Efficacy Of Different Treatments Research Articles

Abstract PO5-03-07: Impact of age and stage on pathologic complete response rates in Black vs White patients with triple negative breast cancer

Abstract Background Triple-negative breast cancer (TNBC) accounts for approximately 10-15% of breast cancers. Women with TNBC have worse survival outcomes, increased rates of relapse, and distant metastasis as compared to women with non-TNBC. Regardless of subtype, Black women have worse breast cancer outcomes than White women. Early stage treatment of TNBC has focused on neoadjuvant therapy (NACT) with a goal of achieving a pathologic complete response (pCR), which is associated with longer event-free survival and overall survival in TNBC patients. NACT with pembrolizumab was presented at the San Antonio Breast Cancer Symposium in December 2019 and FDA approved in July 2021. The Keynote-522 Trial found that patients who received NACT + pembrolizumab were more likely to achieve pCR than women who received NACT + placebo, regardless of stage. The KEYNOTE-522 trial did not examine race or age differences in treatment efficacy. Since TNBC disproportionately affects younger women and Black women, optimizing pCR rates in these groups is essential. Our objective is to examine racial differences in pCR rates by cancer stage and age among patients with TNBC who completed NACT/pembrolizumab. Methods Patient records from Ochsner Health, a regional network, were reviewed for those with early stage TNBC who had completed treatment with NACT/pembrolizumab from January 2020 to January 2022. Exclusion criteria included no surgical treatment for TNBC, unknown receptor status, and age < 18 years-old. Chi-square and Fisher’s Exact tests were used to examine the relationship between race and pCR stratified by stage at diagnosis and age. Risk ratios and 95% confidence intervals were also estimated to examine the strength of these relationships. Results We identified 92 patients with TNBC who completed treatment with NACT/pembrolizumab and underwent surgery. 52 patients (56%) were Black and 40 patients (43%) were White. 53.85% of Black patients had pCR and 67.50% of White patients experienced pCR (p=0.19). Among patients with stage III disease, only 37.50% of Black patients experienced pCR compared to 69.23% of White patients (p=0.09). Notably, Black patients were 46% less likely to experience pCR than = White patients (RR: 0.54, 95% CI: 0.28-1.02) in the stage III group. Among patients less than 50 years of age, 41.18% of Black patients experienced pCR compared to 84.21% of White patients (p=0.01), where younger Black patients were 51% less likely to experience pCR than younger White patients (RR: 0.49, 95% CI: 0.27-0.89) There were no observed racial differences in pCR rates for stage I/II patients (p=1.00) or patients aged 50 years or older (p=0.64). Discussion These data demonstrate that Black women are at a pCR rate disadvantage receiving NACT/pembrolizumab. This is primarily driven by advanced stage and young age. Black patients with stage III cancers had significantly lower pCR rates than their White counterparts after having received the same treatment. Additionally, young patients who are Black have significantly lower pCR rates. For older patients and those with stage I/II disease, there was no statistically significant difference in pCR rates between Black vs White race. Conclusion While NACT/pembrolizumab offers overall increased rates of pCR, Black women, especially those who are young or with more advanced disease at presentation, still have worse outcomes. Further research is needed to determine underlying predictors or alternative treatments to benefit these populations. Table 1 Distribution of Pathological Complete Response Following NACT/pembrolizumab treatment (Nf91) Table 2 Crude Risk Ratios for the Relationship between Race and Pathological Complete Response by Age and Stage (Nf92) Citation Format: Melanie Sheen, Caitlin Taylor, Rabia Cattie, Melyssa Bratton, Meredith Lakey, Victoria Chung, Erin Biggs. Impact of age and stage on pathologic complete response rates in Black vs White patients with triple negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-03-07.

Abstract PO1-15-06: Serum thymidine kinase activity as a “real-time” clinical biomarker of tumor response to CDK4/6 inhibition in hormone receptor positive (HR+), HER2 negative (HER2-) metastatic breast cancer

Abstract Background: CDK4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET) are standard first-line (1L) treatment for hormone receptor positive (HR+), HER2-negative (HER2-) metastatic breast cancer (MBC). Despite general improvements in long-term outcome, not all patients benefit equally from these drugs. The average duration of 1L CDK4/6i therapy is ~2 years. However, 10-15% of patients will progress within 6 months of therapy initiation, while others will derive durable clinical benefit of years. Differences in treatment efficacy cannot be easily explained by clinical-pathological features. No predictive biomarkers are currently available to determine tumor sensitivity to CDK4/6i. There is an unmet need for a complementary diagnostic to identify patients that will or will not respond to these treatments in order to better inform therapy management. Thymidine kinase (TK) is an E2F-regulated enzyme that plays a key role in DNA replication during cell division. The expression and activity of TK is strongly linked to the cell cycle. TK is first expressed in late G1, peaks during S-phase, and then is degraded during mitosis. Because of the restricted expression of TK (only during S phase of the cell cycle) combined with the mechanism of action of CDK4/6i, the measurement of TK activity (TKa) may serve as an ideal pharmacodynamic biomarker to assess a tumor’s response to CDK4/6i-based therapy. DiviTum® TKa is an FDA cleared assay that can quantitate TKa from human serum (sTKa) and is intended to be used as a disease progression monitoring tool for patients with HR+, HER2- MBC. TK IMPACT is a prospective, single arm trial designed to assess the impact of incorporation of DiviTum® TKa on the physician’s decision regarding subsequent timing of routine disease monitoring modalities in patients with advanced HR+, HER2- MBC receiving 1L ET plus CDK 4/6i (NCT04968964). As a part of this ongoing study, DiviTum® TKa values are serially assessed relative to imaging findings and other circulating tumor biomarkers, such as CA15-3 and ctDNA. The primary endpoint is any physician-reported intended change in imaging testing interval post TKa by study cohort, within the first 48-week period of study participation, assessments for which are ongoing. Here we report real-world data and examples of the clinical utility of sTKa as a companion diagnostic from patients treated at Washington University Siteman Cancer Center, St. Louis, MO. Methods: Patients with HR+, HER2- MBC receiving 1L ET + any FDA-approved CDK 4/6i (palbociclib, ribociclib, or abemaciclib) had blood serum samples collected at baseline, weeks 2, 4, 6, 8, every 4 weeks up to week 24, and then every 12 weeks thereafter until disease progression. Samples were analyzed for TKa levels in real-time using the DiviTum® TKa assay. Optional repeat TKa within 2-4 wks (+/- 3 days) is permitted in case of rising TKa. Other standard monitoring assessments were carried out according to institutional guidelines and/or treating clinician discretion. Results: Pre-treatment and early on-therapy TKa levels predicted response to CDK4/6i therapy more accurately than a patient’s clinical characteristics. Rising TKa levels also identified patients with clinically occult disease progression ahead of imaging, and in some cases where radiographic interpretation and serum tumor markers such as CA15-3 were ambiguous. Measurement of TKa levels following CDK4/6i dose reduction was able to confirm continued optimal therapy response at the lower dose. A rise in TKa levels aligned with the re-emergence of ESR1 mutation as identified by ctDNA in one patient and may herald molecular progression. Conclusion: sTKa was able to predict tumor sensitivity and resistance (both intrinsic and acquired) to CDK4/6i + ET therapy in patients with HR+, HER2- MBC. We believe these findings help support the role of sTKa as a non-invasive pharmacodynamic biomarker that can assess in real-time a tumor’s response to CDK4/6i based therapy. Citation Format: Nusayba Bagegni, Amy Williams, Isabella Grigsby, Mattias Bergqvist, Katherine Clifton, Cynthia Ma. Serum thymidine kinase activity as a “real-time” clinical biomarker of tumor response to CDK4/6 inhibition in hormone receptor positive (HR+), HER2 negative (HER2-) metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-15-06.

In vitro Evaluation of Botanical Extracts against Mycelial Growth of Alternaria solani

An experiment was conducted at the laboratory of the Department of Plant Pathology, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj, Uttar Pradesh. To test the efficacy of different treatments viz., Neem (Azadirachta indica), Onion (Allium cepa), Garlic (Allium sativum), Castor (Ricinus communis), Amaltas (Cassia fistula), Henna (lawsonia inermis), Madar (Calotropis gigantea) against Alternaria solani under in vitro condition. Botanicals were tested through the poisoned food technique at 5% and 10 % concentrations and 168 hours of incubation. The Minimum radial growth of observed in  Neem (Azadirachta indica) seed kernel extract @ 5% (14.8mm) followed by Henna (lawsonia inermis) leaf extract @ 10% (43.36mm), Amaltas (Cassia fistula) leaf extract @ 10% (67.13mm),  Castor (Ricinus communis) leaf extract @ 10% (67.6mm), Madar (Calotropis gigantea) leaf extract @ 10% (69.6mm), Onion (Allium cepa) extract @ 10 % (70.8mm), Garlic (Allium sativum) extract @ 10 % (72.2mm) as compared to Control (89.4mm) untreated check.

Comparative efficacy of different interventions on executive function in adolescents with internet use disorder

BackgroundThe formation and relapse of Internet use disorder (IUD) are related to the decline in executive function. Previous studies have indicated that exercise intervention and high-definition transcranial direct current stimulation (HD-tDCS) can improve the cognitive abilities of adolescents with IUD. However, the combined intervention's impact on executive function in these adolescents remains unclear. Therefore, this study aims to explore the effects and differences of multimodal exercise, HD-tDCS intervention, and combined intervention on the executive function of adolescents with IUD. MethodsForty-eight adolescents with IUD were randomly assigned to the multimodal exercise group, HD-tDCS intervention group, combined intervention group, and control group. The intervention groups received 4 weeks of moderate-intensity multimodal exercise, HD-tDCS intervention (2 mA, 20min/session, 3 times/week), or combined multimodal exercise with HD-tDCS intervention. The control group received conventional educational learning. Executive function measurements were taken before intervention, after intervention, and 2 weeks post-intervention. ResultsCompared to pre-intervention, different interventions effectively improved the behavioral performance of adolescents with IUD in executive function tasks. In comparison to single interventions, the combined intervention significantly outperformed multimodal exercise and HD-tDCS intervention in influencing the executive function (especially inhibitory control and working memory) in adolescents with IUD. ConclusionCombined multimodal exercise with HD-tDCS intervention proves to be an effective means of enhancing executive function in adolescents with IUD, particularly contributing to the improvement of explicit behavioral performance related to executive function.

Docetaxel, cyclophosphamide, and epirubicin: application of PBPK modeling to gain new insights for drug-drug interactions.

The new adjuvant chemotherapy of docetaxel, epirubicin, and cyclophosphamide has been recommended for treating breast cancer. It is necessary to investigate the potential drug-drug Interactions (DDIs) since they have a narrow therapeutic window in which slight differences in exposure might result in significant differences in treatment efficacy and tolerability. To guide clinical rational drug use, this study aimed to evaluate the DDI potentials of docetaxel, cyclophosphamide, and epirubicin in cancer patients using physiologically based pharmacokinetic (PBPK) models. The GastroPlus™ was used to develop the PBPK models, which were refined and validated with observed data. The established PBPK models accurately described the pharmacokinetics (PKs) of three drugs in cancer patients, and the predicted-to-observed ratios of all the PK parameters met the acceptance criterion. The PBPK model predicted no significant changes in plasma concentrations of these drugs during co-administration, which was consistent with the observed clinical phenomenon. Besides, the verified PBPK models were then used to predict the effect of other Cytochrome P450 3A4 (CYP3A4) inhibitors/inducers on these drug exposures. In the DDI simulation, strong CYP3A4 modulators changed the exposure of three drugs by 0.71-1.61 fold. Therefore, patients receiving these drugs in combination with strong CYP3A4 inhibitors should be monitored regularly to prevent adverse reactions. Furthermore, co-administration of docetaxel, cyclophosphamide, or epirubicin with strong CYP3A4 inducers should be avoided. In conclusion, the PBPK models can be used to further investigate the DDI potential of each drug and to develop dosage recommendations for concurrent usage by additional perpetrators or victims.

Efficacy of Different Treatment Approaches (Insulin and Metformin) in Women with Gestational Diabetes Mellitus (GDM)

Background and Purpose: The pharmacotherapy options in patients with gestational diabetes mellitus (GDM) are insulin or oral antihyperglycemic agents. Insulin is the preferred medication for treating hyperglycemia, but in recent years, metformin has been increasingly used in the treatment of GDM. Aim: The aim is to assess the efficacy of different treatments (insulin and metformin) in women with GDM. Methods: Screening for GDM was performed in 2422 pregnant women and revealed GDM in 119 women [75 g oral glucose tolerance test (OGTT) was performed at 24–28 weeks of gestation]. All patients started treatment at 24–29 weeks of gestation. The patients were divided into two groups (Gr.): Gr. 1 had 68 patients treated with diet and insulin therapy. Gr. 2 had 51 patients treated with diet and metformin. Results: In the 2nd trimester, HbA1c (%) levels for Gr. 1 and Gr. 2 were 6.7 (0.05) and 6.4 (0.6), respectively. By term, HbA1c levels statistically decreased in both groups, but we did not find a statistical difference between the groups. Women from Gr. 2 gained less weight compared to Gr. 1 (1.89 ± 3.88 vs. 4.53 ± 3.67 kg; P = 0.003). In Gr. 1, the percentage of preeclampsia was 2.9%, and in Gr. 2, 3.9% (P = 0.7773, OR – 1.33). We did not find a statistical difference between the groups. The incidence of preterm delivery before 37 weeks of gestation in Gr. 1 was lower than in Gr. 2 (P = 0.7311, OR – 1.33), and we also did not find a statistical difference between the groups. Perinatal mortality was observed in Gr. 1 – 1.4% and in Gr. 2 – 1.9% (P = 0.8402, OR – 1.33). In both groups, we observed a high percentage of cesarean section (Gr. 1 – 32.3% and Gr. 2 – 29.4% (P = 0.7651, OR -1.0909), but we did not find a statistical difference between the groups. In both groups, the percentage of macrosomia was high, despite good glycemic control maintained through pregnancies: 20.0% and 23.0% for Gr. 1 and Gr. 2, respectively (P = 0.9236, OR – 1.0256), and again no statistical difference was found between the groups. Percent of neonatal hypoglycemia was lower in Gr. 2 (1.9%) than in Gr. 1 (4.41%) (P = 0.9236, OR – 1.0256). Percent of respiratory distress syndrome was 2.94% and 3.92% for Gr. 1 and Gr. 2, respectively (P = 0.9694, OR – 0.9893), with no statistical difference between the groups. Conclusion: We did not find differences between patients treated with diet and insulin therapy and patients treated with diet and metformin. The percentage of preeclampsia, preterm delivery, macrosomia, and perinatal death were similar in both groups; only maternal weight gain was lower in the metformin group.

Management for degenerative lumbar spondylolisthesis: a network meta-analysis and systematic review basing on randomized controlled trials.

Consensus on the various interventions for degenerative lumbar spondylolisthesis (DLS) remains unclear. We searched PubMed, Embase, Cochrane Library, Web of Science, and major scientific websites until Nov 01, 2023, to screen eligible randomized controlled trials (RCTs) involving the treatment of DLS. The seven most common DLS interventions (non-surgical [NS], decompression only [DO], decompression plus fusion without internal fixation [DF], decompression plus fusion with internal fixation [DFI], endoscopic decompression plus fusion [EDF], endoscopic decompression [ED], and circumferential fusion [360F]) were compared. The primary (pain and disability) and secondary (complications, reoperation rate, operation time, blood loss, length of hospital stay, and satisfaction) outcomes were analyzed. Data involving 3,273 patients in 16 RCTs comparing the efficacy of different interventions for DLS were reported. In terms of improving patient pain and dysfunction, there was a significant difference between surgical and NS. EDF showed the greatest improvement in short-term and long-term dysfunction (probability, 7.1% and 21.0%). Moreover, EDF had a higher complication rate (probability 70.8%), lower reoperation rate (probability, 20.2%), and caused greater blood loss (probability, 82.5%) than other surgical interventions. Endoscopic surgery had the shortest hospitalization time (EDF: probability, 42.6%; ED: probability, 3.9%). DF and DFI had the highest satisfaction scores. Despite the high complication rate of EDF, its advantages include improvement in pain, lower reoperation rate, and shorter hospitalization duration. Therefore, EDF may be a good option for patients with DLS as a less invasive surgical approach.

A Bayesian Network Meta-Analysis of the Effect of Targeted Therapies on the Total Length of Hospital Stay in Children with Drug-Induced Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Syndrome.

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare potentially life-threatening hypersensitivity disorders characterized by widespread skin and mucosal involvement. However, there is no standardized evidence-based treatment to reduce the complications of SJS/TEN. This article aims to compare the efficacy of different treatments for pediatric SJS/TEN in terms of length of hospital stay (LOS) using a Bayesian network meta-analysis (NMA). A Bayesian NMA is used to compare and combine evidence from multiple studies and allows clinicians to estimate the relative effectiveness of different treatments/interventions while accounting for heterogeneity in the available evidence. Methods: We conducted a comprehensive electronic database search for studies compatible with our inclusion criteria. Six studies with 103 patients were included in the NMA; of them, 37 patients were treated with intravenous immunoglobulin (IVIG), 37 with systemic corticosteroids (CS), 23 with IVIG + CS, and 3 with Etanercept (ET) + CS. Patients with a median age of 10 years were included in the study. Results: CS had the highest probability of being the most optimal treatment for SJS/TEN in terms of shorter LOS based on the Surface Under the Cumulative Ranking curve levels, and CS + IVIG was associated with a statistically nonsignificant trend toward shorter LOS than IVIG alone. Remarkably, none of the treatments showed a significant benefit over the other interventions in terms of LOS. Conclusion: Current evidence suggests that coadministration of CS and IVIG may be associated with a shorter LOS than IVIG alone. Further research with larger randomized controlled trials is needed to reach a definitive conclusion about the efficacy of specific therapy on LOS in pediatric SJS/TEN and to establish more definitive treatment guidelines.

External treatment of traditional Chinese medicine for cancer pain: A systematic review and network meta-analysis.

Cancer pain is one of the most intolerable and frightening symptoms of cancer patients. However, the clinical effect of the three-step analgesic ladder method (TSAL) is not satisfactory. The combination of external treatment of traditional Chinese medicine (TCM) can improve the clinical effect. This study used network meta-analysis to compare the effects of different external treatment methods of TCM combined with TSAL on cancer pain. Databases searched by our team included Google Scholar, Web of Science, Scopus, Embase, PubMed, and Cochrane Library. Randomized controlled trials related to the external treatment of TCM combined with TSAL for cancer pain were screened from the establishment of the database till now. The above literature extracted clinical efficacy, NRS score, KPS score, analgesic onset time, and duration as the main results after the screening. The 95% confidence interval (95% CI) of OR value and SMD value was used as the effect index to compare the difference in efficacy of different interventions, and the ranking was conducted. STATA 17.0 software was used for the statistical analysis of the above data. A total of 78 studies were included, including 8 interventions and 5742 participants. Based on ranking probability, the clinical effective rate of manual acupuncture combined with TSAL was the best when the intervention time was set at 4 weeks [OR = 5.42, 95% CI (1.99,14.81)], and the improvement effect on KPS score was also the best [SMD = 0.97, 95% CI (0.61, 1.33)]. Acupoint external application was the best intervention in reducing NRS score [SMD = -1.14, 95% CI (-1.90, -0.93)]. Acupoint moxibustion combined with TSAL was considered to be the most effective intervention to prolong the duration of analgesia [SMD = 1.69, 95% CI (0.84, 2.54)] and shortening the onset time of analgesia [SMD = -3.00, 95% CI (-4.54, -1.47)]. TSAL combined with manual acupuncture is the best in terms of clinical efficacy and improvement of patients' functional activity status. With the extension of treatment time, the intervention of this kind of treatment on the clinical effect is more pronounced. Acupoint external application also has a unique advantage in reducing the pain level of patients. From the point of view of analgesic duration and duration of analgesia, combined acupoint moxibustion has the best effect.

Comparison of Efficacy of 5% Tranexamic Acid vs 20% Azelaic Acid in Patients of Melasma

Background: Melasma is a significant cosmetic concern globally, affecting individuals across various ethnic backgrounds, particularly in South Asian populations. The condition's etiology is complex, involving genetic, hormonal, and environmental factors such as sun exposure. Despite numerous treatment options, melasma remains challenging to manage effectively. Recent studies have explored the efficacy of tranexamic acid and azelaic acid, both of which target the melanin synthesis pathway but through different mechanisms. Objective: The aim of this study was to compare the effectiveness of topical 5% tranexamic acid versus 20% azelaic acid in the treatment of melasma, with a focus on changes in the Melasma Area and Severity Index (MASI) scores. Methods: This prospective comparative study was conducted at the Dermatology department of PIMS Hospital, Pakistan, over six months from August 2023 to January 2024. A total of 200 patients with melasma were enrolled and randomly assigned to two groups: Group A received 5% tranexamic acid cream, and Group B received 20% azelaic acid cream, both applied twice daily. Inclusion criteria included men and women aged 18 to 50 years with a diagnosis of melasma for at least six months. Pregnant women, patients with a history of Systemic Lupus Erythematosus (SLE) or Discoid Lupus Erythematosus (DLE), and those on hormonal therapy were excluded. The primary outcome measure was the change in MASI scores from baseline to the end of the study period. Data were analyzed using SPSS Version 25. Results: The study found significant differences in treatment efficacy between the two groups. Group A (tranexamic acid) showed a reduction in MASI scores from 7.94 ± 1.88 at baseline to 5.50 ± 1.61 post-treatment. Group B (azelaic acid) demonstrated a decrease from 8.21 ± 1.96 to 5.89 ± 1.49. The proportion of patients experiencing excellent response was higher in Group A (36.0%) compared to Group B (19.0%), with a statistically significant difference in overall treatment efficacy (P<0.0001). Conclusion: Topical 5% tranexamic acid was more effective than 20% azelaic acid in improving MASI scores in patients with melasma. This study supports the inclusion of tranexamic acid as a preferable treatment option for melasma, offering a promising alternative for those not responding to conventional therapies.

Repurposing DNase I and alginate lyase to degrade the biofilm matrix of dual-species biofilms of Staphylococcus aureus and Pseudomonas aeruginosa grown in artificial sputum medium: In-vitro assessment of their activity in combination with broad-spectrum antibiotics

BackgroundBiofilm-associated pulmonary infections pose therapeutic challenges in cystic fibrosis patients, especially when involving multiple bacterial species. Enzymatic degradation of the biofilm matrix may offer a potential solution to enhance antibiotic efficacy. This study investigated the repurposing of DNase I, commonly used for its mucolytic activity in cystic fibrosis, to target extracellular DNA within biofilms, as well as potential synergies with alginate lyase and broad-spectrum antibiotics in dual-species biofilms of Pseudomonas aeruginosa and Staphylococcus aureus. MethodsDual-species biofilms were grown in artificial sputum medium using S. aureus and P. aeruginosa isolated by pairs from the same patients and exposed to various combinations of enzymes, meropenem, or tobramycin. Activity was assessed by measuring biofilm biomass and viable counts. Matrix degradation and decrease in bacterial load were visualized using confocal microscopy. Biofilm viscoelasticity was estimated by rheology. ResultsNearly complete destruction of the biofilms was achieved only if combining the enzymatic cocktail with the two antibiotics, and if using supratherapeutic levels of DNase I and high concentrations of alginate lyase. Biofilms containing non-pigmented mucoid P. aeruginosa required higher antibiotic concentrations, despite low viscoelasticity. In contrast, for biofilms with pigmented mucoid P. aeruginosa, a correlation was observed between the efficacy of different treatments and the reduction they caused in elasticity and viscosity of the biofilm. ConclusionsIn this complex, highly drug-tolerant biofilm model, enzymes prove useful adjuvants to enhance antibiotic activity. However, the necessity for high enzyme concentrations emphasizes the need for thorough concentration-response evaluations and safety assessments before considering clinical applications.

The nitric oxide-soluble guanylate cyclase-cGMP pathway in pulmonary hypertension: from PDE5 to soluble guanylate cyclase.

The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway plays a key role in the pathogenesis of pulmonary hypertension (PH). Targeted treatments include phosphodiesterase type 5 inhibitors (PDE5i) and sGC stimulators. The sGC stimulator riociguat is approved for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). sGC stimulators have a dual mechanism of action, enhancing the sGC response to endogenous NO and directly stimulating sGC, independent of NO. This increase in cGMP production via a dual mechanism differs from PDE5i, which protects cGMP from degradation by PDE5, rather than increasing its production. sGC stimulators may therefore have the potential to increase cGMP levels under conditions of NO depletion that could limit the effectiveness of PDE5i. Such differences in mode of action between sGC stimulators and PDE5i could lead to differences in treatment efficacy between the classes. In addition to vascular effects, sGC stimulators have the potential to reduce inflammation, angiogenesis, fibrosis and right ventricular hypertrophy and remodelling. In this review we describe the evolution of treatments targeting the NO-sGC-cGMP pathway, with a focus on PH.

Analysis of SARS-CoV-2 transmission in a university classroom based on real human close contact behaviors

Due to high-population density, frequent close contact, possible poor ventilation, university classrooms are vulnerable for transmission of respiratory infectious diseases. Close contact and long-range airborne are possibly main routes for SARS-CoV-2 transmission. In this study, taking a university classroom in Beijing for example, close contact behaviors of students were collected through a depth-detection device, which could detect depth to each pixel of the image, based on semi-supervised learning. Finally, >23 h of video data were obtained. Using Computational Fluid Dynamics, the relationship between viral exposure and close contact behaviors (e.g. interpersonal distance, relative facial orientations, and relative positions) was established. A multi-route transmission model (short-range airborne, mucous deposition, and long-range airborne) of infectious diseases considering real close contact behaviors was developed. In the case of Omicron, the risk of infection in university classrooms and the efficacy of different interventions were assessed based on dose-response model. The average interpersonal distance in university classrooms is 0.9 m (95 % CI, 0.5 m–1.4 m), with the highest proportion of face-to-back contact at 87.0 %. The risk of infection of susceptible students per 45-min lesson was 1 %. The relative contributions of short-range airborne and long-range airborne transmission were 40.5 % and 59.5 %, respectively, and the mucous deposition was basically negligible. When all students are wearing N95 respirators, the infection risk could be reduced by 96 %, the relative contribution of long-range airborne transmission increases to 95.6 %. When the fresh air per capita in the classroom is 24 m3/h/person, the virus exposure could be decreased by 81.1 % compared to the real situation with 1.02 m3/h/person. In a classroom with an occupancy rate of 50 %, after optimized arrangement of student distribution, the infection risk could be decreased by 62 %.

Awareness of the impact of sex and gender in the disease risk and outcomes in hematology and medical oncology-a survey of Swiss clinicians.

Although male and female cancer patients are distinct in many ways, there is a limited understanding in the differences between male and female biology and differing pharmacokinetic responses to cancer drugs. In fact, sex and gender are currently not considered in most treatment decisions in the fields of oncology and hematology. The lack of knowledge about potential sex differences in both disciplines may lead to differences in treatment efficacy, toxicity, and the overall survival (OS) of patients. To evaluate their awareness about sex and gender in clinical practice we surveyed Swiss hematologists and oncologists from September to November 2022. We collected data about the clinical knowledge, experimental research, palliative care, quality of life, as well as the participant perception of the importance of sex and gender. We identified 767 eligible clinicians, of whom 150 completed the survey (20% response rate). While most participants agreed that sex and gender were relevant when treating patients, it became clear that fewer participants knew about sex and gender differences in treatment toxicity and survival, which in turn would affect the treatment of their patients. Most participants agreed that this topic should be integrated into continuing education and research. Our findings indicate the need for more awareness and training on sex and gender in cancer research and clinical care among oncologists and hematologists. Ideally, by better educating medical students and health professionals, a demand is created for improving research policies, publications and therefore patient care.

The effectiveness of various treatment approaches for laryngeal contact granulomas.

To assess and compare the effectiveness of various treatment approaches for laryngeal contact granulomas (LCG). A retrospective analysis was conducted on a cohort of 45 patients diagnosed with LCG at the Second Affiliated Hospital of Xi'an Jiaotong University from October 2017 to May 2023. Based on the treatment modalities administered, patients were categorized into three groups: acid suppression alone, hormone injection combined with acid suppression, and surgery combined with acid suppression. Subsequently, the study compared differences in treatment efficacy and average healing time among these three groups, using various indicators. The findings indicate that the granuloma size in LCG patients with hoarseness (0.126, 95% CI 0.087-0.288) was significantly greater compared to LCG patients without hoarseness (0.047, 95% CI 0.014-0.083) (P = 0.001). However, there were no significant variations in age, morphology (unlobulated/lobulated), laterality ratio (left/right), sex ratio (male/female), history of tracheal intubation (non-intubation/intubation), and RFS score (RFS > 7/RFS ≤ 7) (P > 0.05), regardless of the presence of hoarseness symptoms. At the treatment observation endpoint of 3months, the curative ratio in the group receiving hormone injection combined with acid suppression was found to be significantly higher compared to the group receiving acid suppression alone (P = 0.018). In addition, the average healing time of patients in the hormone injection combined with acid suppression group was notably shorter than that of the acid suppression alone group (P = 0.007). The combination of hormonal injections and acid suppression may enhance the curative ratio and expedite the healing time of LCG.

Efficacy and Safety of Switching from Adalimumab Originator to SB5, Adalimumab Biosimilar for Noninfectious Uveitis.

To evaluate the efficacy and safety of switching from adalimumab originator (Humira, AbbVie) to SB5, adalimumab biosimilar (Adalloce, Samsung Bioepis) in patients with noninfectious uveitis (NIU). Fifteen patients (29 eyes) with NIU who were switched from adalimumab originator to SB5 and followed up for 6 months or longer were retrospectively included. Data consisted of best-corrected visual acuity (BCVA, logMAR), intraocular pressure (IOP, mmHg), anterior chamber (AC) cell grade, anterior vitreous (AV) cell grade, vitreous haze grade, central macular thickness (CMT, μm), and macular volume (MV, mm3) at pre-switching, 2, 4, and 6 months post-switching. There were no significant differences in BCVA, AC and AV cell grades, and vitreous haze grades at 2, 4, and 6 months post- compared with pre-switching, and no significant differences in CMT and MV at 2 and 6 months post-switching. CMT and MV decreased from 260.55 ± 67.44 μm and 8.37 ± 1.14 mm3 at pre-switching to 244.14 ± 60.31 μm (p = 0.032) and 8.11 ± 1.20 mm3 (p = 0.027) at 4 months post-switching, respectively. There was no recurrence of uveitis, as defined by AC cell grade, vitreous haze, or BCVA. Four patients (27%) were switched back to adalimumab originator after a mean of 9 weeks, due to discomfort during the injection (three patients) and technical difficulty with the new injection device (one patient). No other adverse events occurred after switching to SB5. Switching from adalimumab originator to SB5 for NIU does not result in clinically significant differences in treatment efficacy and safety.

Long-term Favorable Efficacy of Regular and Repeated Hospitalizations with a Personalized Diet and Exercise Treatment for Steatotic Liver Disease.

Objective The long-term impact of personalized diet and exercise programs for steatotic liver disease (SLD) remains unclear. Materials The subjects of this retrospective cohort study included 104 consecutive Japanese patients with SLD. The long-term treatment efficacy of personalized diet and exercise treatment was evaluated two years after the start of observation. Regular and repeated hospitalizations every 6 months (RRH group, n=23) indicated the 4 times of the number of hospitalizations, and irregular hospitalizations (IH group, n=56) showed the 1 to three times. The group without hospitalization was defined as the no hospitalization group (NH group, n=25). To balance confounding biases, the difference in treatment efficacy between the RRH and IH groups was evaluated using propensity score (PS)-matched analysis. A diet of 25 to 30 kcal/kg multiplied by ideal body weight (BW) daily, and aerobic and resistance exercise (exercise intensity of 4 to 5 metabolic equivalents daily, respectively) was performed for 6 days. Results At 2 years compared to baseline, the decrease rates of liver function tests, HbA1c, and physical findings in the RRH group were significantly higher than those in the NH or IH groups by multiple comparisons. According to the liver function tests and physical findings, the rate of decrease in the RRH group (17 cases) was significantly higher than that in the IH group (17 cases) using a PS-matched analysis. Conclusion The present study indicated the long-term favorable efficacy of personalized diet and exercise programs for SLD. In particular, this RRH program was effective in improving the findings of liver function tests and might help to sustain diet and exercise.

Improving the utility of non-significant results for educational research: A review and recommendations

When used appropriately, non-significant p-values have the potential to further our understanding of what does not work in education, and why. When misinterpreted, they can trigger misguided conclusions, for example about the absence of an effect of an educational intervention, or about a difference in the efficacy of different interventions. We examined the frequency of non-significant p-values in recent volumes of peer-reviewed educational research journals. We also examined how frequently researchers misinterpret non-significance to imply the absence of an effect, or a difference to another significant effect. Within a random sample of 50 peer-reviewed articles, we found that of 528 statistically tested hypotheses, 253 (48%) were non-significant. Of these, 142 (56%) were erroneously interpreted to indicate the absence of an effect, and 59 (23%) to indicate a difference to another significant effect. For 97 (38%) of non-significant results, such misinterpretations were linked to potentially misguided implications for educational theory, practice, or policy. We outline valid ways for dealing with non-significant p-values to improve their utility for education, discussing potential reasons for these misinterpretations and implications for research.

Examining the efficacy of treatments for arm lymphedema in breast cancer survivors: an overview of systematic reviews with meta-analyses

Lymphedema affects one in six breast cancer survivors making it a global healthcare challenge. There is considerable debate about the efficacy of different treatments for lymphedema. We aimed to summarize the current evidence for treatments for lymphedema in breast cancer survivors. In this overview of systematic reviews with meta-analyses (SRMAs), five databases were searched for SRMAs of randomised controlled trials (RCTs) reporting effects of medications, surgery, exercise, laser therapy, acupuncture, kinesio taping, or complex decongestive physiotherapy (CDP) for breast cancer-related lymphedema published from database inception up to March 7, 2023. Data extraction was performed for the SRMAs and RCTs, and SRMAs were appraised with AMSTAR2. Random effects meta-analyses of the RCTs provided estimates of the pooled effects sizes (Hedges' g) for each treatment modality. This study is registered with PROSPERO, CRD42020184813. 1569 studies were identified by the search and eighteen SRMAs with 51 RCTs were included, investigating manual lymphatic drainage (MLD), compression pump, exercise, kinesio taping, laser, and acupuncture. Overall, the methodological quality of the SRMAs was low. SRMAs reached different conclusions for all treatment modalities, except for kinesio taping where the two SRMAs found no effect. The analysis of 40 RCTs with 1970 participants revealed a small effect across all interventions compared to any control (g=0.20, p=0.047, I2=0.79), corresponding to volume reductions of 119.7ml (95% CI 135-104) and 88.0ml (95% CI 99-77) in the intervention and control groups, respectively, and a small effect of exercise (g=0.26, p=0.022, I2=0.44). The between-group differences in volume reduction were small and did not reach statistical significance for any one treatment modality. Based on the available data, there is no evidence of superiority of any one treatment on volume reduction nor any solid research refuting these treatments. Thus, definitive conclusions to inform clinical practice about the efficacy of these treatments cannot be drawn. Due to poor-quality evidence, more research is needed to untangle the efficacy of each treatment component for different stages of lymphedema. Danish Cancer Society.

Single-Nucleotide Polymorphisms of the PAR2 and IL-17A Genes Are Significantly Associated with Chronic Pain.

Patients with chronic pain are affected psychologically and socially. There are also individual differences in treatment efficacy. Insufficient research has been conducted on genetic polymorphisms that are related to individual differences in the susceptibility to chronic pain. Autoimmune disorders can lead to inflammation and chronic pain; therefore, we focused on the autoimmune-related protease-activated receptor 2 (PAR2/F2RL1) and interleukin 17A (IL-17A/IL17A) genes. PAR2 and IL-17A are associated with autoimmune diseases that lead to chronic pain, and PAR2 regulates T-helper (Th) cell activation and differentiation. We hypothesized that the PAR2 and IL-17A genes are associated with chronic pain. The present study used a case-control design to statistically examine associations between genetic polymorphisms and the vulnerability to chronic pain. The rs2243057 polymorphism of the PAR2 gene and rs3819025 polymorphism of the IL-17A gene were previously reported to be associated with pain- or autoimmune-related phenotypes. Thus, these polymorphisms were investigated in the present study. We found that both rs2243057 and rs3819025 were significantly associated with a susceptibility to chronic pain. The present findings revealed autoimmune-related genetic factors that are involved in individual differences in chronic pain, further aiding understanding of the pathomechanism that underlies chronic pain and possibly contributing to future personalized medicine.