)-1ß, IL-6, or IL-8 mRNA levels were not different between groups. However, ethanol exposure led to significant decreases in hepatic content of ferric iron and gene expression of the iron-regulating hormone hepcidin and tumor necrosis factor (TNF)-α (all P < 0.05). In the placenta, there was no difference in transferrin receptor, divalent metal transporter 1, and ferritin mRNA levels; however, ferroportin mRNA levels were increased in ethanol-exposed animals (P < 0.05), and ferroportin protein tended to be increased (P = 0.054). Plasma iron concentration was not different between control and ethanol-exposed groups; control fetuses had significantly higher iron concentrations than their mothers, whereas maternal and fetal iron concentrations were similar in ethanol-exposed animals. We conclude that daily ethanol exposure during the third-trimester-equivalent in sheep does not alter fetal liver morphology; however, decreased fetal liver ferric iron content and altered hepcidin and ferroportin gene expression indicate that iron homeostasis is altered.

Loss of GGN leads to pre-implantation embryonic lethality and compromised male meiotic DNA double strand break repair in the mouse.

The integrity of male germ cell genome is critical for the correct progression of spermatogenesis, successful fertilization, and proper development of the offspring. Several DNA repair pathways exist in male germ cells. However, unlike somatic cells, key components of such pathways remain largely unidentified. Gametogenetin (GGN) is a testis-enriched protein that has been shown to bind to the DNA repair protein FANCL via yeast-two-hybrid assays. This finding and its testis-enriched expression pattern raise the possibility that GGN plays a role in DNA repair during spermatogenesis. Herein we demonstrated that the largest isoform GGN1 interacted with components of DNA repair machinery in the mouse testis. In addition to FANCL, GGN1 interacted with the critical component of the Fanconi Anemia (FA) pathway FANCD2 and a downstream component of the BRCA pathway, BRCC36. To define the physiological function of GGN, we generated a Ggn null mouse line. A complete loss of GGN resulted in embryonic lethality at the very earliest period of pre-implantation development, with no viable blastocysts observed. This finding was consistent with the observation that Ggn mRNA was also expressed in lower levels in the oocyte and pre-implantation embryos. Moreover, pachytene spermatocytes of the Ggn heterozygous knockout mice showed an increased incidence of unrepaired DNA double strand breaks (DSBs). Together, our results suggest that GGN plays a role in male meiotic DSB repair and is absolutely required for the survival of pre-implantation embryos.

Cardiac remodelling as a result of pre-term birth: implications for future cardiovascular disease.

AIMS: Pre-term birth affects 10-12% of live births and occurs when the myocardium is still developing; therefore, the final structure of the myocardium could be altered. We hypothesized that, in response to pre-term birth, structural remodelling occurs within the myocardium which enables the immature heart muscle to adapt to the haemodynamic transition at birth but results in persistent alterations in its structure. Our objective was to determine how pre-term birth alters the final structure of the myocardium. METHODS AND RESULTS: Using sheep, pre-term birth was induced at 0.9 of term; hearts were examined at 9 weeks after term-equivalent age, when cardiomyocyte proliferation and maturation have ceased. In pre-term lambs, we found that cardiomyocytes of both ventricles and the interventricular septum were hypertrophied. Cardiomyocyte maturation in pre-term lambs was altered in that there was a greater proportion of mononucleated, polyploid (4n) cardiomyocytes in both ventricles compared with controls; importantly, induction of polyploidy is associated with irreversible stress-related changes in DNA. We also found a six- to seven-fold increase in collagen deposition, usually accompanied by lymphocytic infiltration. CONCLUSION: We conclude that pre-term birth leads to remodelling of the myocardium that alters its final structure. This may programme for long-term cardiac vulnerability.