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Summary: We evaluated the effect of parathyroid hormone (PTH) on Wnt10b production by immune system cells in humans. We showed that bone anabolic effect of intermittent PTH treatment may be amplified by T cells through increased production of Wnt10b. Chronic increase in PTH as in primary hyperparathyroidism does not increase Wnt10b expression. Introduction: The aim of this study is to assess the effect of PTH on Wnt10b production by immune system cells in humans. We assessed both the effect of intermittent PTH administration (iPTH) and of chronic PTH hypersecretion in primary hyperparathyroidism (PHP). Methods: Eighty-two women affected by post-menopausal osteoporosis were randomly assigned to treatment with calcium and vitamin D alone (22) or plus 1-84 PTH (42), or intravenous ibandronate (18). Wnt10b production by unfractioned blood nucleated cells and by T, B cells and monocytes was assessed by real-time RT-PCR and ELISA at baseline, 3, 6, 12 and 18 months of treatment. The effect of chronic elevation of PTH was evaluated in 20 patients affected by PHP at diagnosis and after surgical removal of parathyroid adenoma. WNT10b from both osteoporotic and PHP patients was compared to healthy subjects matched for age and sex. Results: iPTH increases Wnt10b production by T cells, whereas PHP does not. After surgical restoration of normal parathyroid function, WNT10b decreases, although it is still comparable with healthy subjects' level. Thus, chronic elevation of PTH does not significantly increase WNT10b production as respect to control. Conclusions: This is the first work showing the effect of both intermittent and chronic PTH increase on Wnt10b production by immune system cells. We suggest that, in humans, T cells amplified the anabolic effect of PTH on bone, by increasing Wnt10b production, which stimulates osteoblast activity. [ABSTRACT FROM AUTHOR]

Study Question: Is IVF indicated for couples with age-related infertility?, Summary Answer: IVF may be of doubtful utility for age-related infertility., What Is Known Already: A diagnosis of unexplained infertility is drawn when the diagnostic work-up fails to identify any patent cause. Although typically managed uniformly, unexplained infertility is likely to comprise a wide range of conditions, including age-related infertility (at least in older women). Unfortunately, no validated tests for the identification of age-related infertility exist and these women are typically treated as unexplained cases. However, homologous ART may be less effective for these women because these techniques may be unable to treat the detrimental effects of ageing on oocyte competence., Study Design, Size, Duration: Women aged 18-42 years who underwent IVF procedures between January 2014 and December 2021 were selected retrospectively. In the first part of the study, we aimed to assess whether the proportion of women with unexplained infertility (i.e. without patent causes of infertility) increased with age. In the second part of the study, women with unexplained infertility were matched 1:1 by age, study period, and duration of infertility, to those with a patent cause of infertility. If our hypothesis is valid, the first part of the study should highlight an increase in the proportion of unexplained infertility with age. Moreover, in the second part of the study, one should observe a sharper decrease in the rate of IVF success of the procedure with age in women with an unremarkable work-up compared to those with a definite cause of infertility., Participants/materials, Setting, Methods: Women were included if: they had been trying to conceive for more than 2 years, they had retrieved more than three oocytes, and had not undergone previous IVF attempts. We exclude couples with severe male factor (criptozoospermia), chronic anovulation, untreated hydrosalpinx, or intracavitary diseases. The first part of the study aimed at investigating the relative proportion of unexplained infertility with age. The outcome of the second part was the distribution of the live births between unexplained versus explained infertility, in women younger or older than 35 years. Only the results of the first IVF cycle were considered (including both fresh and frozen cycles). The live birth rate corresponded to the cumulative chance of a live birth per oocyte retrieval., Main Results and the Role of Chance: One thousand five hundred and thirty-five women were selected for the first part of the study; 742 of them had unexplained infertility (48%). The frequency of this diagnosis was lower among women aged <35 years (40%) compared to those ≥35 years (52%) (P < 0.001). A clear gradient emerged when considering smaller intervals of age (P < 0.001). A total of 1134 women (567 unexplained cases and 567 explained cases) were selected for the second part of the study. Baseline variables were comparable between women with unexplained and explained infertility. Among women younger than 35 years (n = 229 unexplained cases and 229 explained cases), 108 live births were observed in women with unexplained infertility (47%) and 88 in those with explained infertility (38%). In comparison, among women older than 35 years, the live births occurred in 90 (27%) and 114 (34%) couples, respectively (P = 0.03). The adjusted odds ratio (OR) for a live birth in older women with unexplained infertility was 0.63 (95% CI: 0.43-0.94). In other words, the effectiveness of IVF in older women with unexplained infertility is reduced by an additional 37% when compared to women of similar age with a patent cause of infertility. Moreover, when considering smaller intervals of age, a gradient of the adverse effect of age on the distribution of live births between unexplained and explained infertility emerged (P = 0.003). Overall, these results support the hypothesis that IVF may be of modest benefit in women with age-related infertility. The decline in IVF success is sharper in women with unexplained infertility compared to those with explained infertility, indirectly suggesting that IVF cannot effectively treat age-related infertility., Limitations, Reasons for Caution: We postulated that the greater decline in IVF success with age in the unexplained group could be related to the concomitant increase in the proportion of women with age-related infertility. However, even if this is theoretically logical, the unavailability of validated tools to diagnose age-related infertility makes our inference speculative. We cannot exclude that the prevalence of other unknown causes of infertility that cannot also be effectively overcome with IVF could increase with age., Wider Implications of the Findings: Our findings suggest that IVF may be of modest utility for treating age-related infertility. Offering this procedure to older women with an unremarkable infertility work-up may be questioned. However, the diagnosis of age-related infertility remains challenging and identifying a biomarker that could reliably diagnose age-related infertility is a priority., Study Funding/competing Interest(s): The study was partially funded by the Italian Ministry of Health-current research IRCCS and by a specific grant supported by Ferring. ES declares receiving honoraria for lectures at meetings from IBSA and Gedeon-Richter and he also handles private grants of research from Ferring, IBSA, Theramex, and Gedeon-Richter. All the other authors do not have any conflict of interest to declare., Trial Registration Number: N/A., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Competing Interests: The authors have no conflicts of interest to declare.

A significant body of evidence has supported a negative impact of endometriosis on ovarian follicles; however, the origin and relevance of this ovarian impairment in endometriosis is still a matter of debate. The ovarian damage can be caused by endometriosis itself or by surgeries aiming to remove endometriotic lesions. In this review, we summarized the existing knowledge on the mechanisms by which endometriosis can impact the ovarian follicles, from molecular to clinical points of view. From a molecular standpoint, the presence of endometriosis or its consequences can induce oxidative stress, inflammation, aberrant mitochondrial energy metabolism and inappropriate steroid production in granulosa cells, phenomena that may impair the quality of oocytes to variable degrees. These alterations may have clinical relevance on the accelerated exhaustion of the ovarian reserve, on the ovarian response to gonadotrophin stimulation in IVF cycles and on the competence of the oocytes. Critical points to be considered in current clinical practices related to fertility issues in endometriosis are discussed., Competing Interests: Declaration of competing interest E.S. declares honoraria and grants from Theramex, Merck-Serono and Ferring. P.V. declares honorarium for Editorial engagement. All the other authors have nothing to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Study Question: Do low levels of anti-Müllerian hormone (AMH) or antral follicle count (AFC) properly predict miscarriage in young women conceiving with ART?, Summary Answer: Low ovarian reserve, as indicated by AMH or AFC, is not associated with miscarriage in young women conceiving with ART., What Is Known Already: Presently, the impact of low ovarian reserve on the risk of miscarriage remains controversial. Some studies have reported an association between serum AMH levels and AFC and miscarriage, but others have failed to confirm these findings. The main limitation that undermines the reliability and consistency of the results is the confounding effect of female age. Indeed, after 35 years of age, on the one hand, the risk of miscarriage starts increasing because of impaired oocyte quality while, on the other, the physiological decline in AMH and AFC levels continues, thus hampering the possibility to properly explore the real effects of reduced ovarian reserve. Indeed, the two processes, i.e. the gradual loss of resting primordial follicles and the loss of oocyte quality, progress in parallel. In other words, the older the woman becomes, the higher is the risk of miscarriage, but one cannot distinguish between the effects of biological aging on oocyte quality and those mediated by a lower ovarian reserve., Study Design Size Duration: The present retrospective monocentric cohort study was carried out at Fondazione IRCSS Ca Granda Ospedale Maggiore Policlinico, Milan. All women referred to the ART Unit between 2014 and 2021 and who underwent either conventional IVF (c-IVF), ICSI, or IUI were reviewed. Only women younger than 35 were eligible because, up to this age, the risk of miscarriage is steady and not strictly related to age., Participants/materials Setting Methods: Women younger than 35 who achieved a singleton clinical pregnancy with c-IVF, ICSI, or IUI were selected. Women with patent causes of recurrent miscarriage were excluded, as well as those undergoing pregnancy termination for fetal or medical causes. Women who did and did not have a pregnancy loss before 20 weeks' gestation were compared. Detailed information was obtained from charts of the consulting patients. ART procedures were performed according to the standardized policy of our Unit. All women underwent serum AMH measurement and a transvaginal assessment of AFC prior to initiation of treatment. AMH levels were measured by a commercially available ELISA assay. To assess AFC, all identifiable antral follicles 2-10 mm in diameter at ultrasound were recorded. The primary outcome was the risk of miscarriage for women with serum AMH levels below 5 pmol/l., Main Results and the Role of Chance: There were 538 women were included, of whom 92 (17%) had a miscarriage. The areas under the ROC curves for prediction of miscarriage based on AMH levels and AFC were 0.51 (95% CI: 0.45-0.58) and 0.52 (95% CI: 0.45-0.59), respectively. The odds ratio (OR) of miscarriage for women with serum AMH levels below 5.0 pmol/l was 1.10 (95% CI: 0.51-2.36); the adjusted OR was 1.12 (95% CI: 0.51-2.45). Analyses were repeated considering other thresholds for AMH (2.9, 3.6 and 7.9 pmol/l) and for AFC (thresholds of 7 and 10). No associations emerged., Limitations Reasons for Caution: The retrospective design of the study hampered the collection of more precise but potentially relevant clinical information of the couples. We did not exclude women suffering from PCOS, a condition possibly associated with miscarriage. Moreover, the baseline characteristics of women who did and did not have a miscarriage differed in some characteristics. Thus, we adjusted the OR using a multivariate analysis, but we cannot fully exclude residual confounding effects. Finally, our results cannot be inferred to women older than 35. The mechanisms causing premature exhaustion of ovarian reserve may be different in younger and older women and this may lead to a different impact on the risk of miscarriage., Wider Implications of the Findings: Women embarking on ART with low ovarian reserve should be informed of their likely poor response to ovarian stimulation but can be reassured that, if conception occurs, their risk of miscarriage is not increased., Study Funding/competing Interests: This study was partially funded by Italian Ministry of Health-Current research IRCCS. E.S. reports grants from Ferring and honoraria for lectures from Merck-Serono and Gedeon-Richter. All the other authors do not have any competing interest to declare., Trial Registration Number: N/A., Competing Interests: E.S. reports grants from Ferring and honoraria for lectures from Merck-Serono and Gedeon-Richter. All the other authors do not have any competing interest to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

With the implementation of COVID-19 vaccine up-take, doubts regarding the impact of immunization on future fertility have begun to emerge. We have examined vaccine safety on male reproductive health. We set up a multicentre (three infertility centers), retrospective study in order to assess semen parameters and fertilization rate of one hundred-six men in a pairwise comparison between the first and second assisted reproduction technology (ART) attempt, performed respectively before and after COVID-19 vaccination. Median time (range) between the first vaccine dose and the second ART cycle was 75 days (39-112). Semen parameters did not change before and after the exposure. Fertilization rate was also similar before and after vaccination. Twenty-five patients (24%) were oligozoospermic before the vaccination while 26 (25%) after the exposure ( P = 0.87). Severe asthenozoospermia were present in 11 patients before as well as after the exposure. No difference was observed even after considering different types of vaccines (mRNA or viral vector). COVID-19 vaccination did not affect sperm quality and fertilization capacity of men undergoing ART treatments and should be considered safe for men's reproductive health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Reschini, Pagliardini, Boeri, Piazzini, Bandini, Fornelli, Dolci, Cermisoni, Viganò, Somigliana, Coccia and Papaleo.)

Purpose: To evaluate the safety and efficacy of autologous concentrated adipose tissue for the treatment of knee OA., Methods: Eighty-seven patients with knee arthritis from grade 1 to 3, according to Kellgren-Lawrence scale, have been treated with knee arthroscopy and successive intra-articular injection of concentrated adipose tissue. The efficacy of the treatment has been evaluated by the Knee Society Score, Lysholm Score, Forgotten Joint Score, Knee Injury and Osteoarthritis Outcome Score and Noise Reporting Scale., Results: A total of 78/87 patients concluded the study. Overall, the patients were satisfied with the intervention and a significant reduction of the pain was observed in 67 patients, while the others did not report any change in pain severity or worsening. A statistically significant improvement was observed in the considered orthopaedic index, and no major adverse effects were described. The first week after the intervention, most patients reported knee swelling. Five patients failed because they underwent knee replacement surgery between five and nine months from treatment., Conclusions: In patients with knee OA, a single intra-articular injection of autologous adipose tissue reduced knee pain, stiffness, improved knee function and quality of life without severe complications.

Objectives: To evaluate the accuracy of a new COVID-19 prognostic score based on lung ultrasound (LUS) and previously validated variables in predicting critical illness., Methods: We conducted a single-center retrospective cohort development and internal validation study of the COVID-19 Worsening Score (COWS), based on a combination of the previously validated COVID-GRAM score (GRAM) variables and LUS. Adult COVID-19 patients admitted to the emergency department (ED) were enrolled. Ten variables previously identified by GRAM, days from symptom onset, LUS findings, and peripheral oxygen saturation/fraction of inspired oxygen (P/F) ratio were analyzed. LUS score as a single predictor was assessed. We evaluated GRAM model's performance, the impact of adding LUS, and then developed a new model based on the most predictive variables., Results: Among 274 COVID-19 patients enrolled, 174 developed critical illness. The GRAM score identified 51 patients at high risk of developing critical illness and 132 at low risk. LUS score over 15 (range 0 to 36) was associated with a higher risk ratio of critical illness (RR, 2.05; 95% confidence interval [CI], 1.52-2.77; area under the curve [AUC], 0.63; 95% CI 0.676-0.634). The newly developed COVID-19 Worsening Score relies on five variables to classify high- and low-risk patients with an overall accuracy of 80% and negative predictive value of 93% (95% CI, 87%-98%). Patients scoring more than 0.183 on COWS showed a RR of developing critical illness of 8.07 (95% CI, 4.97-11.1)., Conclusions: COWS accurately identify patients who are unlikely to need intensive care unit (ICU) admission, preserving resources for the remaining high-risk patients., (© 2021 Wiley Periodicals LLC.)

An increasing prevalence of overweight and obesity was reported in youth with type 1 diabetes, likely due to the intensive insulin treatment and/or an unhealthy lifestyle. Analyses of body composition may help describe the real increase in fat mass, which contributes to the diabetes-related cardio-metabolic risk. This systematic review evaluated the current literature on body composition assessments in youth with type 1 diabetes and the potential association with cardio-metabolic, functional, or behavioural risk factors. A systematic search of literature studies reporting assessments of body composition in youth with type 1 diabetes published until April 2018 was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Twenty-three articles with different study designs reported assessments of body composition. The following methods were used to assess body composition: computerized dual energy X-ray absorptiometry (n = 10), bioelectrical impedance analysis (n = 8), skinfold thickness measurement (n = 4), and air displacement plethysmography (n = 1). Higher fat mass values were found in youth with type 1 diabetes in seven of the 13 studies that included a healthy control group. Most studies investigating the association between body composition and cardio-metabolic risk factors showed that youth with higher fat mass levels had poor glycaemic control, dyslipidaemia, or higher blood pressure. Assessments of body composition may represent a useful clinical procedure to support decision-making in type 1 diabetes management. Further research is needed to standardize the assessment of body composition and develop a consensus guideline., (© 2019 John Wiley & Sons, Ltd.)

Background: The nitrate content of foods and water is highly variable, which has implications for the compilation of food-composition databases and assessment of dietary nitrate intake., Objective: A systematic review was conducted to ascertain the dietary assessment methods used and to provide estimates of daily nitrate intake in humans., Design: Relevant articles were identified by a systematic search of 3 electronic databases (PubMed, Web of Science, and Embase) from inception until February 2018. Observational studies conducted in adult populations and reporting information on dietary assessment methods and daily nitrate intake were included. Ecological analyses were conducted to explore the association of nitrate intake with indexes of economic development [Gross Domestic Product (GDP) and KOF Index of Globalization]., Results: A total of 55 articles were included. Forty-two studies investigated associations between nitrate intake and disease risk; 36 (87%) of these studies examined the association between nitrate intake and cancer risk, whereas only 6 studies explored the association of nitrate intake with the risk of diabetes, glaucoma, kidney failure, hypertension, and atherosclerotic vascular disease. The majority of studies used food-frequency questionnaires to assess nitrate intake (n = 43). The median daily nitrate intakes in healthy and patient populations were 108 and 110 mg/d, respectively. We found a significant inverse correlation of nitrate intake with GDP (r = -0.46, P < 0.001) and KOF index (r = -0.31, P = 0.002)., Conclusions: The median estimated daily nitrate intakes by healthy and patient populations were similar, and these values were below the safe upper intake of daily intake (3.7 mg nitrate ion/kg body weight). However, there is considerable heterogeneity in the application of food-composition tables, which may have implications for the accuracy of estimated daily nitrate intake. The association between nitrate intake and risk of cardiometabolic diseases needs further investigation. The protocol for this systematic review has been registered in the PROSPERO database (https://www.crd.york.ac.uk/prospero; CRD number: 42017060354).

The relationship between the immune system, estrogen deficiency and bone loss is an intriguing and, as yet, unexplained challenge of the past two decades. Here we summarize the evidence that links immune cells, inflammation, cytokine production and osteoclast formation and activity with particular regard to humans.