Preventive colostomy is required for colorectal surgery, and the incidence of complications associated with ileostomy and colostomy remains controversial. This study aimed to compare the incidence of postoperative complications between ileostomy and colostomy procedures.Data analysis was conducted on 30 studies, and meta-analysis and trial sequential analysis (TSA) were performed on five studies. The basic indicators, such as stoma prolapse, leak, wound infection, ileus, and a series of other indicators, were compared.No statistically significant differences were observed with complications other than stoma prolapse. Meta-analysis and TSA showed that the incidence of ileostomy prolapse was lower than that of colostomy prolapse, and the difference was statistically significant. Apart from the four complications listed above, the general data analysis showed differences in incidence between the two groups. The incidence of skin irritation, parastomal hernia, dehydration, pneumonia, and urinary tract infections was higher with ileostomy than with colostomy. In contrast, the incidence of parastomal fistula, stenosis, hemorrhage, and enterocutaneous fistula was higher with colostomy than with ileostomy.There were differences in the incidence of ileostomy and colostomy complications in the selected studies, with a low incidence of ileostomy prolapse.CRD42022303133.The online version contains supplementary material available at 10.1186/s12893-023-02129-w. In recent years, the incidence of rectal cancer has increased annually . ConsequThis problem can be resolved with the use of preventive stomas . AlthougWhile a well-functioning stoma can significantly improve a patient’s quality of life, it is a nonphysiological condition that can inevitably lead to many complications, such as stoma prolapse, retraction, bleeding, necrosis, and hernia. The incidence of these complications ranges approximately from 21 to 70% . There aThis study assessed a total of 30 papers, including five randomized control trials (RCTs), to further investigate the incidence of stoma complications. Thereafter, this study used a meta-analysis and trial sequential analysis (TSA) to study the complications of ileostomy and colostomy, as well as a systematic review of the 30 publications to study the incidence of these complications.A systematic review of the literature published through October 2022 was performed by searching for abstracts in conference papers and the MEDLINE, EMBASE, Cochrane Library, and Clinicaltrials.gov databases. Medical subject headings and keywords were used for the search, and this study included RCTs and excluded non-comparative studies, reviews, and descriptive research.Retrieval strategy (PubMed): Search: ((((ileostomy) OR (loop ileostomy)) OR (colostomy)) OR (loop colostomy)) AND (complication) Filters: Randomized controlled trial.The search results were reviewed manually, and disagreements were discussed and resolved by all the authors.The inclusion criteria were: (1) studies that compared “ileostomy” versus “colostomy” or only analyzed data on “ileostomy” or “colostomy”; (2) studies that reported the perioperative outcomes and postoperative complications of stoma surgery; and (3) RCTs.The exclusion criteria were: (1) studies that did not distinguish between “ileostomy” and “colostomy,” or the combinations with data that were difficult to extract; and (2) studies without complete data, evaluation criteria for complications, or exact complication rates.the Cochrane Collaboration’s tool for assessing the risk of bias in randomized trials.Data from the published articles, including baseline characteristics and incidence of complications, were collected using Microsoft Excel. Baseline characteristics included the authors’ names, publication time, number of patients, age, sex, overall mortality, tumor size, intraoperative blood loss, operative time for stoma formation and closure, time to ileostomy closure, and length of hospital stay. The complication rate was the main study index, and complications included prolapse, retraction, skin irritation, parastomal hernia, parastomal fistula, incisional hernia, high output, leak, stenosis, wound sepsis, bleeding, wound infection, enterocutaneous fistula, intestinal obstruction/ileus, pneumonia, and urinary tract infections. Two reviewers independently extracted the data and consulted each other in case of disagreement. The quality assessment of the selected studies was based on 2), with values of 0–25%, 25–75%, and 75–100% representing low, moderate, and substantial heterogeneity, respectively. It is generally accepted that if I2 is relatively low while assuming a fixed value for the theoretical effect size, a fixed-effects model is used; otherwise, if I2 indicates significant heterogeneity, a random-effects model is used. The Mantel-Haenszel method was used to analyze the data and set the odds ratio (OR) as the effect size with a 95% confidence interval (CI). Forest and funnel plots were also obtained. “Favorable ileostomy” was considered when 95% CI of OR was < 1, and “favorable colostomy” was considered on the contrary.The statistical data were analyzed using reviewer manager 5.4  and SPSS version 18.0 . A binary variable was used to compare the incidence of complications between the ileostomy and colostomy groups. Heterogeneity was assessed using the inconsistency index . A binary variable was used for the analysis, and a fixed-effects model was applied. TSA was performed using the TSA software .The original TSA data were the same as those used in the meta-analysis. In addition, conventional test boundaries and alpha-spending boundaries were added to the data analysis for the significance test. The conventional option allowed the addition of a boundary for the Z-curve, which corresponded to a single significance test with a maximum type-I error risk, alpha (α). The α-spending option allowed the addition of adjusted significance boundaries for the Z-curve using the α-spending method. The required IS was calculated for each variable based on a 5%-value for α and 20% for beta (β)  using the O’Brien–Fleming function.Using TSA prevented the occurrence of false-positive results due to the lack of sample size and led to a more accurate conclusion. For example, if the cumulative Z-curve exceeded the IS or intersected with the O’Brien-Fleming boundaries, the difference between “ileostomy” and “colostomy” showed firm or weak evidence.A total of 680 RCTs were identified from the database following the retrieval strategy. Of these, 650 were excluded based on the inclusion and exclusion criteria. Thus, this study included 30 RCTs, and five were compared for the complication rates of ileostomy and colostomy procedures Fig. . Among tThere were no differences in study characteristics observed among these five studies Table .The quality assessment results are shown in Fig. 2 = 0% meant there was no heterogeneity, and a fixed-effects model was used. The total prolapse rate was 8.51%, with 1.27% (2/157) for ileostomy and 15.63% (25/160) for colostomy. There was a significant difference in the prolapse rate between the ileostomy and colostomy groups (OR (95% CI): 0.10 (0.03–0.34); p = 0.0002), meaning that the prolapse rate in the ileostomy group was lower than that in the colostomy group , reported the complication rate of prolapse; I2 = 0% meant there was no heterogeneity, and a fixed-effects model was used. The total leakage rate was 17.03%, with 13.38% (21/157) for ileostomy and 20.63% (33/160) for colostomy. There was no significant difference in the leak rate between the ileostomy and colostomy groups  , reported the complication rate of leaks; I2 = 0% meant there was no heterogeneity, and a fixed-effects model was used. The total wound infection rate was 8.25%, with 6.67% (10/150) for ileostomy and 9.80% (15/153) for colostomy. There was no significant difference in the wound infection rate between the ileostomy and colostomy groups  , reported the complication rate of wound infection; I2 = 0% meant there was no heterogeneity, and a fixed-effects model was used. The total ileus rate was 5.47%, with 5.88% (9/153) for ileostomy and 5.06% (8/158) for colostomy. There was no significant difference in ileus rate between the ileostomy and colostomy groups  , reported the complication rate of ileus; IVisual inspection of the funnel plot Fig.  showed nTSA analysis was performed for prolapse, leakage, wound infection, and ileus Fig. . Among tIn addition to the meta-analysis and TSA of these indexes, a comparative analysis of the 30 RCTs was also performed –28. TwenTo the best of our knowledge, although several similar meta-analyses have compared ileostomy and colostomy complications , 30, thiWith the high incidence of colorectal cancer, the utilization rate of ostomy is also increasing annually , 32. AppStoma prolapse refers to the protrusion of the intestinal stoma loop through the stoma, which is more common in loop stomas. Symptoms such as edema, bleeding, ulcers, and incarceration can be observed in the protruding bowel . ExcessiIn addition to the above comparison items, other complication rates were compared. However, because these complications were not fully addressed in these five RCTs, the scope of the included literature was expanded to include all RCTs that investigated the complications of ileostomy and colostomy. A total of 25 RCTs that examined the incidence of other interventions  limitedExcept for the four complications stated above, the general data analysis showed differences in the incidence of complications between the two groups. The incidence of skin irritation, parastomal hernia, dehydration, pneumonia, and urinary tract infections was higher for ileostomy. In contrast, the incidence of parastomal fistula, stenosis, hemorrhage, and enterocutaneous fistula was higher for colostomy. For skin irritation and dehydration, probably because the colonic and ileal contents are different, the colon has a strong absorptive capacity and can absorb more than 5 L of fluid and electrolytes daily. For patients with ileostomy, the output increases in the early stage and normalizes in the later stage; this process lasts for 1–8 weeks . HoweverMoreover, based on actual clinical experience, it has been observed that patients with transverse colostomy often express concerns about the social inconvenience caused by the odor of stoma excreta. Conversely, individuals with ileostomy commonly face challenges related to stoma and skin care due to the thin, large, and irritating nature of their excreta. In addition, the specific type of ostomy surgery can also have a impact. A study has demonstrated that creating skin bridge loop stoma leads to improved early stoma management, enhanced adhesion of stoma appliances, and ultimately, a better quality of life for the patient , 40. HowThe advantages of this study are that it updates the previous meta-analyses, consolidates the conclusions using TSA analysis, adopts stricter quality control, and includes more RCT studies to obtain more abundant conclusions. However, this study had some limitations. First, the study included only five comparative RCTs, including 317 participants (157 with ileostomy and 160 with colostomy). The small number of RCTs, small number of participants, and low incidence of complications may be one of the reasons for only partially positive conclusions. Twenty-five high-quality RCTs were included for comparison, with a total of 3679 participants (1977 with ileostomy and 1702 with colostomy) to solve this problem. The other aspects of the conclusions were positive, but owing to differences in operators, medical conditions, and diagnosis and treatment processes, the evidence level of this aspect was low. Second, five RCTs included in this study were conducted at a relatively early age, and the description of experimental and bias control methods was not precise; hence, the control of data bias could not be guaranteed. In recent years, few comparative RCT studies of ileostomy and colostomy have been published, making it difficult for some conclusions that have become an expert consensus to be confirmed by a higher level of evidence.In this study, we compared the complication rates of ileostomy and colostomy through parameter testing. Our findings revealed distinct differences in the incidence of various complications between patients with ileostomy and colostomy. Additionally, the meta-analysis indicated that, apart from a lower occurrence of colostomy prolapse in the ileostomy group compared to the colostomy group, there were no significant differences in complication rates between the two groups. More high-quality RCTs are required to conclude with more significant differences in the incidence of complications.Below is the link to the electronic supplementary material.Additional File 1: PRISMA 2020 Checklist


Technical clothing has recently been brought into the spotlight as one of the most promising tools to improve sports performance and to enhance sports recovery. Among technical clothing items, garments engineered to emit far infrared (FIR) spectrum frequencies have come to the fore as a treatment for pain, muscle fatigue, and tissue healing due to their potential antioxidative and anti-inflammatory properties, with applications not only during recovery phases but also in the active phases of exercise. These garments, composed of fibers mixed with noble metals and/or bioceramics that respond to body infrared frequencies by returning an FIR emission backwards, are thought to improve muscle oxygenation and therefore recovery. In this double-blind, randomized, placebo-controlled, crossover study, ten male trail running athletes wore a whole-body-covering suit marketed as Accapì-FIR , while a total body suit with the same polyester fiber without metal components was used as control for the intervention. Parameters such as weight, height, bioimpedance parameters (BIVA), lactate from capillary sampling, salivary cortisol, and average temperatures of different body areas were obtained before and after a twelve-minute incremental work run protocol on a treadmill whilst wearing the two kinds of garment. Using the intervention suit, compared to control, statistically significant reductions in BIVA parameters such as body resistance (−6.7%) and reactance (−5.4%) were observed before and after exercise while a greater, but not significant, weight reduction was observed with the intervention suit. Decrease in resistance could be the result of a different distribution of fluids and ions due to FIR influence on capillary and superficial circulation, leading ultimately to more efficient management of body heat and promoting recovery and supercompensation. Further studies on larger samples will be necessary to confirm and clarify these results. The search for techniques and solutions that can optimize performance and recovery processes is an element of great interest in sports medicine. Among the many feasible solutions, technical clothing has enjoyed one of the greatest successes in recent years, producing technological solutions, for example, capable of modulating body temperature and humidity, promoting better blood circulation and muscle contraction, and improving performance and recovery. Among the various technologies developed, that which makes it possible to exploit garments specially engineered to emit frequencies falling within the far infrared (FIR) spectrum represents a potential yet to be explored. The acronym FIR refers to a specific band of electromagnetic radiation, defined differently in different classification models. One of the most widely used classifications is the one proposed by Byrnes et al., which places the FIR between 15 and 1000 μm of the infrared spectrum (IR), the mid-wavelength infrared (MWIR/IR-C DIN) between 3 and 8 μm and the long-wavelength infrared (LWIR/IR-C DIN) between 8 and 15 μm . Every lThis preliminary study was performed in a double-blind, randomized, placebo-controlled, crossover study evaluating trail running athletes subjected to high-intensity activity under controlled conditions. During the training, the athletes wore technical clothing made with FIR fabrics or technical clothing made with conventional materials. The study was conducted following the rules of good clinical practice established by the Declaration of Helsinki and following the European Union Directive 2001/20/EC, according to the protocol approved by the Ethics Committee for Human Experimentation of Urbino University Carlo Bo .2, as indicated in The enrolled subjects were ten male recreational trail running athletes with a mean age of 40.9 (±5.9) years, mean weight of 78.3 (±8.9) kg, mean height of 1.76 (±0.05) cm, and mean BMI of 25.3 (±2.9) kg/mOnly subjects with a valid sports medical certification for competitive activity, competitive practice of trail running for at least five years, and an average level of training to guarantee participation in competitive events over distances greater than 20 km with differences in height greater than 500 m were included. Exclusion criteria considered were for the use of medicines, drug use, alcohol abuse, inadequate possibility of physical/muscular recovery following competitions and training, injuries suffered in the last 60 days not fully recovered , unfitness to practice competitive physical activity (even temporary), finding of paramorphism, pains of any kind.The product tested during the evaluation is a whole-body covering suit marketed as Accapì-FIR . The product is made of polyester fibers that contain noble metal powders which, when excited by the infrared frequency produced by the body, emit a constant infrared emission between 5 and 20 µm, producing emissions in the MWIR, LWIR, and FIR frequencies. A total body suit made by the same manufacturer with the same polyester fiber without metal components was used as a control product, obtaining indistinguishable garments. Both products were manufactured in compliance with the ISO 10993-1 standard for cytotoxicity , skin irritation , and allergic potential from contact dermatitis (rLLNA) , due to the absence of cytotoxicity, sensitization reactions, and irritation. For subjects with a BMI between 22 and 25, we used the L size and between 25.1 and 28 we used the XXL size to guarantee homogeneous wearing conditions based on the evaluations made when the subjects tried the fabrics. The technical characteristics of the product are summarized in ® software  [The enrolled subjects received an anonymous kit containing the Accapì FIR technical clothing and the control technical clothing, marked with an alphanumeric code so that the two could not be distinguished by the subjects being evaluated or the examiners. The subjects were acclimatized in a controlled laboratory environment  for 30 min . Utilizi, Italy) ,28,29,30, Italy) ,28,29,30, Italy) ,28,29,30, Italy) ,32 using, Italy) . The the, Italy) . The sal, Italy)  accordin, Italy)  began. Tp < 0.001); the changes over time are significantly different, considering the set of dependent variables . The subsequent univariate analyses are reported in In p < 0.001) but overlapping (p = 0.138) between the two evaluation sessions (−0.3% vs. −0.5%) when using the Accapì FIR suit and the control product, respectively, with a slightly higher weight reduction using FIR fabrics. The proposed exercise increased lactate (p = 0.034) and cortisol (p < 0.001) levels for both groups, which was non-significant between the two groups . The analysis of bioimpedance parameters suggests a more complex situation. Using the Accapì FIR suit yielded statistically significant reductions in Rz (−6.7%) and Xc (−5.4%) between pre- and post-exercise. In contrast, for the bioimpedance values in the control group, an increase is observed in Rz (+4%) and Xc (+2.5%). The surface temperature of the various body districts shows a peculiar behavior; when wearing the FIR fabrics, there was a minor increase and consequently a minor reduction in the temperature upon suspension of the activity compared to the control fabrics, where instead, the situation is opposite. The most relevant parameters are summarized in The analysis of anthropometric parameters revealed a weight variation significantly different from zero (p < 0.001) in body resistance (Rz) compared to the control fabric. In particular, we found a reduction in Rz in the treated group while there was an increase in the control group. In such a situation, following fluid loss and acute response to exercise, one would expect an increase in Rx and essentially unchanged Xc as it occurs substantially using control tissue. It should also be noted that the reduction in resistance observed in the Accapì FIR group was accompanied by an acute weight loss which was small but greater than that of the control group, which instead showed a small increase in resistance consistent with the performance of physical activity and relative weight loss through sweating. The slight increase in reactance in the control group is consistent with what has been shown in patients undergoing hemodialysis, where the variations in bioimpedance indices were inversely related to the volume of body fluid removed [In this preliminary crossover study, carried out in a double-blind, randomized and placebo-controlled fashion, we examined the acute effects of wearing a suit made of fabric with FIR technology (Accapì FIR) 30 min before and during the performance of intense physical exertion, compared to an indistinguishable control fabric with the same proportion of fabric composition (73% polyester—22% polyamide—5% elastane) but in the presence of noble metals and bioceramics. The results that emerged suggest that the use of the material with FIR technology is associated with a significant variation  have been documented for FIR fabrics, their use could significantly improve the comfort of athletes during prolonged exercise ,19.In this preliminary evaluation, we considered the variation in bio-impedance parameters, lactate and cortisol values, and surface temperatures of certain skin areas that occurs when using a fabric (Accapì FIR) capable of producing, when stimulated by body heat, an emission of FIR infrared according to the classification proposed by Zati and Valent . The res


Prescription opioids remain an important contributor to the United States opioid crisis and to the development of opioid use disorder for opioid-naïve individuals. Recent legislative actions, such as the implementation of state prescription drug monitoring programs (PDMPs), aim to reduce opioid morbidity and mortality through enhanced tracking and reporting of prescription data. The primary objective of our study was to describe the opioid prescribing trends in the state of Pennsylvania (PA) as recorded by the PA PDMP following legislative changes in reporting guidelines, and discuss the PDMP’s role in a multifactorial approach to opioid harm reduction.State-level opioid prescription data summaries recorded by the PA PDMP for each calendar quarter from August 2016 through March 2020 were collected from the PA Department of Health. Data for oxycodone, hydrocodone, and morphine were analyzed by quarter for total prescription numbers and refills. Prescription lengths, pill quantities, and average morphine milliequivalents (MMEs) were analyzed by quarter for all 14 opioid prescription variants recorded by the PA PDMP. Linear regression was conducted for each group of variables to identify significant differences in prescribing trends.p < 0.0001). Refills fluctuated less consistently with general peaks in Q3 of 2017 and Q3 of 2018 (p = 0.2878). The rate of prescribing for all opioid prescription lengths decreased, ranging in frequency from 22 to 30 days (47.5% of prescriptions) to 31+ days of opioids (0.8% of prescriptions) (p < 0.0001). Similarly, decreased prescribing was observed for all prescription amounts, ranging in frequency from 22 to 60 pills (36.6% of prescriptions) to 60–90 pills (14.2% of prescriptions) (p < 0.0001). Overall, the average MME per opioid prescription decreased by 18.9%.For total prescriptions dispensed, the number of oxycodone, hydrocodone, and morphine prescriptions decreased by 34.4, 44.6, and 22.3% respectively (Per the PA PDMP database, opioid prescribing has decreased significantly in PA from 2016 to 2020. The PDMP database is an important tool for tracking opioid prescribing trends in PA, and PDMPs structured similarly in other states may enhance our ability to understand and influence the trajectory of the U.S. opioid crisis. Further research is needed to determine optimal PDMP policies and practices nationwide. Today’s opioid epidemic in the United States (U.S.) is a public health crisis, instigated partly by healthcare provider overprescribing . While tIn response to the severity of the U.S. opioid crisis, interventions targeted at the prescriber-level have included initiatives such as opioid management recommendations from government agencies  and the Although the opioid epidemic is a nationwide population health issue, the state of Pennsylvania (PA) consists of a particularly vulnerable demographic. In 2016, the state was third in the nation for opioid overdose morbidity and mortality . There wGiven the potential of PDMPs to serve as an important tool for tracking opioid distribution and quantifying areas of significant opioid distribution per population in states with high opioid morbidity and mortality, the purpose of our study was two-fold. First, we aimed to publicly present the trends of the three most commonly prescribed opioids in PA – oxycodone, hydrocodone, and morphine – from August 2016 to March 2020, as reported by the PA PDMP. In addition to presenting these prescribing trends, we also aimed to provide data on prescription lengths, quantities, and average morphine milliequivalents (MME) for all 14 opioid medications recorded by the PA PDMP so that this data may be utilized in further studies and compared to prescribing trends in other states for distribution mapping purposes. The second aim of our study was to discuss PA’s approach to regulating prescription opioids through the PDMP from August 2016 to March 2020. During the time period that coincides with our data, several key legislations were enacted to promote opioid stewardship that may offer harm reduction insight when compared to interventions in other states –23. In tThis retrospective, cross-sectional study using de-identified, aggregate prescription data was determined exempt by the Thomas Jefferson University Institutional Review Board.Monitored by the PA Department of Health (DOH), the PA PDMP is an electronic, statewide database that obtains information on all controlled substance (Schedule II-V) prescriptions filled at a dispensary . For opiFor the purposes of this study, the PA DOH provided de-identified state-level opioid prescription data summaries recorded by the PDMP for each calendar quarter from August 2016  through March 2020. The dataset used in this study came from a database that provides statewide and countywide surveillance of opioid prescribing. As the dataset used statewide and countywide data, calculation of sample sizes was not required.Data summaries included prescribing metrics for 14 different prescription opioids: belladonna-opium, codeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, sufentanil, and tapentadol. Buprenorphine was excluded from all provided metrics. Metrics reported per quarter included the total number of each type of opioid prescribed, the total number of each type of opioid prescription refill, the length of these prescriptions categorized into five groups , and the quantity of these prescriptions categorized into four groups . The average prescription morphine milliequivalent (MME) calculated from all opioids prescribed per quarter was also provided.P-values, as well as F-test values were reported. Graphs were created and simple linear regression of data was conducted using GraphPad Prism v.9.0.0 for Windows .From the metrics of total number of prescription opioids and their respective refill data, we selected to analyze oxycodone, hydrocodone, and morphine. During any quarter from August 2016 to March 2020, these three prescription opioids comprised approximately 90% of opioids prescribed by healthcare providers in PA and represent a comprehensive demographic of prescribers by type and geography . The remTable p < 0.0001; F = 249.5, DFn = 2, DFd = 39).Overall, a total of 20,959,676 oxycodone, hydrocodone, and morphine prescriptions were dispensed in PA from the third quarter (Q3) of 2016 to the first quarter (Q1) of 2020. Of these prescriptions, 11,680,654 were oxycodone, 7,432,538 were hydrocodone, and 1,846,484 were morphine .Following an initial opioid prescription, a total of 11,683 oxycodone, 5489 hydrocodone, and 7267 morphine prescription refills were dispensed in PA from Q3 of 2016 to Q1 of 2020 .For all opioids prescriptions dispensed in PA from Q3 of 2016 to Q1 of 2020, 3,866,781 (16.8%) were prescribed for 3 days or less, 3,832,481 (16.6%) were 4–7 days, 4,204,336 (18.3%) were 8–21 days, 10,936,993 (47.5%) were 22–30 days, and 174,029 (0.8%) were 31 or more days in length .In terms of individual opioid prescription amounts dispensed in PA from Q3 of 2016 to Q1 of 2020, 5,993,229 (26.1%) prescriptions consisted of 21 pills or less, 8,432,979 (36.6%) consisted of 22–60 pills, 3,263,516 (14.2%) consisted of 60–90 pills, and 5,324,879 (23.1%) consisted of 90 pills or more (Table Overall, the average MME amount per opioid prescription dispensed in PA from Q3 of 2016 to Q1 of 2020 was 59.78 (Table Our longitudinal review of the PA PDMP opioid prescription data demonstrates that total prescriptions, length of prescriptions, prescription pill quantities, and average MMEs have decreased significantly in the state of PA. Per our complete annual data available following attainment from the PA DOH from 2017 to 2019, the rate of prescribing in PA was 53.7 per 100 population in 2017, 46.2 per 100 population in 2018, and 40.7 per 100 population in 2019 . To undeWhile this decrease in national opioid prescribing rates is attributed to awareness engendered by the opioid epidemic and interventions at federal and state levels targeting different levels of prevention , 30, theRegarding the nationwide effects of the emergence of PDMPs on opioid prescriptions, Bao et al. analyzed national ambulatory care data during the emergence of PDMPs from 2001 to 2010 and found that PDMP implementation was associated with a 30% reduction in the rate of Schedule II opioid prescribing . ImportaWhile the PA PDMP mandates are an important part of PA’s approach to opioid harm reduction, we emphasize that these changes in prescription opioid regulations in PA have been accompanied by initiatives targeted at patients particularly vulnerable to opioid overdose risk as part of a heterogenous approach. In November 2016, the Drug Enforcement Agency 360 Initiative was launched to combat the severity of opioid misuse and overdose in Pittsburgh, PA . Using PAlthough available data on overdose deaths in PA attributed to prescription opioids show a simultaneous decrease congruent with our PDMP data trends starting in Q4 of 2016 , we cautTo our knowledge, this study is the first to directly report and analyze statewide prescribing trends using the PA PDMP data in the context of legislative PA PDMP initiatives via a multi-database review with PubMed, Scopus, Ovid MEDLINE, CINAHL and ScienceDirect. However, we warrant caution in drawing definitive conclusions from this data – rather, the effectiveness of the PDMP and related legislation should be considered in the context of multiple interventions. Other initiatives such as increased provider opioid education and awareness occurring amidst today’s opioid crisis have likely impacted prescribing trends, hence our emphasis that this significant decrease in prescribing is multifactorial. Per the Drug Enforcement Agency, prescription opioid sales have been declining since 2014  which prBased on a longitudinal review of dispensed opioid prescriptions reported to the PA PDMP database from 2016 to 2020, opioid prescribing has decreased significantly in PA. Although we cannot attribute decreased prescribing directly to the PDMP but rather to a collection of legislative actions and increased provider education, we show that PDMP data is an important tool to track the prescribing of controlled substances and measure the impact of prescription opioid harm reduction initiatives. Additionally, the implementation of mandatory PDMP reporting for controlled substances creates the potential for a nationally linked database that may enhance opioid prescription tracking. Further research is needed to compare and improve the effectiveness of different legislative PDMP policies and practices nationwide.


KRAS in a large series of TGCT from a single reference cancer center.Testicular Germ Cell Tumors (TGCT) are the most common cancer among young adult men. The TGCT histopathology is diverse, and the frequency of genomic alterations, along with their prognostic role, remains largely unexplored. Herein, we evaluate the mutation profile of a 15-driver gene panel and copy number variation of KRAS gene in 51 cases, and the mutation analysis was performed using the TruSight Tumor 15 (Illumina) panel (TST15) in 65 patients. Univariate analysis was used to compare sample categories in relation to mutational frequencies. Survival analysis was conducted by the Kaplan–Meier method and log-rank test.A cohort of 97 patients with TGCT, diagnosed at the Barretos Cancer Hospital, was evaluated. Real-time PCR was used to assess copy number variation (CNV) of the KRAS copy number gain was a very frequent event (80.4%) in TGCT and presented a worse prognosis compared with the group with no KRAS copy gain . Among the 65 TGCT cases, different variants were identified in 11 of 15 genes of the panel, and the TP53 gene was the most recurrently mutated driver gene (27.7%). Variants were also detected in genes such as KIT, KRAS, PDGFRA, EGFR, BRAF, RET, NRAS, PIK3CA, MET, and ERBB2, with some of them potentially targetable.Although larger studies incorporating collaborative networks may shed the light on the molecular landscape of TGCT, our findings unveal the potential of actionable variants in clinical management for applying targeted therapies. The (GCNIS) . The TGC (GCNIS) .The genetic composition of TGCTs portrays the embryonic characteristics of their precursor, the primordial germ cells (PGCs). The molecular biology of TGCTs is not still fully elucidated, despite intensive research on the molecular mechanisms involved in their development , 15. CopKIT and KRAS oncogenes that are frequently described  tumoral tissues were retrieved by macrodissection guided by hematoxylin and eosin-stained slides. The macrodissection of mixed tumor cases was performed combining all histology subtypes in the sample. All the samples are from primary tumor before any systemic treatment exposure and were reviewed by an independent pathologist. Biological samples of fresh frozen tumoral tissue were retrieved at the Biobank of the Barretos Cancer Hospital (BB-BCH), ensuring the quality of processes and the suitability of the biospecimens for research .For mutational analysis, among the 183 cases diagnosed with TCGT feasible for inclusion in this study, 75 did not meet the quality control criteria for DNA extraction ; so 108 cases had their genetic material extracted. After the multiplex PCR for the GAPDH gene, used as a quality control for FFPE samples, 12 cases did not present intact and good quality DNA and, for this reason, could not proceed to the preparation of libraries for sequencing. Of the 96 samples that went on to prepare libraries, 32 did not have their targets amplified. Ultimately, only 65 cases were included for the Next Generation Sequencing (NGS) variant identification analyses. For Copy Number Variation (CNV) analysis for KRAS, among the 183 cases diagnosed with TCGT and feasible for inclusion in this study, 66 cases did not have fresh frozen tissue samples available in the Biobank. Out of 117 cases with available samples, seven post-chemotherapy cases were excluded. Among the 110 cases feasible for inclusion in this study, 59 did not meet the quality control criteria for DNA extraction . Ultimately, only 51 cases were included for the CNV analysis for KRAS gene. The cases selection flowchart is presented in the 2.22O until the extraction step. Tumor DNA from FFPE was extracted using QIAamp DNA FFPE Tissue Kit (Qiagen), following the manufacturer’s protocols as previously reported (® 2.0 Fluorometer technology (Invitrogen). A multiplex PCR for GAPDH gene was used as quality control for FFPE samples, and those with amplifications of longer fragments  (2 (Invitrogen), 0.2 mM dNTPs (Invitrogen), 0.133 µM of each primer, 1 unit of Taq DNA Polymerase (Invitrogen), and 50 ng of tumor DNA. The reactions were performed in a ProFlex thermocycler (Thermo Fisher Scientific) using the following amplification parameters: 94°C for 4 minutes, 35 cycles of 94°C for 1 minute, 56°C for 1 minute, 72°C for 1 minute, and a final extension of 72°C for 7 minutes. The amplified DNA was assessed on a 2% agarose gel and only samples with 200 bp or more were accepted for further preparation of sequencing libraries for mutation analysis.FFPE samples were kept in the stove for 20 min at 80°C. The rehydration of the sample was then performed by incubation with decreasing alcohol percentages  for 1 min at room temperature (RT). After that, samples were left in milli-Q Hreported . Tumor Dd 400bp)  were con® Hilden-Germany), following the manufacturer’s instructions, and by Biobank Barretos procedures . DNA was quantified using NanoDrop™ Spectrophotometer (Thermo Scientific).Tumor DNA from fresh frozen tissue samples was extracted using the DNeasy Blood and Tissue kit (Qiagen2.3KRAS gene (Hs02739788_cn—Thermo Fisher Scientific) was used. The reference gene Ribonuclease P (RNAse P 4403326 —Thermo Fisher Scientific), located on chromosome 14, is known to contain two copies in the human genome and was used to calculate the number of copies of the target gene. The TaqMan®KRAS Copy Number Assay contained two primers and an FAM™ dye-labeled MGB probe to detect the target genomic DNA sequence; the Ribonuclease P reference assay contained two primers and a VIC® and TAMRA™ dye-labeled probe to detect the genomic DNA reference sequence. As controls for KRAS copy number, DNA from the GCT cell line (NTERA-2), which contains five copies of KRAS and a normal blood sample, which contains two copies, were used. The qPCR reactions were performed using 20 ng of DNA, 10 μL TaqMan Genotyping Master Mix (Thermo Fisher Scientific), 1 μL of probes and region-specific primers and controls, and nuclease-free ultrapure water in a total volume of 20 μL. The copy number variation assays were performed simultaneously with the reference assay in a qPCR duplex using QuantStudio 6 equipment (Thermo Fisher Scientific) and cycling with an initial temperature of 95°C for 10 minutes, followed by 40 cycles of 95°C for 15 seconds, and 60°C for 1 minute. The Ct values of each reference sample and gene were exported to the CopyCaller™ software , in which a comparative Ct quantification (ΔΔCt) analysis of the real-time data was performed. The comparative Ct (ΔΔCt) method calculated the difference (ΔCt) between the threshold cycles of the target and reference assay sequences and then compared the ΔCt values of the test samples to a calibrator sample , which contained a known number of copies of the target sequence (two copies). All qPCR reactions were performed in technical triplicates. A variation in the number of copies of the KRAS gene was considered when the cases presented a copy number different from two for this gene. Via the method used, it was not possible to differentiate gain from amplification, only to define a variation in the number of copies different from normal (two copies of the KRAS gene).For CNV analysis (n=51), a specific TaqMan assay for the 2.4TP53, KRAS, KIT, NRAS, BRAF, EGFR, MET, PIK3CA, PDGFRA, AKT1, ERBB2, RET, GNA11, GNAQ, and FOXL2). For library preparation, targets were enriched in a multiplex PCR, with an initial input of 20 ng/μL of DNA, according to the manufacturer’s instructions. After library preparation, the DNA amplification was verified by electrophoresis. The libraries were paired-end-sequenced using MiSeq Reagent Kit v3, 600 Cycles on the Illumina MiSeq instrument (Illumina). Demultiplexed data and FASTQ files were generated using BaseSpace software (Illumina).To evaluate the driver mutations (n=65), the TruSight Tumor 15 panel (TST15 - Illumina) was used, as reported by the manufacturer’s instructions . The pan®  using the algorithm BWA-MEM-PAIRED, and Sequence Alignment Map (SAM) output format files were converted to the Binary SAM (BAM) format using SAMtools. BAM files were processed using the Genome Analysis ToolKIT (GATK). Realignment and variant calling were performed using GATK HaplotypeCaller and the Freebayes genetic variant detector using BED–Capture. The annotation of variants was performed using the Varstation®  analysisA customized analysis filter was used, which retained pathogenic and likely pathogenic variants of uncertain/unknown significance (VUS) and drug response, as well as those with population frequency less than 1% ; allelic frequency (VAF) greater than or equal to 3%; vertical coverage (depth) greater than or equal to 500x in the exonic and splicing regions, and frameshift, non-synonymous, or stopgain type. Variants leading to loss of function, “high‐impact” variants , and missense variants were selected. In addition, benign and likely benign variants were excluded from the analyses.TP53, Varsome, COSMIC, gnomAD, ABraOM, and CGI) for the better classification of the detected variants according to their effect, pathogenicity, and frequency in the general population. CGI was also employed to verify the status of driver variants, and only known variants or those predicted as drivers in cancer-related genes were retained. The variants were classified according to public databases as pathogenic, likely pathogenic, uncertain significance (VUS), and drug response.The manual curation of the variants was carried out using public databases  were considered for the outcome of overall survival (OS). Alive patients and those lost to follow-up were discounted. Univariate comparisons of survival times were performed using the log-rank test. Statistical analyses were performed using IBM SPSS Statistics for Windows, Version 2.0 (IBM), and alpha=0.05 with 80% power in a two-tailed hypothesis test.33.1Out of the 97 cases analyzed, the average age at diagnosis was 32.5 years , and most cases (57.7%) were non-seminomas  combination (57.7%). Considering all of the chemotherapy regimens, 63.9% were responsive and 6.2% were refractory. The remaining 29.9% corresponds to those who did not undergo chemotherapy (n = 25) and/or to those who died (n = 4) before the date set for the first cycle.The overall survival probability of the analyzed cohort was 91.5% in the 5-year follow-up period and 83.2% in the 10-year follow-up period; the overall survival according to AJCC staging, histological group, IGCCCG risk, and chemosensitivity status were evaluated and did not differ from the results in the literature  showed at least one copy number gain, with a variation of three to seven KRAS copies , and none of the cases showed loss of copy number.In total, 51 cases were analyzed for KRAS copy gain was compared to the clinicopathologicdata of the TGCT patients, including age, histological group, stage (AJCC), risk (IGCCCG), chemosensitivity to cisplatin-based treatment, and overall survival; however, no significant association between KRAS CNV status and patient’s features was observed   , followed by KIT , KRAS , PDGFRA , EGFR , BRAF , RET , NRAS , PIK3CA , MET  and ERBB2 . No variants were identified on AKT1, FOXL2, GNAQ, or GNA11 genes in any of the cases , risk (IGCCCG), and chemosensitivity  (Only one chemotherapy-refractory non-seminoma case (staging III and intermediate risk) presented two different variants in the KIT gene were identified more frequently among seminomas when compared to non-seminomas, and more than one variant was observed in only one case. L576P and A829P variants were observed in more than one case. One non-seminoma case with a poor prognosis, a carrier of the N655K variant, died before the date set for the first cycle of adjuvant chemotherapy, at 20 years old. No variant in the KIT gene was found in chemotherapy-refractory cases , were observed in seminoma cases. The A146T variant was identified in non-seminoma case (staging III and intermediate risk) (Mutations in the KIT (p = 0.007) was significantly mutated in seminomas, and EGFR (p = 0.010) in stage IS. All clinical and molecular comparisons of the other genes are shown in Analysis comparing the mutational status of genes with clinicopathologic data revealed that We further compared the mutational status with overall survival, but no significant association was found  have not been described in TGCT previously. Although there were no cases of Li–Fraumeni syndrome in our dataset, some of the variants found were associated with that syndrome  in some aspects , presumably also encode a constitutively activated protein that confers resistance to imatinib  and two NRAS variants , and this is the first time the NRAS G60R variant has been described. None of the PDGFRA variants identified have been previously described in TGCT either.eminomas , 52, 53.ly stage . We founimatinib , 56. Addnt TGCTs , but we BRAF, EGFR, and RET. BRAF mutations are rare in TGCT , and the T790M variant has been described in advanced non-small cell lung cancer (NSCLC) as an acquired variant associated with Tyrosine Kinase Inhibitors (TKIs) resistance , and none of them have been reported in TGCT before. Although rare, targetable mutations in TGCT increase the opportunities for precision medicine within the scenario of the accelerated approval of new drugs, mainly in cases of refractory disease.Interestingly, targetable variants were found in genes such as  in TGCT , 52 and  variant . Four gesistance . A thirdsistance . RET inherations . We founThere are limitations to our study, such as the low number of TGCT cases, the retrospective design, the single institution setting, the low number of events to analyze survival, and the large number of mixed tumors. All these limitations increase bias and might lead to misinterpretation of the results. Additionally, the sequencing analysis of the presence study was limited tumor tissue, since it was a retrospective nature of the study and we did not have availability of blood or normal tissue of the cases. Therefore, we could not exclude the germline or somatic nature of the variants identified. The analysis based on important and consolidated databases might minimize the presence of polymorphisms. However, we found new variants never described before in TGCT, and we were able to show targetable variants using a reliable mutational panel. Moreover, patients with admixed American ancestry, like Brazilian people, are commonly underrepresented in genomic profile studies, although it has been increasing . The popKRAS gene is a very frequent event in TGCT, and non-seminomas are most highly associated with a higher rate of this amplification. Although point mutations are rare events in TGCTs, relevant gene variants are identified mainly in TP53, KIT, KRAS, and NRAS genes, and 40% of the evaluable genes have at least one known and/or predicted driver variant in one of the 15 genes tested, with TP53 being the most commonly mutated gene. Although larger studies enrolling collaborative networks might shed light on the molecular landscape of TGCTas well as limited evidence available for use of targeted approaches in TGCT, our findings unveil the potential of actionable variants in clinical management when applying targeted therapies, and further evaluation of these approaches is necessary.In conclusion, the increase in the number of copies of the https://www.ncbi.nlm.nih.gov/sra/PRJNA942937)The data presented in the study are deposited in the Sequence Read Archive (SRA) repository, accession number PRJNA942937 (The studies involving human participants were reviewed andapproved by Barretos Cancer Hospital IRB under Protocol No. 784/2014. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.FC, MTP, and RR designed the study and critically revised the results. EC and MFP performed the study. AL, MR, and LL supervised the experiments. EC, ML, AS and IP analyzed the data. EC wrote the manuscript draft. FC, MTP, RR, LL, and MR revised the manuscript. All authors contributed to the article and approved the submitted version


Allium is a common functional vegetable with edible and medicinal value. Allium plants have a special spicy taste, so they are often used as food and seasoning in people’s diets. As a functional food, Allium also has abundant biological activities, some of which are used as drugs to treat diseases. By consuming Allium on a daily basis, people can receive active compounds of natural origin, thereby improving their health status and reducing the likelihood of disease. Steroidal saponins are important secondary metabolites of Allium, which are formed by the steroidal aglycone group and sugar. Steroidal saponins have various physiological activities, such as hypoglycemic, antiplatelet aggregation, anti-inflammatory, antitumor, antimicrobial, and enzyme activity inhibition, which is one of the key reasons why Allium has such significant health benefits. The structural diversity and rich biological activities of steroidal saponins make Allium important plants for both food and medicine. In this paper, the chemical structures, biological activities, and structure–activity relationships of steroidal saponins isolated from Allium are reviewed, and the biosynthetic pathways of some key compounds are proposed as well, to provide a molecular reference basis based on secondary metabolites for the health value of Allium. Allium plays an indispensable role in people’s diets, whether it is directly eaten as a vegetable or pickled condiments. The unique taste of natural Allium enhances people’s appetite, and its abundant biological activities bring people health and nutrition. A. sativum (garlic), for example, is a nutritious vegetable that is widely used as a condiment throughout the world. Fresh garlic bulbs contain about 65% water, 28% carbohydrates, 2.3% organic sulfur compounds, 2% protein, and 1.2% free amino acids . Garlic contains 146 kcal/100 g of edible parts. It is also a rich source of vitamin C. There are 10–78.8 mg of this vitamin in 100 g of the edible parts of the product. Garlic also contains minerals—relatively high amounts of potassium, iron, and phosphorus  i increase in guinea pig cardiomyocytes, suggesting that it may enhance myocardial function [87 inhibited the KCl-induced [Ca2+]i increase, suggesting its potential for the treatment of heart failure.Calcium ions play an important role in the regulation of cell physiological function. Under normal physiological conditions, the intracellular calcium levels are relatively stable and in dynamic regulation; otherwise, it may lead to cell damage or apoptosis. Compounds function . In contA. chinense G. Don, and hydrogen peroxide was selected to induce a neuronal oxidative damage model in PC12 cells [57 had a significant protective effect on neuronal cell injury induced by hydrogen peroxide in a dose-dependent manner, which may be related to its H at C-22 and the higher amounts of glucose and galactose in the sugar chain.The antioxidant activity was investigated using the CCK-8 method for six compounds isolated from 12 cells . Compare177, 181, and 220 isolated from the bulbs of A. ampeloprasum var. porrum, have all shown hemolytic ability, with HD50 values of 20 μg/mL, 6.5 μg/mL, and 13 μg/mL, respectively [Quillaja saponaria (HD50 5 μg/mL).Steroidal saponins can bind to cholesterol on the erythrocyte membrane to form insoluble complexes, disrupting the osmotic pressure of the cell membrane and inducing hemolysis. Usually, spirostane saponins have stronger hemolytic activity due to a higher affinity with cholesterol. Compounds ectively ,59,64. TThe biosynthetic pathway of steroid saponins is acetyl coenzyme A through the mevalonate (MVA) pathway or pyruvate through the methylerythritol 4-phosphate (MEP) pathway to produce farnesyl pyrophosphate (FPP), which is then catalyzed by squalene synthase (SQS) to produce squalene, and by squalene epoxidase (SQE) to produce 2, 3-oxidized squalene, and then catalyzed by cycloatenol synthase (CAS) to produce cycloatenol, which is the precursor of steroid compounds. The cycloatenol further synthesizes cholestanol, which is then hydroxylated at C-22, C-26, and C-16 to form semi-ketal structure compounds, which in turn synthesizes furostane saponin. The glycosidic bond at C-26 of furostane saponin is easily hydrolyzed, and after hydrolysis, it cyclizes into a spiral ketal structure to synthesize spirostane saponin.259 and 260 can be produced by the glycosylation of 1,16,22-trihydroxycholestrol. Pregnane compound 274 can be synthesized from cholesterol by multi-step oxidative breakage to produce pregnenolone, which in turn synthesizes compound 274 by glycosylation. Compound 271 can be synthesized from furostane compound 24 by oxidative breakage at C-22, and compound 272 can be synthesized from furostane compound 35 by a similar mechanism. The oxygen bridge of the A-ring of spirostane compound 253 can be synthesized by the dehydration cyclization of compound 116. Compound 269 can be synthesized from compound 141 by oxidation at C-2 and C-3, and then C-3 is dehydrated with C-6 to form a lactone ring. The proposed biosynthetic pathways of Allium steroidal saponin are shown in Cholestane compounds Allium plants have been extensively studied for their important edible and medicinal values. Undoubtedly, their secondary metabolite, a steroidal saponin, is one of the most important chemical bases for the healthcare functions of Allium. In this paper, we have summarized the chemical constituents, biological activities, and structure–activity relationships of steroidal saponins isolated from Allium and have proposed the biosynthetic pathways of some key compounds to clarify the molecular basis of the rich health function of Allium as a vegetable and condiment from the perspective of secondary metabolites. In addition, we have explored the positive role of Allium in the prevention and treatment of diseases more comprehensively.In recent decades, as common functional vegetables, a wide variety of


Aims and objectives: The aim is to determine the frequency of potential drug-drug interactions (pDDIs) and to analyze the clinically relevant drug interactions among hypertensive pregnant women.Materials and methods: This was an observational, cross-sectional study conducted at a tertiary care hospital. The prescriptions of the hypertensive pregnant women admitted to the hospital from June 2021 to December 2021 were analyzed for potential drug-drug interactions using the database from Lexicomp ® Solutions android mobile application version 7.5.4 .Results: A total of 127 patients were evaluated during the study period of 6 months, of which 70 (55.12%) had pDDIs. The total number of pDDIs was 85, of which 70 (82.35 %) were clinically relevant interactions with the majority of them having moderate severity (81.17%) followed by minor severity (17.65%) and major severity (1.18%). The most frequently interacting pDDIs were between Labetalol and Lornoxicam (42.35%), followed by Labetalol and Diclofenac (22.35%).Conclusion: This study highlights the high prevalence of potential drug interactions among hypertensive pregnant women and the need for rational drug use and strict vigilance in their monitoring. A change in the therapeutic impact and safety of one or both pharmaceuticals as a result of the concurrent or subsequent administration of two different medications is known as a drug interaction. Changes in the medication's pharmacokinetics, which modify the drug's delivery to the site of action, or changes in the drug's pharmacodynamics, which vary the response of the drug targets, may lead to drug interactions . PotentiPrescription and administration of medications should be done with care due to the poorly known alterations in pharmacodynamics and pharmacokinetics caused by the physiological adaptations that happen during pregnancy . AdditioParenteral magnesium sulphate, antihypertensives including calcium channel blockers, methyldopa, hydralazine, diuretics, and labetalol are all required as part of intense treatment for certain pregnancy issues, like hypertensive symptoms of pregnancy, such as pre-eclampsia and eclampsia -11.Despite the rampant use of these medications, literature on the prevalence of drug interactions in such patients is lacking. Only clinical trials with carefully chosen patient groups or short case series have been noted in few published studies to investigate drug interactions related to magnesium sulphate -14.As a result, this study was designed to determine the prevalence of pDDIs, to analyze clinically relevant pDDIs, record commonly used drug combinations, and classify them according to severity in order to increase clinicians' awareness and understanding in this field and reduce the negative effects caused by pDDIs.The current study was an observational, cross-sectional investigation conducted at a tertiary care hospital. After receiving clearance from the Institutional Ethics Committee, one prescription from each hypertensive pregnant woman admitted to the Obstetrics and Gynaecology Department between June 2021 and December 2021 was gathered retrospectively and evaluated. A prescription within 48 hours after admission was chosen.A proforma was filled out using the data where the demographic and patient identifying information, including the patient's age, diagnosis, parity, date of admission, and length of hospital stay, were included in Section 1. And the information on the recommended medications, including their name, dose, and frequency of administration, was included in Section 2. Using the database from the Lexicomp ® Solutions Android mobile application version 7.5.4  the following was done.The drugs and pDDIs were classified and quantified according to the Anatomic Therapeutic Chemical (ATC) Classification, pDDIs were assessed for - severity: minor/moderate/major/contradicted, scientific evidence (documentation): fair/good/excellent, risk rating: A - No known interaction, B - No action needed, C - Monitor therapy, D - Therapy modification, X - Avoid combination and the frequently interacting drug combinations were analyzed.The class of drugs that were included in the study were antibiotics, anti-hypertensives, analgesics, antipyretics, oral hypoglycemic agents, anti-thyroid drugs, synthetic hormones such as levothyroxine, steroids, proton pump inhibitors, anti-convulsant, antihistamines, anti-inflammatory drugs, diuretics, anti-coagulants, antiplatelet agents, anti-arrhythmic drugs, and inotropic agents. The study did not include substances like vitamins, hydro electrolytic components, or dietary supplements.MS Excel and SPSS version 22 for Windows were used to conduct the descriptive statistical analysis. A “p” value of 0.05 or below was regarded as statistically significant. The Spearman correlation coefficient was used to assess the relationship between the frequency of pDDIs and age, hospital stay length, diagnoses made, and medications administered.A total of 127 women were included during the six-month period; of these, 70 of them (55.12%) had pDDIs, with ages ranging from 18 to 40 years old and a mean of 25.16 ± 3.91 years , General anti-infectives (25.26%) and alimentary canal and metabolism (25.05%)  were clinically significant interactions. 55.12% of the individuals had one or more pDDIs, with an average of one to four per subject while a majority of pDDIs were due to drugs associated with the cardiovascular system (88.23%) , followed by Labetalol and Diclofenac (22.35%) in which the common probable mechanism was thought to be the diminishing effect of the anti-hypertensive effect of the β-blockers by the NSAIDs , +0.637 p=0.0001), and +0.034 (p=0.701), respectively. However, only the association between pDDIs and the number of drugs was statistically significant , moderate in 69 (81.1%), and severe in one (1.3%), which was consistent with earlier studies . AccordiThe method of interaction includes a decrease in flow in the calcium channels in myocardial cells as well as inhibiting norepinephrine production from the adrenal glands, thus counteracting the vasopressor effects . For theThe true impact of these pDDIs should also be assessed on an individual basis, which necessitates the careful analysis of the risk-benefit relationship between stopping the medication and continuing it with ongoing monitoring. Most management best practices adopt this strategy and always conduct a risk-benefit analysis .The current study highlights the high prevalence of potential drug interactions among hypertensive pregnant women which were mostly moderate in severity, with comorbidities and polypharmacy being important determinants. Due to the increasing number of diagnoses and concurrent diseases, polypharmacy is a prevalent issue in pregnant women, necessitating extra safety precautions to monitor and avoid pDDIs. The occurrence of drug interactions may be decreased with the use of suitable software or with the help of a clinical pharmacist in charge of keeping an eye on drug interactions and alerting a physician about possible issues. Additional clinical correlation studies are required, and an education program for medical professionals is required to increase awareness and improve therapeutic regimens to provide better healthcare quality.


Coronavirus disease 2019 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Influential variants and mutants of this virus continue to emerge, and more effective virus-related information is urgently required for identifying and predicting new mutants. According to earlier reports, synonymous substitutions were considered phenotypically silent; thus, such mutations were frequently ignored in studies of viral mutations because they did not directly cause amino acid changes. However, recent studies have shown that synonymous substitutions are not completely silent, and their patterns and potential functional correlations should thus be delineated for better control of the pandemic.In this study, we estimated the synonymous evolutionary rate (SER) across the SARS-CoV-2 genome and used it to infer the relationship between the viral RNA and host protein. We also assessed the patterns of characteristic mutations found in different viral lineages.We found that the SER varies across the genome and that the variation is primarily influenced by codon-related factors. Moreover, the conserved motifs identified based on the SER were found to be related to host RNA transport and regulation. Importantly, the majority of the existing fixed-characteristic mutations for five important virus lineages  were significantly enriched in partially constrained regions.Taken together, our results provide unique information on the evolutionary and functional dynamics of SARS-CoV-2 based on synonymous mutations and offer potentially useful information for better control of the SARS-CoV-2 pandemic. Since its first appearance 3 years ago, coronavirus disease 2019, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been declared a global pandemic, and influential variants continue to emerge and spread globally. For better monitoring and research  value, where dN or Ka represents the number of non-synonymous substitutions/number of non-synonymous sites and dS or Ks represents the number of synonymous substitutions/number of synonymous sites, is always used to determine whether there is evidence for the selection of species, lineages, or proteins and gene areas  in the open reading frames (ORFs) of the SARS-CoV-2 genome, the factors that influence the SER, and what rules can be drawn through comparison of fixed-characteristic amino acid mutations with different lineages. To answer these questions, using a mutation network approach , the probability between them was 1. Therefore, we believed that only transmission and no evolution occurred between the two sequences and that they could not provide more evolutionary information. Next, we conducted stratified sampling per country (region) per day. Finally, a total of 10,089 sequences were included in this study  program to locate the motif position with a P-value of <1e−4 for double chains in the sequence  with a sequence length of 3–30 bp  were obtained from a previous study  value, which represents the selection of entire ORFs, was estimated using the BUSTED method in HyPhy v2.5.2 with default parameters , we divided the dinucleotide frequency within the sequence by the product of the frequency of each nucleotide  regression model was constructed for determining the SER, and R-squared values were used to measure any explicable variations . Characteristic mutations in the lineages Alpha, Beta, Gamma, Delta, and Omicron  were used in our analysis .Fixed-characteristic amino acid mutations, including deletions accumulated in different lineages, were downloaded from the Cov-Lineages repository  were used with the stats.kruskal function, stats.mannwhitneyu function, and stats.chi2_contigency function, respectively, in SciPy 1.5.2 package in Python 3.8.5. Furthermore, the ggplot2 3.3.5 package in R 4.1.1 and matplotlib 3.3.2 in Python 3.8.5 were used to generate most figures.We constructed the mutation network such that it was scale-free . Based o−4  per site per year across all regions  and between any of the ORFs (adjusted P < 0.05) were significantly different. The SERs within the SARS-CoV-2 genome were also substantially different  of 6 × 10 regions . The SERper year . Moreoveifferent . The fluifferent . The oveifferent , which wifferent . This diifferent . MoreoveP = 6e−4) (To check whether conserved sequences (motifs) existed in the constrained region , we perf = 6e−4) . Further = 6e−4) .YBX1, which was identified to bind Motifs3 and Motif6, was found to be associated with viral infections, including SARS-CoV-2 and Zika, and previous experiments have shown that knockout of this gene can reduce the infection intensity  . For BA.2.75, a marginal P-value of 0.054 was obtained, indicating insufficient significance.The characteristic mutations accumulated in the five main lineages  were mapped onto the SER landscape of the SARS-CoV-2 genome to investigate their associations . Based o= 0.036) . For theViral synonymous changes are considered phenotypically silent, not functionally important, and frequently ignored; however, considering the continuing emergence of variants, it is necessary to speculate the significance of each type of mutation and its functional associations from the standpoint of synonymous substitutions, which are generally less studied. In this study, we found variations in the SERs across the SARS-CoV-2 genome. These variations can be partly explained by some factors, including the codon usage index, selection index, dinucleotide composition, structure index, and conserved motifs. Relevant motifs with extremely low SERs and potential functional constraints were identified in the constrained regions. Possible RBPs and their functions were also explored. The most important factor influencing the SER is the codon usage index. Fixed amino acid mutations are more likely to occur in partially constrained regions with potentially important functions and better adaptability. Our results indicated that the synonymous changes in the SARS-CoV-2 genome are not completely random and may be impacted by some fundamental functions and linked to the adaptation of future dominant variants.−3 per site per year) (−4-10−3 per site per year) based on the observed diversity   are sligIn addition to the very high and very low SER values owing to the strong selection, we divided the middle 80% of the SERs into two groups. In contrast to the results obtained using traditional methods, where mutation events and entropy are considered, SER was found to be low in the S region in which diversity was previously thought to be high compare . The S pYBX1, which is associated with Motif3 and Motif6, reduces the viral RNA levels in both SARS-CoV-2 and Zika virus  that are associated with viral transmissibility or infectivity  Our results are only based on the SARS-CoV-2 genome, and similar investigations in other viruses are warranted in the future. (2) The conserved motifs and their potential binding relationships with the host RBPs were mainly inferred through computational analyses, which require further experimental validation. (3) Some factors may not have been included in the SER variation analysis, which may have biased the understanding presented herein, and therefore, further investigation is warranted. (4) To identify important variants, other clues still need to be found and explored. Taken together, rather than ignoring synonymous mutations, one must pay further attention to them and explore the relationship between the synonymous mutations and other factors and the underlying mechanisms. All the relevant evidence gathered over time will ultimately help us to better prevent and control existing and future infectious diseases.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/XD conceived and designed the study and supervised the study. QS analyzed the data and drafted the manuscript. QS, JZen, and JZha collected the data. QS and JZha cleaned the data. QS, JZen, KT, HL, CZ, JZha, YX, JT, JZhe, SL, and LS commented on and revised the manuscript drafts. All authors read and approved the final report.


EF) of As, Cr, Cu, Ni, Zn, and Pb indicate no contamination, and the EFs of Cd and Hg suggested minor contamination. Although the concentrations of Cd and Hg in soil are lower than others, they are more biotoxic and exhibit a moderate–high ecological risk. The index of geoaccumulation (geoI) values reflect that most of the stations, especially the three groups of samples from depths of 10–20 cm, 20–40 cm, and 40–80 cm, are below the contamination threshold for all heavy metals. The chemical speciation of heavy metals, principal component analysis, and correlation analysis showed that Cr, Cu, Pb, Cd, Ni, and Zn mainly come from the natural accumulation upon weathering of soil-forming matrices. Hg and As mainly come from anthropogenic contributions. The effect of agricultural crop cultivation on soil heavy metal contamination is mainly through farm irrigation and crop–soil interactions, which accelerate the release of heavy metals through the weathering of soil-forming parent material and irrigation, which transports the heavy metals below the surface. The results of this study can provide a scientific basis for the involved authorities to formulate reasonable policies on environmental protection and pollution control.Shiyang River Watershed is an important ecological barrier and agricultural production area in Northwest China, and the study of soil heavy metal content, distribution, and sources is important for agricultural product safety, pollution control, and ecosystem health. In this paper, 140 soil samples were collected from 28 stations to assess the level of heavy metal (Arsenic (As), Copper (Cu), Lead (Pb), Cadmium (Cd), Chromium (Cr), Mercury (Hg), Nickel (Ni), Zinc (Zn)) contamination, pollutant sources and influencing factors of soil in Shiyang River Watershed through determination of the metal contents and statistical analysis. The results indicated that the soils in the study area are typical saline soils in arid zones. The enrichment factors ( Soil heavy metal contamination is a growing concern worldwide due to its potential negative impacts on human health, the environment, and agriculture ,5,6,7,8.EF), Index of Geo-Accumulation (geoI), Potential Ecological Risk Index (RI), and Risk Assessment Code (RAC) were calculated. The heavy metals and ions were investigated by principal component analysis to understand the heavy metal sources and influencing factors. This paper presents the ecological risk assessment and source identification of heavy metals in soil samples collected from cultivated, abandoned, and newly cultivated land. It could provide a scientific basis for the prevention and control of potential contamination of cropland soils in the Shiyang River Watershed.The Shiyang River Watershed, situated in the eastern part of the Qilian Mountains in Gansu Province, is a crucial agricultural region that plays a significant role in the country’s food production. Covering an area of approximately 22,000 square kilometers and home to over 2 million people, the Watershed primarily relies on agriculture for livelihood. Wheat, maize, and potatoes are the main crops grown in the region. However, the problem of water shortage has become increasingly serious over the past decade, despite rapid economic and social development in Wuwei City, located within the watershed. Agricultural land in the area is affected by various factors, including desertification, loess erosion, agro-biology, industrial emissions and salinization ,29,30,31The Shiyang River Watershed is located in the eastern part of the Heshi area of Gansu Province, at the northern foot of the Qilian Mountains, between the Badanjilin Desert and Tengger Desert ,33. The A total of 140 soil samples were collected in September–November 2022, involving 28 stations, mainly in Liangzhou District, Minqin County, and Gulang County of Wuwei City . Each st−, +, Na+, Ca2+, and Mg2+. All soil samples were dried and finely ground to 18 mesh for indoor analysis. Five grams (g) of air-dried soil sample were placed in a 50 mL flask, mixed with 25 mL of distilled water, shaken for 5 min and left to stand for 10 min. The pH and conductivity of the suspension were determined using a pH meter (PB−10)  and a coitration .3-HClO4). The acid was heated to 150 °C on an electric heating plate, and then the sample was cooled down to room temperature, brought to 50 mL volume and then filtered through a 0.45 μm membrane to be stored for measurement [The soil samples were dried in an oven at 55 °C, the obvious foreign matter was removed, and the remaining part was ground and sieved , then the samples were mixed homogeneously and stored in a self-sealing bag. A certain amount of the sample was weighed and put into a digestion tube, where the sample underwent microwave digestion with nitric acid–hydrofluoric acid–perchloric acid , 30 mL of 0.1 mol/L NH2OH-HCl was used; for the oxidizable fraction (F3), 5 mL of 8.8 mol/L H2O2 was followed by 25 mL of 1 mol/L CHCOONH4; for the residual fraction (F4), HNO3-HF-HClO4 was used [To analyze soil heavy metal forms, 28 surface soil samples were chosen and weighed accurately to 1.00 g in 100 mL polypropylene centrifuge tubes. A modified BCR procedure was used for the analysis. For the exchangeable fraction (F1), 30 mL of 0.11 mol/L CHwas used . The extSoil soluble ions  were detected with a limit of detection of 1 mg/kg and an error of detection of ±5%. ICP-OES and ICP-MS were used for elemental measurements using a standard reference sample (GSS−18), blanks, and replicate samples in order to control the quality of the whole analytical process. The reproducibility of the elements in the samples was greater than 95% and the recoveries of the standard samples ranged from 90% to 105% .EF) [geoI) [RI) [The enrichment factor (EF) ,41,42, g) [Igeo) ,44, poteeo) [RI) ,46,47 aneo) [RI)  were useeo) [RI) ,6,7,8.The background element values were obtained from the samples at station S21 , which iCorrelation analysis and principal component analysis (PCA) were carried out using Origin 2022 . Maps of the sampling sites  were pro2+, K+, Mg2+, Na+, −, 2+, K+, Mg2+, and Na+ exhibited mean values of 287.0988, 39.880, 45.665, and 511.503 mg/L, respectively. The underlying layers also reveal analogous concentration trends for these cations, each characterized by distinct concentration ranges and corresponding mean values , oxidizable (organic bound), and residue. The acid extractable form encompasses the highly mobile exchangeable and carbonate bound forms, which can be readily absorbed and utilized by organisms. On the other hand, heavy metals in the residue form are primarily found in the crystalline matrix of primary and secondary minerals like silicates. These minerals are quite stable and are not easily released under normal natural conditions. The chemical speciation of heavy metals in soil is closely related to the study of heavy metals and migration, transformation, cycling processes and environmental impacts. Chemical speciation analysis of heavy metals is more critical than the total soil content. This helps to accurately assess the environmental impact of soil heavy metals. The heavy metal composition of newly reclaimed, continuously cropped, and abandoned farmlands has been analyzed in this study. The results indicate that, except for Cd and Pb, the residual fractions of As, Cr, Cu, Hg, Ni, and Zn are predominantly hosted by scarcely soluble minerals . This imEF mean value of the samples showed the following order: Hg (1.86) > Cu (1.35) > Ni (1.34) > Cd (1.33) > Zn (1.27) > Cr (1.24) > As (1.23) > Pb (1.00). The EF of all the heavy metals was less than 2 in the Shiyang River Watershed, indicating that the detected heavy metals do not pose any remarkable environmental trouble  layer, contrary to the surface transport effect as in the case of soluble salts.The  trouble a. The avrder: Hg .86 > Cu ) > Zn 1.7 > Cr (1) > Cu 1.5 > Ni , Cr (0.33), Cu (0.34), Ni (0.34), and Zn (0.13) in the samples showed low contamination. Overall, the geoI mean value of these samples showed the following order: Hg (0.28) > Cu (−0.06) > Ni (−0.05) > Cd (−0.09) > Zn (−0.13) > As (−0.16) > Cr (−0.17) > Pb (−0.47)  b. As witThe ecological risk of heavy metal contaminants in 140 soil samples was evaluated by calculating the sum of eight potential risk coefficients. The results showed that the majority of samples exhibited a medium level of ecological risk, with only 3 samples from site S27 displaying a very high risk and 16 samples showing high risk. Two samples were found to have a low ecological risk. The order of potential ecological risk for individual heavy metals in the study area was Hg > Cd > As > Cu > Ni > Pb > Cr > Zn, with Hg and Cd posing a moderate risk and As, Ni, Cu, Cr, Pb, and Zn posing a slight risk. These findings suggest that most heavy metals in the soil had a low ecological risk. These results are presented in EF and geoI focus on the enrichment and accumulation of total soil heavy metals relative to soil background values, while RI assesses ecological risk based on the biotoxicity of different heavy metals. RAC emphasizes the mobility of heavy metals, i.e., their ability to be taken up by plants. In general, most of the soils in the study area had low levels of heavy metals and were uncontaminated or lightly contaminated. In conclusion, the RAC results suggest that most soils in the study area are not significantly contaminated with heavy metals, with the exception of Hg and Cd. However, the levels of Hg and Cd in the soils of the study area are much lower than the national and international standards for soil contamination [Risk Assessment Codes (RACs) for heavy metals in topsoil samples from 28 sites are presented in mination ,5,6,7,8.p < 0.001), confirming the appropriateness of the PCA method. The first principal component (PC1), second principal component (PC2) and third principal component (PC3) explained 53.7%, 13.3% and 8.8% of the total variance of the soil samples, respectively. PC1 showed positive loadings for Al, Fe, Mn, Cr, Cu, Pb, Cd, Ni, Zn, Ti, and P, suggesting that it may represent migratory accumulation of detrital minerals. PC2 shows significant positive loadings for EC, Ca and Mg and negative loadings for pH. This suggests that PC2 may represent chemical precipitates such as CaCO3 and MgCO3. PC3 showed significant positive loadings for EC and Na and negative loadings for As and Hg. This suggests a specific source of arsenic and mercury in the samples.In this study, principal component analysis (PCA) and correlation analysis were used to determine the sources of heavy metals and their influencing factors. The elements analyzed included As, Cd, Cr, Cu, Hg, Ni, Pb, Zn, pH, EC and other elements . The resSummarizing, three sources of soil heavy metals in the Shiyang River watershed were identified. The heavy metals Cr, Cu, Pb, Cd, Ni, and Zn have a positive correlation with Al, Mn, Fe and Ti , and areThe results of this study have revealed a clear order in the accumulation of soil heavy metals for different years of cultivation. It was found that continuously cropped farmlands have the highest levels of heavy metals, followed by newly reclaimed farmlands and abandoned farmlands . These fIrrigation water in the Shiyang River Basin mainly comes from deep groundwater and a small amount of Yellow River water (purified by sedimentation), while the principal component analysis shows that, except for Hg and As, the source of heavy metals is mainly the weathering of soil-forming substrates. Moreover, heavy metals have a significant cumulative effect in the deep layer (tillage layer). It can be assumed that the impact of agricultural production on soil heavy metals in the study area is mainly manifested by (1) the migration and fixation of heavy metals to deeper depths as a result of prolonged irrigation (drip irrigation), and (2) accelerated weathering and accumulation of heavy metals as a result of the interaction of the soil with the root system of agricultural crops.+ and Ca2+, while the anions are Cl− and geoI values reflect that most of the stations, especially the three groups of samples from depths of 10–20 cm, 20–40 cm, and 40–80 cm, are low in Cd and Hg, and all other heavy metals are below the contamination levels. Although the concentrations of Cd and Hg in the soil are low, they are more biotoxic and may eventually represent an ecological risk, especially Cd, which is mainly bound to the exchangeable and reducible fraction in the study area.The research shows that the integrated approach, including the modified ecological risk assessment method and biotoxicity assessment method, effectively identifies the potential ecological risk and sources of heavy metals in the soil samples from the Shiyang River Watershed. The results indicated that the soils in the study area are typical saline soils in arid zones. The main cations in the soluble salt of the surface soil are NaEF and geoI were the highest in old cropland and at 40–80 cm.The chemical speciations of heavy metals, principal component analysis, and correlation analysis showed that Cr, Cu, Pb, Cd, Ni, and Zn mainly come from the natural accumulation through the weathering of soil-forming matrices. Hg and As mainly come from industrial emissions, transportation pollution sources, and other human activities. The effect of agricultural crop cultivation on soil heavy metal contamination in the study area is mainly through farm irrigation and crop–soil interactions, which accelerate the release of heavy metals through the weathering of soil-forming parent material on the one hand, and irrigation on the other hand, which transports the heavy metals below the surface layer. This effect was manifested in the study area as


Abnormal thyroid function is a metabolic disorder and can lead to several complications, including cardiovascular diseases. In this study, we aimed to examine the relationship between clinical traits and outcomes and the thyroid hormone level of euthyroid individuals with valvular heart disease (VHD).The thyroid function was evaluated in 526 euthyroid VHD patients and 155 healthy control people. As well as clinical indicators were collected and analyzed.No difference in TSH levels (p>0.05) was recorded; however, fT3, TT3, and TT4 levels were lower in the euthyroid VHD patients than in healthy control, while the fT4 level was higher . Moreover, all showed a continuous trend with the change of NYHA grade which does not consist of the incidence of euthyroid sick syndrome(ESS). Further analysis showed that for every 10-fold increase in BNP, fT4 increases by 83%, fT3 decreases by 30%, and TT3 decreases by 12% after being adjusted for other influencing factors. Meanwhile, adjusted fT4 was correlated with multiple worse clinical indicators, which were influenced by age.Thyroid hormones are widely regulated in VHD patients even with acceptable cardiac function, except for TSH level. And the adjusted fT4 is related to worse clinical indicators and outcomes which are only recorded in patients under 53 years old. Thyroid hormone impacts on the body can have a positive impact on the heart and vascular system . The actIn addition to the considerable effects thyroid hormones have on the circulatory system, heart diseases are distinct pathophysiological disorders that may also have an effect on the level of thyroid hormones . In the Thus, studying the thyroid hormone levels in euthyroid patients with valvular heart disease and analyzing their correlation with clinical traits and outcomes are the goals of this clinical study.From January 2019 to June 2021, the Sichuan Provincial People’s Hospital’s Department of Endocrinology, cardiac surgery, intensive care unit, and health examination center conducted this retrospective study. It was accepted by the Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital Research Ethics Committee, and all trials were carried out in accordance with the necessary standards and laws.The thyroid function profile, which comprises TT3, TT4, fT3, fT4, TSH, TgAb, and TPOAb (thyroid peroxidase antibody), was assessed in 526 euthyroid patients with valvular heart disease who were hospitalized for cardiac surgery department from January 2019 to June 2021. At the same time, data on 155 healthy individuals’ thyroid function and demographics, such as their age and gender, were gathered from the Sichuan Provincial People’s Hospital’s Health Examination Center. The primary first exclusion requirements were: 1) A TPOAb level of greater than 30 IU/ml or a TgAb level of greater than 75 IU/ml; 2) A history of thyroid disease; 3) A history of thyroid-related drug use, including lithium, amiodarone, interferon-alpha, interleukin-2, tyrosine kinase inhibitors, phenytoin, phenobarbiturates, iodine contrast, and carbamazepine; and 4) A history of pituitary disease.Patients with valvular heart disease demographic data were gathered, including their age, sex, weight, height, smoking, alcohol consumption, history of chronic illness, and drug use. Heart rate, blood pressure, pulse rate, and respiration rate were recorded as baseline clinical features. On the first day of admission, blood samples were taken and examined concurrently. Lymphocyte count, CRP, alanine transaminase, aspartate aminotransferase, total bilirubin, direct bilirubin, glucose, creatinine, blood urea nitrogen, cardiac troponin I, creatine kinase (CK), creatine kinase (CK), creatine kinase (CK), creatine kinase (CK), and creatine kinase, muscle and brain (CK-MB). The level of heart failure was also determined by looking at the brain natriuretic peptide (BNP). Heart surgery indicators such as cardiopulmonary bypass time (CPBT) and aortic occlusion time were gathered (AOT). Patients recovering from heart surgery in our cardiac surgery center are frequently transferred to the intensive care unit (ICU) for post-operative observation. For the severity assessment of the post-cardiac surgery patients, we additionally recorded ICU characteristics such as the sequential organ failure assessment (SOFA) score and acute physiology and chronic health illness categorization system II (APACHE II). The use of invasive and non-invasive ventilators, endotracheal intubation time, the likelihood of re-tracheal intubation, lung infections, intra-aortic balloon pumps (IABP), continuous renal replacement therapy (CRRT), extracorporeal membrane oxygenation (ECMO), and ICU time was also noted. After being released, the outcome of the hospital stay and deaths were also recorded. During or after data collection, none of the authors had access to information that may identify specific participants.As patients were admitted, doctors and patients graded the NYHA class  scores following the NYHA functional classification .An automated chemiluminescence assay  was used to evaluate the thyroid function profile, including TT3, TT4, fT3, fT4, TSH, TgAb, and TPOAb, immediately after sampling at the central laboratory of the Sichuan Provincial People’s hospital under routine external quality control. Based on data showing an analytical sensitivity of 0.0025 IU/ml for TSH, 1.5 pg/ml for fT3, and 0.22 ng/dl for fT4, the test was given regulatory approval. The intra- and inter-assay coefficients of variance were 5% and 10%, respectively, across all assays. TSH 0.35-4.94 mIU/l, fT3 2.43-6.01 pmol/l, fT4 9.01-19.05 pmol/l, TT3 (0.88-2.44nmol/L), and TT4 (62.68-150.8nmol/L) are the reference ranges used in our lab. TPOAb has a 30 IU/mL upper limit, while TgAb has a 75 IU/mL upper limit.The presence of both a normal serum TSH level (0.35–4.94 mIU/L) and a serum T3 level below the lowest laboratory normal limit (0.88nmol/L) was used to diagnose ESS .post hoc comparison procedure, Dunnett’s unequal variance procedure, and Kruskal-Wallis one-way ANOVA were employed, respectively, for post hoc comparisons. For categorical variables, the Chi-squared test and Fisher exact probability approach were employed. In parametric statistical analysis, log-transformed was used for variables with known lognormal distributions (such as TSH and BNP). To investigate the correlations between the thyroid function and continuous variables, Pearson or Spearman rank correlation analysis and linear regression analysis were carried out. Analysis of covariance was used to examine how various effect modifiers interacted with one another. Also, the extent to which age influences the association between thyroid function and the clinical features of valvular heart disease was investigated using hierarchical analysis.Statistical evaluations were carried out utilizing SPSS version 23. . Statistical significance was set at p 0.05 for all two-sided analyses. Depending on the situation, data are reported as mean ± SD (standard deviation), median (quartile range), or n(%). ANOVA and the student’s t-test were used for normally distributed variables, and the Mann-Whitney U and Kruskal-Wallis tests were used for nonparametric variables. Bonferroni’s To further explore the connection between thyroid function and heart function, we divided the VHD patients into subgroups using the NYHA classification Table 2.Meanwhile, we compared several cardiac functions to describe the prevalence of ESS in valvular heart disease Table 3.Influencing factors of thyroid function in euthyroid patients with valvular heart diseaseAge, sex, body mass index (BMI), and β-blocker therapy were investigated as variables impacting thyroid function in euthyroid patients with valvular heart disease. There was no gender-related difference in thyroid function (p>0.05). The findings indicated that older age was related to lower TSH levels . The relationship between fT3 and TT3 levels and BMI was found to be minimal (p< 0.05). Lower fT3 and TT3 levels were discovered to be related to treatment with β-blockers . fT3 decreased by 30%, fT4 increased by 83%, and TT3 decreased by 12% for every 10-fold rise in BNP level, demonstrating the close relationship between thyroid function and BNP Figure 2To conduct a hierarchical analysis, we divided all patients with valvular heart disease into three equal groups based on fT4 levels, using 53 as the age cutoff Figure 3Our study revealed that, even with acceptable cardiac function, with an increase in NYHA grade, euthyroid patients with valvular heart disease exhibited a continuous trend of decreased fT3, TT3, and TT4 levels and increased fT4 levels compared to healthy people, except for TSH levels, which is inconsistent with the typical profile of patients with the ESS. Further investigation revealed that even after adjusting for other contributing factors (such as BMI and use of β-blockers), there was an 83% increase in fT4, a 30% decrease in fT3, and a 12% decrease in TT3 for every 10-fold increase in BNP. Also, other clinical signs are worse when fT3 levels are altered, but age is a significant influencing factor. Higher fT4 levels, higher heart rate, increased heart rate, elevated diastolic BP, higher total bilirubin, higher direct bilirubin, and elevated BNP levels, higher SOFA scores, are associated with longer ICU stay and overall length of stay in individuals under the age of 53 years. Many of the connections; however, were not present in patients over the age of 53 years.The present study was a significant retrospective inquiry that targeted individuals with valvular heart disease who did not have any other metabolic disorders other coronary heart disease , 18. To The ESS has been implicated in numerous earlier investigations as the cause of aberrant thyroid functioning in patients with cardiac insufficiency . In patiTraditionally, studies on thyroid function have primarily focused on TSH levels, which have been associated with a higher risk of heart failure, changes in cardiac function, and even mortality. However, the CORONA experiment found no association between TSH levels and heart failure with a lower ejection fraction , 11, 24.Additionally, to the changes in T3 levels, patients with valvular heart diseases also experienced different changes in fT4 levels when compared to healthy individuals and the fT4 level increased with the increase of NYHA grade and BNP level. While T3 is recognized as the active cellular form of thyroid hormones, it`s important not to underestimate the role of T4. The Penn Heart Failure Study found that atrial fibrillation was positively associated with higher levels not fT3 or TT3, meanwhile, higher fT4 levels were also linked to incident heart failure, and sudden cardiac death , 13, 14.The analysis of thyroid function and clinical features yielded intriguing results, indicating a connection between fT4 levels and several clinical parameters, with age playing a significant role in this association. The strength of the association between fT4 levels and clinical characteristics appears to be more pronounced in younger patients, while it is less prominent in older patients. This could be attributed to the fact that cardiac performance and clinical indicators in older patients are influenced by multiple uncorrected factors, making it more challenging to achieve favorable outcomes. These findings suggest the potential use of certain interventions, such as administering thyroxine to younger patients, to improve clinical outcomes. By targeting fT4 levels and addressing thyroid function in younger patients, it may be possible to enhance their overall prognosis.The absence of the rT3 level due to technical limitations in our center’s laboratory is the study’s limitation; however, this does not affect our analysis of the results, and in addition, most laboratories are unable to detect the level of rT3, so there are some restrictions on its potential clinical applications. At the same time, it was impossible to completely rule out the potential of central hypothyroidism. The second drawback is that patient mortality and death outcomes cannot be studied due to the low mortality rate before discharge and the short follow-up period. Monitoring thyroid function at multiple time points may provide a better understanding of the changes in thyroid hormone levels throughout the process. However, due to the retrospective design of the study, this may be considered a limitation of the current trial. Meanwhile, due to limited resources, we were unable to obtain sufficient imaging-based indicators before and after cardiac surgery, which may partially limit the scope of our study. In the future, more research can be done to get beyond these restrictions.In conclusion, our study showed that euthyroid patients with valvular heart diseases had decreased fT3, TT3, and TT4 levels compared to healthy individuals, but increased levels of fT4 even with acceptable cardiac function. Additionally, they showed a continuous trend with the change in NYHA grade, which is inconsistent with the profile of ESS. Further research showed that for every 10-fold rise in BNP, fT4 increases by 83%, fT3 decreases by 30%, and TT3 lowers by 12%, even after accounting for other influencing variables. Additionally, there are various clinical indications that are connected to the adjusted level of fT4 that are associated with worse outcomes; however, age is a crucial influencing factor since many of the associations between the adjusted level of fT3 and clinical indicators are only evident in individuals under the age of 53. As a result, not only TSH but also T3, and T4 levels should be of concern in some trials, especially in patients with abnormal cardiac function, and T4 levels can even be used as a management target other than TSH. Further research is required to explore the use of thyroxine to improve clinical outcomes in abnormal thyroid function of valvular heart disease at a younger age.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital Research Ethics Committee. The patients/participants provided their written informed consent to participate in this study.The authors confirm their contribution to the paper as follows: study conception and design: PW, SW, SL,YW. Data collection: PW, SL, YY, LL. Analysis and interpretation of results: PW, SL, GZ. Draft manuscript preparation: PW, JZ, DN. All authors reviewed the results and approved the final version of the manuscript.