A Victorian nature cure philosophy as a reconciliation of Romantic Naturalism and laboratory medicine: the case of E.W. Lane's (1823-89) hygienic medicine.

This article primarily concentrates on the theoretical and intellectual dimensions of nature cure, particularly efforts to revive it during the second half of the nineteenth century. Little is known about specific medical professionals or theories concerning the Victorian philosophy of nature cure, although this philosophy is mentioned in general terms in studies on alternative medicine and hygiene. This article illuminates a Victorian nature cure philosophy through the works of Edward W. Lane (1823-1889). As a physician and hydropathist, Lane aspired to create a new form of medical system, 'hygienic medicine', seeking answers to the questions 'What is disease?' and 'What is medicine?' throughout his career. Lane was among many physicians interested in nature's healing power during his time. However, few undertook as thorough a theorisation of nature cure philosophy as Lane did in the latter half of the nineteenth century, a period that presented unprecedented challenges in reconciling medicine with nature. This study explores the subtle nuances of the concepts that Lane actively used in his theoretical explanations, including 'nature', 'laws of health' and 'vital force', interpreting his efforts as a reconciliation between Romantic naturalism and laboratory medicine. The aim of this study is not to re-evaluate the significance of Lane's medical theory itself. It rather uses Lane as a lens to reveal the intricacies of Victorian nature cure philosophy.

Pancreatic ß cell models for screening insulin secretagogues and cytotoxicity.

In the past 2-3 decades, numerous attempts have been made to create an insulin-secreting ß cell line that maintains normal insulin secretion. However, primary ß cell cultures have finite life and, therefore, cannot be used for long-term experiments. The most widely used insulin-secreting cell lines are Insulinoma-1, rat insulinoma cell line, hamster pancreatic ß cell line, mouse insulinoma, and ß tumor cell line. Insulinoma-derived cell lines show infinite growth in tissue culture but exhibit varying differences in their insulin responsiveness to glucose levels compared to normal ß cells. Despite difficulties with ß cell cultures, these cell lines have offered some useful insights in diabetes research concerning physiological functions and pathological investigations. In this review, we describe insulinoma cell lines used for drug screening, insulin secretion, cell viability, proliferation, and other relevant cellular functions. In addition, we have also incorporated recently developed human ß cell lines. These cell lines have provided some helpful insights into physiological activities and pathology in diabetes research, despite challenges with ß cell culturing. We propose that these cell lines could also be explored for screening Ayurvedic Rasayanas and homeopathy preparations for their cytotoxicity and insulin secretagogue activities to have evidence-based data on alternative and complementary medicines.

Intracytoplasmic sperm injection versus conventional in vitro fertilization in infertile couples with normal total sperm count and motility: does sperm morphology matter?

STUDY QUESTION: Among couples with infertility and normal total sperm count and motility, can sperm morphology be used as a biomarker to identify couples who benefit more from ICSI over conventional IVF (c-IVF) on fertility outcomes? SUMMARY ANSWER: Based on this secondary analysis of a large randomized clinical trial (RCT), sperm morphology has limited value as a biomarker to identify couples who benefit more from ICSI over c-IVF on live birth, ongoing pregnancy, clinical pregnancy or total fertilization failure. WHAT IS KNOWN ALREADY: Our recent RCT showed that ICSI did not result in higher live birth rates in couples with normal total sperm count and motility. It is unclear whether sperm morphology can be used as a biomarker to identify couples who benefit more from ICSI over c-IVF in this population. STUDY DESIGN, SIZE, DURATION: This was a secondary analysis of an open-label, multi-centre, RCT comparing ICSI versus c-IVF in 1064 couples with infertility and normal total sperm count and motility. In this secondary study, we evaluated the effectiveness of ICSI over c-IVF in relation to sperm morphology. PARTICIPANTS/MATERIALS, SETTING, METHODS: Couples were eligible if they had ≤2 previous IVF/ICSI attempts, and the male partner had normal total sperm count and motility according to the fifth edition of the WHO laboratory manual for the examination and processing of human semen. Sperm morphology was measured from samples obtained during the first consultation and data for sperm morphology were available in partners of all participants in this trial. The outcomes of interest were live birth, ongoing pregnancy, clinical pregnancy, and total fertilization failure. We first conducted a logistic regression analysis with an interaction term (sperm morphology as a continuous variable by treatment (ICSI versus c-IVF)) on the four outcomes. We also used restricted cubic spline analysis to evaluate non-linear interaction and plotted the treatment effects of ICSI over c-IVF at different sperm morphology levels and the predicted probability of these outcomes in both ICSI and c-IVF groups. MAIN RESULTS AND THE ROLE OF CHANCE: The median proportion of sperm with normal morphology in both groups was 3% (Interquartile range 1-6%). Live birth rates were (184/532) 34.6% for ICSI versus (166/532) 31.2% for c-IVF. No significant interaction was found between sperm morphology and treatment effect of ICSI versus c-IVF on the rates of live birth, ongoing pregnancy, clinical pregnancy, and total fertilization failure (P = 0.181, 0.153, 0.168, and 0.788 respectively). In the analyses using restricted cubic splines, no evidence of interaction between sperm morphology and the treatment effect was found. Interaction figures showed that the treatment effect of ICSI over c-IVF at different sperm morphology levels was fluctuating around no effect line, and the predicted outcomes for the two groups were mostly overlapping at different sperm morphology levels. LIMITATIONS AND REASONS FOR CAUTION: This secondary analysis may be underpowered to detect a difference in treatment effects at different sperm morphology levels due to relatively small number of events at some sperm morphology levels. Moreover, sperm morphology assessment was performed during the first consultation, rather than on the day of randomization. WIDER IMPLICATIONS OF THE FINDINGS: In couples with infertility and normal total sperm count and motility, sperm morphology has a limited role as a biomarker to identify couples who benefit more from ICSI over c-IVF on fertility outcomes. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by My Duc Hospital, Ho Chi Minh City, Vietnam. RW was supported by an NHMRC EL Investigator Grant (GNT2009767). LNV has received speaker and conference fees from Merck, grant, speaker, conference fees from Merck Sharpe and Dohme, and speaker, conference, and scientific board fees from Ferring. TMH has received speaker fees from Merck, Merck Sharp Dohme, and Ferring. BWM reports consultancy, travel support and research funding from Merck and consultancy for Organon and Norgine. BWM holds stock from ObsEva. TRIAL REGISTRATION NUMBER: NCT03428919.

Preterm birth in assisted reproduction: the mediating role of hypertensive disorders in pregnancy.

STUDY QUESTION: To what extent can hypertensive disorders in pregnancy (HDP) explain the higher risk of preterm birth following frozen embryo transfer (frozen-ET) and fresh embryo transfer (fresh-ET) in ART compared with naturally conceived pregnancies? SUMMARY ANSWER: HDP did not contribute to the higher risk of preterm birth in pregnancies after fresh-ET but mediated 20.7% of the association between frozen-ET and preterm birth. WHAT IS KNOWN ALREADY: Risk of preterm birth is higher after ART compared to natural conception. However, there is also a higher risk of HDP in pregnancies after ART compared to natural conception, in particular after frozen-ET. HDP increases the risk of both spontaneous and medically indicated preterm birth. It is not known to what extent the higher risk of preterm birth in ART-conceived pregnancies is mediated through HDP. STUDY DESIGN, SIZE, DURATION: This registry-based cohort study included singleton pregnancies from the Committee of Nordic ART and Safety (CoNARTaS) cohort from Denmark (1994-2014), Norway (1988-2015), and Sweden (1988-2015). The analysis included 78 300 singletons born after fresh-ET, 18 037 after frozen-ET, and 4 426 682 after natural conception. The exposure was ART conception with either frozen-ET or fresh-ET versus natural conception. The main mediator of interest was any of the following HDP: gestational hypertension, preeclampsia, eclampsia, or chronic hypertension with superimposed preeclampsia. The main outcome was any preterm birth, defined as delivery <37 weeks of gestation. Secondary outcomes were spontaneous and medically indicated preterm birth, and different severities of preterm birth based on the gestational age threshold. PARTICIPANTS/MATERIALS, SETTING, METHODS: We linked data from the national Medical Birth Registries, ART registries/databases, and the National Patient Registries in each country using the unique national identity number of the mother. Criteria for inclusion were singleton pregnancies with birth order 1-4 in women aged ≥20 years at delivery. We used logistic regression to estimate odds ratios (ORs) with 95% CIs of preterm birth and decomposed the total effect into direct and mediated (indirect) effects to estimate the proportion mediated by HDP. Main models included adjustment for the year of delivery, maternal age, parity, and country. MAIN RESULTS AND THE ROLE OF CHANCE: Pregnancies following frozen-ET had a higher risk of any preterm birth compared to natural conception (occurrence 6.6% vs 5.0%, total effect OR 1.29, 95% CI 1.21-1.37) and 20.7% of the association was mediated by HDP (mediated effect OR 1.05, 95% CI 1.04-1.05). The mediation occurred primarily in medically indicated preterm births. Pregnancies following fresh-ET also had a higher risk of any preterm birth compared to naturally conceived pregnancies (occurrence 8.1% vs 5.0%, total effect OR 1.49, 95% CI: 1.45-1.53), but none of this could be mediated by HDP (mediated effect OR 1.00, 95%CI 1.00-1.00, proportion mediated 0.5%). Sensitivity analyses with extra confounder adjustment for body mass index and smoking, and restriction to primiparous women, were consistent with our main findings. Furthermore, the results were not driven by differences in ART procedures (intracytoplasmic sperm injection, culture duration, or the number of embryos transferred). LIMITATIONS, REASONS FOR CAUTION: Although we could adjust for some important confounders, we cannot exclude residual confounding, particularly from factors associated with infertility. WIDER IMPLICATIONS OF THE FINDINGS: This population-based mediation analysis suggests that some of the higher risk of preterm birth after ART treatment may be explained by the higher risk of HDP after frozen-ET. If causality is established, investigations into preventive strategies such as prophylactic aspirin in pregnancies after frozen-ET may be warranted. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by NordForsk (project number: 71450), the Nordic Federation of Obstetrics and Gynaecology (project numbers NF13041, NF15058, NF16026, and NF17043), the Norwegian University of Science and Technology (project number 81850092), an ESHRE Grant for research in reproductive medicine (grant number 2022-2), and the Research Council of Norway's Centres of Excellence funding scheme (project number 262700). D.A.L.'s and A.E.'s contribution to this work was supported by the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreements No 101021566) and the UK Medical Research Council (MC_UU_00032/05). D.A.L. has received support from Roche Diagnostics and Medtronic Ltd for research unrelated to that presented here. Pinborg declares grants from Gedeon Richter, Ferring, Cryos, and Merck, consulting fees from IBSA, Ferring, Gedeon Richter, Cryos, and Merck, payments from Gedeon Richter, Ferring, Merck, and Organon,travel support from Gedeon Richter. All other authors declare no conflicts of interest related to this work. TRIAL REGISTRATION NUMBER: ISRCTN 35879.

Association between infertility and incident onset of systemic autoimmune rheumatic disease after childbirth: a population-based cohort study.

STUDY QUESTION: What is the association between infertility with or without fertility treatment and incident onset of systemic autoimmune rheumatic disease (SARD) among women who give birth? SUMMARY ANSWER: Women who experienced infertility but did not use fertility treatment had a higher incidence of SARD up to 9 years after delivery than those who did not experience infertility, even after accounting for their higher rates of preeclampsia, spontaneous preterm birth, and stillbirth. WHAT IS KNOWN ALREADY: Infertility is increasingly common and is an under-appreciated risk marker for chronic diseases in women. Despite several studies documenting abnormal immune activity in women with infertility, little is known about the association between infertility and incidence of autoimmune diseases such as SARD which disproportionately develops in reproductive-aged women. STUDY DESIGN, SIZE, DURATION: This population-based cohort study using linked administrative data for all of ON, Canada, 2012-2021 and included 568 053 singleton births among 465 078 women aged 18-50 years without known pre-existing SARD. PARTICIPANTS/MATERIALS, SETTING, METHODS: The exposures were: (i) no infertility with unassisted conception (referent [88.0% of the cohort]); (ii) infertility without fertility treatment (9.2%); (iii) infertility with non-invasive fertility treatment (ovulation induction or intrauterine insemination [1.4%]); and (iv) infertility with invasive fertility treatment (IVF or ICSI [1.4%]). SARD was identified by a validated algorithm based on diagnostic codes at two physician visits, one rheumatologist visit, or one hospitalization and measured from the index delivery date, with censoring at death, loss of health insurance, or study end of 31 March 2021. Marginal structural Cox proportional hazards models generated hazard ratios (HR) and 95% CIs representing total effects adjusted for sociodemographic characteristics, comorbidities, and smoking, and controlled direct effects additionally accounting for adverse pregnancy outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: The median (IQR) duration of follow-up was 6.5 (4-9) years. The incidence rate of SARD was 9.3 per 10 000 person-years in women without infertility, 12.5 per 10 000 person-years in those with infertility and no fertility treatment, 10.9 per 10 000 person-years following non-invasive fertility treatment, and 10.9 per 10 000 person-years after invasive fertility treatment. Infertility without treatment was associated with an elevated risk of SARD, even after accounting for adverse pregnancy outcomes (controlled direct effect HR 1.25, 95% CI 1.12-1.40). Neither non-invasive (total effect HR 1.06, 95% CI 0.79-1.42) nor invasive (total effect HR 0.97, 95% CI 0.69-1.36) fertility treatments were associated with SARD. LIMITATIONS, REASONS FOR CAUTION: Exposure and outcome misclassification is possible as this study used published algorithms in health administrative data with unknown or imperfect sensitivity and specificity. Data on individual-level social and lifestyle factors and underlying causes of infertility were not available and thus were not included in the analysis. WIDER IMPLICATIONS OF THE FINDINGS: Infertility in the absence of fertility treatment may be an important risk marker for SARD in women who give birth. Greater health provider awareness of SARD symptoms and related gynaecological issues that may be present in women with infertility could facilitate earlier detection and treatment of SARD during the reproductive years. STUDY FUNDING/COMPETING INTERESTS(S): This research was funded by the Canadian Institutes of Health Research through a Banting Postdoctoral Fellowship to N.V.S. and Canada Research Chair to H.K.B. (2019-00158) and was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ministry of Long-Term Care. The analyses, conclusions, opinions, and statements expressed herein are solely those of the authors and do not reflect those of the funding organizations; no endorsement is intended or should be inferred. The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication. M.Y.C. has consulted for Celltrion, Werfen, Organon, MitogenDx, AstraZeneca, Mallinckrodt Canada Inc, and Glaxo Smith Kline. All other authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Particulate air pollution at the time of oocyte retrieval is independently associated with reduced odds of live birth in subsequent frozen embryo transfers.

STUDY QUESTION: Does exposure to particulate matter (PM) air pollution prior to oocyte retrieval or subsequent frozen embryo transfer (FET) affect the odds of live birth? SUMMARY ANSWER: Live birth rates are lower when particulate matter (PM2.5 and PM10) levels are higher prior to oocyte retrieval, regardless of the conditions at the time of embryo transfer. WHAT IS KNOWN ALREADY: Exposure to air pollution is associated with adverse reproductive outcomes, including reduced fecundity and ovarian reserve, and an increased risk of infertility and pregnancy loss. It is uncertain whether the effect on ART outcomes is due to the effects of pollution on oogenesis or on early pregnancy. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study included 3659 FETs in 1835 patients between January 2013 and December 2021, accounting for all FETs performed at a single clinic over the study period. The primary outcome was the live birth rate per FET. Outcome data were missing for two embryo transfers which were excluded. Daily levels of PM2.5, PM10, nitric oxide, nitrogen dioxide, sulphur dioxide, ozone and carbon monoxide were collected during the study period and calculated for the day of oocyte retrieval and the day of embryo transfer, and during the preceding 2-week, 4-week, and 3-month periods. PARTICIPANTS/MATERIALS, SETTING, METHODS: Clinical and embryological outcomes were analysed for their association with pollution over 24 hours, 2 weeks, 4 weeks, and 3 months, with adjustment for repeated cycles per participant, age at the time of oocyte retrieval, a quadratic age term, meteorological season, year, and co-exposure to air pollutants. Multi-pollutant models were constructed to adjust for co-exposures to other pollutants. Median concentrations in pollutant quartiles were modelled as continuous variables to test for overall linear trends; a Bonferroni correction was applied to maintain an overall alpha of 0.05 across the four exposure periods tested. MAIN RESULTS AND THE ROLE OF CHANCE: Increased PM2.5 exposure in the 3 months prior to oocyte retrieval was associated with decreased odds of live birth (linear trend P = 0.011); the odds of live birth when PM2.5 concentrations were in the highest quartile were reduced by 34% (OR 0.66, 95% CI 0.47-0.92) when compared to the lowest quartile. A consistent direction of effect was seen across other exposure periods prior to oocyte retrieval, with an apparent dose-dependent relationship. Increased exposure to PM10 particulate matter in the 2 weeks prior to oocyte retrieval was associated with decreased odds of live birth (linear trend P = 0.009); the odds of live birth were decreased by 38% (OR 0.62, 95% CI 0.43-0.89, P = 0.010) when PM10 concentrations were in the highest quartile compared with the lowest quartile. Consistent trends were not seen across other exposure periods. None of the gaseous pollutants had consistent effects, prior to either oocyte retrieval or embryo transfer. LIMITATIONS, REASONS FOR CAUTION: This was a retrospective cohort study, however, all FETs during the study period were included and data were missing for only two FETs. The results are based on city-level pollution exposures, and we were not able to adjust for all possible factors that may affect live birth rates. Results were not stratified based on specific patient populations, and it was not possible to calculate the cumulative live birth rate per commenced cycle. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to specifically analyse FETs to separate the effects of environmental exposures prior to oocyte retrieval from those around the time of embryo transfer. Our findings suggest that increased PM exposure prior to oocyte retrieval is associated with reduced live birth rate following FET, independent of the conditions at the time of embryo transfer. Importantly, the air quality during the study period was excellent, suggesting that even 'acceptable' levels of air pollution have detrimental reproductive effects during gametogenesis. At the low pollution levels in our study, exposure to gaseous pollutants did not appear to affect live birth rates. This has important implications for our understanding of the effects of pollution on reproduction, and highlights the urgent need for effective policies limiting pollution exposure to protect human health and reproduction. STUDY FUNDING/COMPETING INTEREST(S): No funding was provided for this study. S.J.L. is supported by the Jean Murray Jones Scholarship from the Royal Australian and New Zealand College of Obstetricians and Gynaecologists, has received educational sponsorship from Besins, Ferring, Merck, and Organon, honoraria from Hologic and Organon, consulting fees from Merck unrelated to the current study, and is a member of the Reproductive Technology Council of Western Australia. S.J.L. and R.J.H. are board members of Menopause Alliance Australia. C.S.R., M.W., and E.N. have no conflicts of interest to declare. R.J.H. is the Medical Director of Fertility Specialists of Western Australia, the National Medical Director of City Fertility Australia, and a shareholder in CHA SMG. He chairs the Western Australian Minister's Expert Panel on ART and Surrogacy. R.J.H. has made presentations for and received honoraria from Merck, Merck-Serono, Origio, Igenomix, Gideon-Richter, and Ferring, and has received support for attending meetings from Merck, Organon, and Ferring. TRIAL REGISTRATION NUMBER: N/A.

Psychosocial and physical wellbeing in women and male partners undergoing immediate versus postponed modified natural cycle frozen embryo transfer after ovarian stimulation and oocyte pick-up: a sub-study of a randomized controlled trial.

STUDY QUESTION: Are there differences in psychosocial and physical wellbeing among women and male partners undergoing modified natural cycle (mNC) frozen embryo transfer (FET) in immediate compared to postponed cycles after ovarian stimulation (OS) and oocyte pick-up (OPU)? SUMMARY ANSWER: Significantly more women in the immediate group reported physical symptoms than women in the postponed group whilst fewer were emotionally affected by waiting time, although the latter difference lost statistical significance after adjustment for multiple testing. WHAT IS KNOWN ALREADY: Infertility and fertility treatment are known to cause psychosocial distress in women and couples longing for a child. The treatment may be long-term and delayed for various reasons, such as the elective postponement of FET after a fresh transfer without pregnancy or an elective freeze-all cycle, possibly further increasing the level of distress. STUDY DESIGN, SIZE, DURATION: Sub-study of an ongoing multicentre randomized controlled, non-inferiority trial assessing the optimal timing for mNC-FET treatment after OS and OPU. Participants were randomized 1:1 to mNC-FET in the cycle immediately following OS or mNC-FET in a subsequent cycle. The study is based on data from the first women (N = 300) and male partners (N = 228) invited to answer a self-reported questionnaire assessing psychosocial and physical wellbeing. Data were collected from April 2021 to March 2024. PARTICIPANTS/MATERIALS, SETTING, METHODS: Questionnaires were distributed to all randomized women and their male partners on cycle day 2-5 of mNC-FET cycles and returned before the administration of ovulation trigger. The questionnaire consisted of validated items originating from the Copenhagen Multicentre Psychosocial Infertility-Fertility Problem Stress Scale (COMPI-FPSS) and Marital Benefit Measure (COMPI-MBM). Emotional reactions to waiting time in fertility treatment, mental health, general quality-of-life, and physical symptoms were also assessed. MAIN RESULTS AND THE ROLE OF CHANCE: Questionnaire response rates were 90.3% for women and 80.0% for male partners in the immediate group, and 82.3% for women and 57.3% for male partners in the postponed group. Approximately 90% of all women worried to some or a great extent about whether the treatment would be successful. More women in the postponed group reported that they were emotionally affected by the waiting time from OPU to blastocyst transfer to some or to a great extent (57.4% versus 73.9% in the immediate versus postponed group, P = 0.014), but the results were not significant after adjustment for multiple testing (P = 0.125). For male partners, no difference in emotional reactions to waiting time between groups was found. There was no significant difference in total infertility-related stress or symptoms of severe depression between the immediate and the postponed group for women or male partners, but women were generally more distressed than their partners. There was a significantly higher incidence of stomach and/or pelvic pain (24.0% versus 9.4%, adjusted P = 0.013), feeling of being bloated (33.8% versus 15.1%, adjusted P = 0.010) and swollen or tender breasts (24.8% versus 0.9%, P < 0.001) in the immediate group. LIMITATIONS, REASONS FOR CAUTION: All items were self-reported. No assessment of psychosocial or physical wellbeing was performed before participant enrolment. The sample size of male partners was relatively small, and female partners were not included in this sub-study due to a very small number of participants in this group. WIDER IMPLICATIONS OF THE FINDINGS: If immediate mNC-FET proves to be effective, physical and emotional factors may play a key role in choosing treatment strategy for the individual patient. This study demonstrated more physical symptoms related to OS in the immediate cycles. STUDY FUNDING/COMPETING INTEREST(S): The RCT was supported by Rigshospitalet's Research Foundation and an independent research grant from Merck A/S (MS200497_0024). Merck A/S had no role in the design of this study and will not have any role during its execution, analyses, interpretation of data, or decision to submit results. The authors are fully responsible for the content of this manuscript, and the views and opinions described in the publication reflect solely those of the authors. A.P. received grants from Gedeon Richter, Ferring Pharmaceuticals, Merck A/S and Cryos as payment to the institution. A.P. received consulting fees from IBSA, Ferring Pharmaceuticals, Gedeon Richter, Cryos and Merck A/S, and honoraria from Organon, Ferring Pharmaceuticals, Gedeon Richter and Merck A/S. A.P. received support for meeting attendance from Gedeon Richter. M.S. benefitted from a grant from Gedeon Richter. S.B. and C.C. benefitted from a grant from Merck A/S. S.B. is currently employed by Novo Nordisk. N.C.F. received grants from Gedeon Richter, Merck A/S and Cryos as payment to the institution. N.C.F. received consulting fees from Merck A/S and support for meeting attendance from Merck A/S, Ferring Pharmaceuticals, IBSA, and Gedeon Richter. N.C.F. is chair of the steering committee for the guideline groups for The Danish Fertility Society. E.L. received a radiometer contract on blood gas validation as a payment to the institution. E.L. received honoraria from Pfizer and support for meeting attendance from Astella. B.N. received grants from IBSA, Ferring Pharmaceuticals, Merck A/S, and Gedeon Richter as payment to the institution. B.N. received honoraria from Merck A/S and Organon and support for meeting attendance from IBSA and Gedeon Richter. B.N. and L.P. participate in an Advisory Board at Ferring Pharmaceuticals. L.P. received support for meeting attendance from Merck A/S, Ferring Pharmaceuticals, and Gedeon Richter. L.P. declare stocks in Novo Nordisk. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT04748874.

Syzygium cumini (L.) skeels mitigate diabetic nephropathy by regulating Nrf2 pathway and mitocyhondrial dysfunction: In vitro and in vivo studies.

ETHNOPHARMACOLOGICAL PREVALENCE: Hyperglycemia in diabetes increases the generation of advanced glycation end products (AGEs) through non-enzymatic reactions. The interaction between AGEs and their receptors (RAGE) leads to oxidative and inflammatory stress, which plays a pivotal role in developing diabetic nephropathy. Syzygium cumini (SC) L. (DC.) homeopathic preparations viz. 200C, 30C, and mother tincture [MT] are used to treat diabetes. This study aimed to elucidate the regulatory effects of SC preparations (200C, 30C, and MT) on the nuclear factor erythroid 2-related factor 2 (Nrf2) - nuclear factor-κB (NF-κB) pathways and mitochondrial dysfunction in mitigating diabetic nephropathy (DN). MATERIALS AND METHODS: Streptozotocin-induced diabetic rats were treated with SC preparations (200C, 30C, MT; 1:20 dilution in distilled water; 600 µL/kg body weight) and metformin (45 mg/kg body weight) twice daily for 40 days. DN was evaluated through biochemical parameters and histological examination. Renal tissue lysates were analyzed for glycation markers. Protein and gene levels of Nrf2, NF-κB, and mitochondrial dysfunctional signaling were determined via western blotting and RT-qPCR. An immunohistochemical analysis of the kidneys was performed. In vitro, human serum albumin (HSA - 10 mg/ml) was glycated with methylglyoxal (MGO - 55 mM) in the presence of SC preparations (200C, 30C, MT) for eight days. Glycated samples (400 µg/mL) were incubated with renal cells (HEK-293) for 24 h. Further reactive oxygen species production, Nrf2 nuclear translocation, and protein or gene expression of Nrf2 and apoptosis markers were analyzed by western blotting, RT-qPCR, and flow cytometry. Molecular docking of gallic and ellagic acid with the HSA-MGO complex was performed. RESULT: In vivo experiments using streptozotocin-induced diabetic rats treated with SC preparations exhibited improved biochemical parameters, preserved kidney function, and reduced glycation adduct formation in a dose-dependent manner. Furthermore, SC preparations downregulated inflammatory mediators such as RAGE, NF-κB, vascular endothelial growth factor (VEGF), and Tumor necrosis factor α (TNF-α) while upregulating the Nrf2-dependent antioxidant and detoxification pathways. They downregulated B-cell lymphoma 2 (Bcl-2) associated X-protein (BAX), C/EBP homologous protein (CHOP), Dynamin-related protein 1 (DRP1), and upregulated BCL 2 gene expression. Notably, SC preparations facilitated nuclear translocation of Nrf2, leading to the upregulation of antioxidant enzymes and the downregulation of oxidative stress markers. Molecular docking studies revealed favorable interactions between gallic (-5.26 kcal/mol) and ellagic acid (-4.71 kcal/mol) with the HSA-MGO complex. CONCLUSION: SC preparations mitigate renal cell apoptosis and mitochondrial dysfunction through Nrf2-dependent mechanisms.

A Split-Mouth Comparison Between Platelet-Rich Plasma and Lymphomyosot for Management of the Postoperative Sequelae After the Extraction of Impacted Third Molars: A Case Report.

Third molar extraction is one of the most common interventions in oral surgery. It is usually associated with postoperative pain, edema, and trismus. The severity of these sequelae can be related to the amount of surgical trauma and the duration of the extraction. Prevention strategies, including different local and systemic medications, autologous platelet concentrates, and physical therapy, can be beneficial for reducing postoperative discomfort and risk of complications. This case report compares the local application of platelet-rich plasma (PRP) and the systemic use of the homeopathic combination medication Lymphomyosot to reduce the postoperative sequelae after third molar extraction. The study results revealed the superior qualities of PRP in reducing postoperative edema and trismus, while both methods gave similar results regarding pain control.

Investigating the relationship between opium use and coronary slow flow: a propensity score matched case-control study.

OBJECTIVES: Recent studies have suggested a potential link between opium consumption and microvascular dysfunction in coronary arteries, which may contribute to the development of coronary slow-flow syndrome. This study aims to investigate the relationship between opium use and coronary slow-flow syndrome. DESIGN AND SETTING: This retrospective study analysed medical records of patients who underwent coronary angiography at the Tehran Heart Center from 2006 to 2020. It focused on those with coronary slow flow phenomenon (CSFP) or non-obstructive coronary artery disease, excluding patients with significant left ventricular dysfunction (left ventricular ejection fraction <40%), previous coronary revasculariation, arrhythmias or coronary artery ectasia. The coronary slow flow was assessed using thrombolysis in myocardial infarction flow grade and frame count. Propensity score matching and inverse probability weighting were applied to minimise confounding variables. Conditional logistic regression and logistic regression models were then used to examine the association between opium use and coronary slow flow, controlling for potential confounders. RESULTS: Among 21 835 patients with normal coronary angiograms, 767 were identified with CSFP and matched with 3068 controls. The mean age of CSFP patients was 51.59 years, with 64.6% male. Opium use was similar, reported in 8.9% of CSFP patients and 9.5% of controls (p=0.96). Within the CSFP group, opium use was associated with more extensive coronary artery involvement (33.3% vs 18.9%, p=0.03). Initial analysis indicated a higher risk for CSFP in opium users (OR: 1.74, p=0.001), but after adjustments, no significant association was found (OR: 1.06, p=0.70; OR: 1.15, p=0.55). CONCLUSION: Our study indicates that opium use is not an independent risk factor for CSFP but may exacerbate the severity of coronary artery involvement, noted by a higher incidence of multivessel disease among users. This suggests that opium may affect the extent of coronary artery issues rather than cause CSFP directly.

Revealing the scientific connotation of compatibility of Chinese medicine medica based on self-assembly technology.

Chinese materia medica (CMM) compatibility is one core content in the theory of Traditional Chinese Medicine (TCM), and elaborating the scientific connotation of CMM compatibility is of great significance to promote the modernization of TCM. Self-assembly is the combination of active ingredients into aggregates through non-covalent bonds, such as hydrogen bonding, electrostatic interactions, ionic interactions, and hydrophobic interactions. The complex properties and special structures of CMM components create the basis for self-assembly. The self-assembled materials formed after CMM compatibility is an important part of the material basis for the efficacy of TCM, which can help explain the scientific connotations of CMM compatibility. This review summarizes the self-assembly phenomenon from the perspective of drug pair combinations in recent decades and explains the scientific connotation of CMM compatibility about the material basis, pharmacodynamic changes, and mechanism of action, providing new ideas and methods for the study of TCM.

Estimating the public economic gains in Taiwan from in vitro fertilization (IVF) subsidy changes implemented in 2021.

STUDY QUESTION: What is the governmental fiscal impact of a new assisted reproduction subsidy scheme based on projected lifetime net taxes attributed to resulting live births in Taiwan? SUMMARY ANSWER: We estimate that the new fertility reimbursement scheme has generated favorable lifetime fiscal gains for the Taiwanese government, resulting in a return on investment (ROI) of NT$5.6 for every NT$1.0 spent based on those families receiving public subsidies for fertility care under the new scheme. WHAT IS KNOWN ALREADY: Globally, there is variation in the amount of public reimbursement for assisted reproduction provided to infertile couples. Cost is an important consideration for many infertile couples that can influence the amount of services provided and the types of services used. STUDY DESIGN, SIZE, DURATION: The analysis is based on the number of live births resulting from those couples receiving public subsidies for assisted reproduction. The cohort is based on those children born between March 2022 and July 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS: A lifetime fiscal model was developed to project age-specific lifetime tax revenue and age-dependent benefits likely received from government attributed to the children born. The analysis is based on age-specific projected earnings adjusted for work activity and applied to published income tax burden data, in addition to estimated indirect consumption taxes paid. Furthermore, we estimate the lifetime national insurance contributions per worker, including employer contributions. To account for changes over the modeling period, we increased wages based on historical economic growth, government benefits were increased based on the rate of consumer price inflation rate, and all costs and taxes were discounted at 3.5%. MAIN RESULTS AND THE ROLE OF CHANCE: A child born in Taiwan in 2022 is expected to pay discounted gross tax revenues of NT$7 257 438 and receive NT$5 373 730 in discounted future benefits from the government. Following implementation of the new funding policy, based on the number of resulting births, the cost per live birth is NT$331 918. Applying the cost per live birth, we estimate the discounted net tax revenue to be NT$1 551 789 for each child born from the subsidy. The ROI for the Taiwanese government is estimated at 568% over the lifetime of the IVF-conceived children. LIMITATIONS, REASONS FOR CAUTION: Several assumptions are applied in making long-term financial projections. Should economic conditions change dramatically, this could influence the projections described in our work. WIDER IMPLICATIONS OF THE FINDINGS: The results suggest the government benefits from public subsidy for fertility services when taking into consideration the long-term work activity of these children and future tax revenue generated for government. The results are broadly applicable to other markets, although variations in wages, lifetime work activity, and taxation rates would influence the conclusions reported here. STUDY FUNDING/COMPETING INTEREST(S): The work was sponsored by the Merck Group in Singapore (funding to N.K. and M.P.C.). The sponsoring organization was given an opportunity to review the final manuscript; however, the authors retained full editorial control over the final published materials. The authors hold no financial interests in the sponsoring company. N.K. and M.P.C. have received consulting fees from Merck and Organon and payment/honoraria from Merck. M.-J.C. received no funding for this work but has received honoraria for lectures from the Taiwanese Society for Reproduction Medicine, Taiwanese Association of Obstetrics and Gynecology, Japanese Society of Obstetrics and Gynecology, The Endocrine Society of the ROC, Merck, Organon, and Ferring; attendance fees for expert meetings from Health Promotion Administration, Ministry of Health and Welfare, Taiwan, and the National Science and Technology Council of Taiwan; and support for attending meetings and/or travel from the National Science and Technology Council of Taiwan and Merck. None of the other authors report any conflicts in relation to this work. TRIAL REGISTRATION NUMBER: N/A.

China officinalis as Possible Homeopathic Prophylaxis for the Brazilian Dengue Epidemic.

Dengue, a hyperendemic arbovirus thriving in tropical and sub-tropical climates globally, has seen a significant surge in Brazil over the past 5 years. Presently, the country faces an epidemic, posing a huge challenge to Public Health authorities due to the potentially lethal nature of severe infections. Based on Hahnemannian concepts and on the historically reported efficacy of homeopathy in fighting epidemics, this study aimed to provide supporting evidence for a homeopathic genus epidemicus approach to prevent severe forms of dengue. Symptoms related to the severe phase of the disease were prioritised in the repertorisation: China officinalis (Chin) received the highest total symptoms score (43 points from 21 symptoms) followed by Arsenicum album (31/13) and Phosphorus (29/14). In the asymptomatic population exposed to the etiological agent, the use of Chin might contribute as an additional strategy in the prophylaxis of dengue.

MONARCH Inventory for Causal Attribution in Homeopathy Case Reports: Explanation and Elaboration.

BACKGROUND: The Modified Naranjo Criteria for Homeopathy (MONARCH) inventory is a novel and useful tool for assessing the likelihood of a causal relationship between the homeopathic intervention and the ultimate clinical outcome. OBJECTIVES: To explain and elaborate on the use of the MONARCH inventory to improve its consistency of use and thereby elevate the overall quality and evidentiary value of homeopathy case reports. EXPLANATION AND ELABORATION: Each of the 10 MONARCH inventory domains is explained and elaborated with the aid of references from published literature and hypothetical clinical situations. The MONARCH total score can range from -6 to +13; within that range, an arithmetic total of +6 is available from the scores of four critical domains, which should be given prominence in the overall consideration of causality. In reporting a clinical case, great importance should be placed on the narrative of the MONARCH evaluation process, domain by domain. CONCLUSION: The application of MONARCH allows us to evaluate the likelihood of a causal relationship between the intervention and the observed clinical outcomes in successfully treated cases, thereby augmenting their evidentiary value.

[Textual research on Zitan].

In recent years, with the continuous deepening of the theory of Wu Yun Liu Qi, the application of Zitan in Shenping Decoction and Shengming Decoction has gradually become widespread. Because Zitan is an imported herbal medicine, it is not commonly used in modern medicine and known as an unusual medicinal material. The unclear original plants may affect the clinical application of this medicine. This study reviewed the ancient Chinese books of materia medica and analyzed the records about Zitan in various aspects with consideration to the introduction and cultivation of Santalum album and leguminous rosewood and the history of furniture in the Ming and Qing Dynasties. Comprehensive textual research was carried out regarding the nomenclature, producing area, original plant, and efficacy. The results indicated that Zitan had a long history of application. The ancient Chinese books of materia medica recorded that Zitan was mainly distributed in Southeast Asian countries, with a salty taste and a cold nature, entering the blood. It was primarily used to treat toxin-and wind-related conditions and wounds and stop bleeding. With the rise of hardwood furniture in the Ming Dynasty, various leguminous rosewood species were imported into China. Because of the purple color, Pterocarpus santalinus and P. indicus were mistakenly named Zitan, leading to confused original plants of this medicine. Consequently, after the Qing Dynasty, these leguminous rosewood plants started to be used medicinally. This textual research confirms that the Zitan used as a traditional Chinese medicine refers to a purple variant of S. album rather than P. santalinus or P. indicus. This clarification narrows the scope of identification and supports the clinical application of Zitan.

[Textual research on ancient geo-authentic producing areas of Chaenomeles speciosa based on literature and historical records from materia medica and local chronicles].

Chaenomeles speciosa, a commonly used traditional Chinese medicine(TCM) material, has the effects of stimulating the circulation of the blood and causing the muscles and joints to relax, as well as harmonizing the stomach and resolving dampness. It was first recorded in the Ming Yi Bie Lu during the Northern and Southern Dynasties, and its cultivation history can be traced back to the Bencao Tujing in the Song Dynasty. Modern research mainly focuses on the producing areas of Ch. speciosa based on the textual research of materia medica works, and there are few studies on the producing areas and geo-authentic producing areas of Ch. speciosa based on local chronicles. This paper systematically referred to literature and historical records from materia medica and local chronicles. Combined with the modern distribution of producing areas, the paper conducted textual research on the geo-authentic producing area of Ch. speciosa in literature and historical records, so as to clarify the changes in the geo-authentic producing area of Ch. speciosa. From the Song Dynasty to the Qing Dynasty, basically all materia medica works have recorded that the geo-authentic producing area of Ch. speciosa was Xuancheng City, Anhui province, while local chronicles showed that Zhejiang province had been the geo-authentic producing area of Ch. speciosa from the Tang Dynasty to the Qing Dynasty. A comprehensive review of the literature and historical records indicated that Zhejiang province and Hunan province were the geo-authentic producing areas of Ch. speciosa during the Tang Dynasty, while Zhejiang province and Anhui province were the geo-authentic producing areas of Ch. speciosa during the Song Dynasty. In addition, Zhejiang province, Hunan province, and Anhui province were the geo-authentic producing areas of Ch. speciosa during the Ming Dynasty, and Zhejiang province and Anhui province were the geo-authentic producing areas of Ch. speciosa during the Qing Dynasty. Anhui province, Zhejiang province, and Hubei province were the geo-authentic producing areas of Ch. speciosa during the Republic of China and later periods. There have been changes in the geo-authentic producing areas of Ch. speciosa since ancient times. Zhejiang province and Anhui province have been the geo-authentic producing areas of Ch. speciosa since the Tang Dynasty and Song Dynasty, respectively. This paper effectively supplemented the omissions in materia medica works through historical records from local chronicles, providing historical evidence from local chronicles for further research on the producing areas and geo-authentic producing areas of Ch. speciosa.

A Delphi Study on the Management of Female Infertility by Homeopaths in South Africa.

Background: Infertility affects millions of people worldwide and has a negative social and psychological impact on the lives of infertile couples. Homeopathy offers an alternative treatment option for female infertility; however, there is currently no research describing how homeopaths manage this condition in their practice. Aim: To determine homeopathic practitioners' approaches to managing female infertility. Method: The electronic Delphi technique consisting of three rounds was used to establish consensus among homeopaths. Twelve registered homeopaths with a minimum of 5 years of clinical experience in managing female infertility participated, 11 of whom completed the study. In round one, participants elaborated on interventions found beneficial in clinical practice for female infertility. Responses were qualitatively analysed to create a structured list of items; participants rated their level of agreement with these items on a 5-point Likert scale in the second and third rounds. Consensus was determined for items that reached an agreement level of 75% or more. Results: Thirty-two statements achieved expert consensus, which were placed into the following categories: homeopathic treatment, dietary and lifestyle modifications, supplementation and referrals. Conclusion: The results of this study provide a baseline depicting the homeopathic approach to treating female infertility. Several research gaps have been identified and further studies are necessary to explore these interventions to improve future patient care. Contribution: This study highlights the various approaches used by homeopathic practitioners in the management of female infertility.

Flexible progestin-primed ovarian stimulation versus a GnRH antagonist protocol in predicted suboptimal responders undergoing freeze-all cycles: a randomized non-inferiority trial.

STUDY QUESTION: Are live birth rates (LBRs) per woman following flexible progestin-primed ovarian stimulation (fPPOS) treatment non-inferior to LBRs per woman following the conventional GnRH-antagonist protocol in expected suboptimal responders undergoing freeze-all cycles in assisted reproduction treatment? SUMMARY ANSWER: In women expected to have a suboptimal response, the 12-month likelihood of live birth with the fPPOS treatment did not achieve the non-inferiority criteria when compared to the standard GnRH antagonist protocol for IVF/ICSI treatment with a freeze-all strategy. WHAT IS KNOWN ALREADY: The standard PPOS protocol is effective for ovarian stimulation, where medroxyprogesterone acetate (MPA) is conventionally administered in the early follicular phase for ovulatory suppression. Recent retrospective cohort studies on donor cycles have shown the potential to prevent premature ovulation and maintain oocyte yields by delaying the administration of MPA until the midcycle (referred to as fPPOS), similar to GnRH antagonist injections. With milder pituitary suppression, the fPPOS protocol may be a less costly option for women expected to have a low or suboptimal response if a fresh embryo transfer is not intended. STUDY DESIGN, SIZE, DURATION: This was a non-inferiority, open-label randomized controlled trial conducted at a tertiary assisted reproduction center. A total of 484 participants were randomized in the study between July 2020 and June 2023 with a 1:1 allocation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Infertile women with a predicted suboptimal ovarian response (<40 years old, antral follicle count <10, and basal serum FSH < 12 mIU/ml) were randomly assigned to receive either fPPOS treatment or GnRH antagonist treatment. MPA (10 mg) or GnRH antagonist (0.25 mg) was administered daily once the leading follicle reached 14 mm and continued until the day of trigger. All viable embryos were cryopreserved for subsequent frozen-thawed embryo transfer in both groups. The primary endpoint was the proportion of live births per woman within 12 months post-randomization (with a non-inferiority margin of -12.5%). The analysis was assessed in the per-protocol population. MAIN RESULTS AND THE ROLE OF CHANCE: Twenty-two women withdrew at the beginning of the stimulation phase due to COVID-19. Eight women did not proceed with the assigned frozen embryo transfer, and six switched from the fPPOS to the antagonist protocol. Overall, 449 women were included in the per-protocol analysis, with 216 in the fPPOS group and 233 in the GnRH antagonist group. The LBRs per woman were 44.4% (96/216) for participants in the fPPOS group and 48.9% (114/233) for participants in the GnRH antagonist group [risk ratio (RR) 0.91 (95% CI, 0.74, 1.11), risk difference (RD) -4.5% (95% CI, -13.7, 4.7)], which did not meet the non-inferiority criterion (-12.5%). Oocyte and embryonic parameters were not significantly different between the two groups. Nine women (4.17%) in the fPPOS group experienced a premature luteinizing hormone surge, compared to five women (2.15%) in the antagonist group. Only one woman in the fPPOS group ovulated before oocyte retrieval. LIMITATIONS, REASONS FOR CAUTION: The distinct routes of administration for the medications precluded blinding in this open-label trial, potentially influencing outcome assessments. All participants were recruited in a single center from one country, limiting the generalizability. WIDER IMPLICATIONS OF THE FINDINGS: While MPA is considered a patient-friendly alternative to antagonists for women undergoing scheduled freeze-all cycles, the GnRH antagonist protocol should still be the preferred treatment for anticipated suboptimal responders in terms of LBR. STUDY FUNDING/COMPETING INTEREST(S): This trial was funded by Science and Technology Department of Shaanxi Province, China (2021SF-210). Innovation Team of Shaanxi Provincial Health and Reproductive Medicine Research (2023TD-04); Key Industrial Chain Projects in Shaanxi Province: Research on Assisted Reproductive Technologies and Precision Prevention System for Genetic Diseases Preconception (2023-ZDLSF-48). Science and Technology Department of Shaanxi Province, China (2022SF-564). B.W.M. reports consultancy, travel support and research funding from Merck KGaA and consultancy for Organon and Norgine; owning stock in ObsEva; and holding an NHMRC Investigator Grant (GNT1176437). Other authors declare no conflicts of interest. All other authors have nothing to declare. TRIAL REGISTRATION NUMBER: Registered at Chinese clinical trial registry (www.chictr.org.cn). Registry Identifier: ChiCTR2000030356. TRIAL REGISTRATION DATE: 29 February 2020. DATE OF FIRST PATIENT'S ENROLMENT: 11 March 2020.

Over 40% of cancer patients use complementary and alternative medications while receiving anticancer treatment.

BACKGROUND: The use of complementary and alternative medications (CAM) is popular among cancer patients. CAM includes vitamins, minerals, phytotherapy, homeopathy, nutritional supplements and probiotics. CAM use may lead to unwanted risks by interacting with anticancer drugs; therefore, it is important for healthcare providers to be aware of CAM use by their patients. This article describes the prevalence and potential risk of CAM use in an adult Dutch cancer population. This is the first study in which CAM use was investigated using medication reconciliation. METHODS: A descriptive, observational study was conducted at Amsterdam UMC between August 2021 and July 2022. Data regarding the use of CAM was obtained by medication reconciliation reviews with inpatients and outpatients with cancer who received systemic anticancer treatment. Acquired data were evaluated by the research team, and the risks of interactions were classified into relevant, potential, unknown or no interaction. Ultimately, patient-specific recommendations on the use of CAM were provided. RESULTS: Of the 100 included patients, 73% used CAM during the past year and 41% used CAM actively while receiving anticancer treatment. The most common CAM were vitamins and multivitamins (both 28%). Some 10% of CAM were classified as having a relevant interaction with one or more concurrently used anticancer drugs. No association between age or gender and CAM use was found, while outpatients used significantly more CAM than inpatients (72.7% vs 32.1%; p=0.001). Patients received personalised advice from the hospital pharmacy about their CAM use. CONCLUSIONS: More than 40% of oncology patients investigated in this study used CAM while receiving anticancer treatment, leading to unwanted risks. This prevalence is higher than reported in other studies, possibly due to the use of medication reconciliation interviews. To guarantee safety and efficacy of anticancer treatment, communication between healthcare professionals and patients about CAM is essential.