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KRASG12C inhibitors, such as sotorasib and adagrasib, have revolutionized cancer treatment for patients with KRASG12C-mutant tumors. However, patients receiving these agents as monotherapy often develop drug resistance. To address this issue, we evaluated the combination of the PAK4 inhibitor KPT9274 and KRASG12C inhibitors in preclinical models of pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). PAK4 is a hub molecule that links several major signaling pathways and is known for its tumorigenic role in mutant Ras-driven cancers. We found that cancer cells resistant to KRASG12C inhibitor were sensitive to KPT9274-induced growth inhibition. Furthermore, KPT9274 synergized with sotorasib and adagrasib to inhibit the growth of KRASG12C-mutant cancer cells and reduce their clonogenic potential. Mechanistically, this combination suppressed cell growth signaling and downregulated cell-cycle markers. In a PDAC cell line-derived xenograft (CDX) model, the combination of a suboptimal dose of KPT9274 with sotorasib significantly reduced the tumor burden (P= 0.002). Similarly, potent antitumor efficacy was observed in an NSCLC CDX model, in which KPT9274, given as maintenance therapy, prevented tumor relapse following the discontinuation of sotorasib treatment (P= 0.0001). Moreover, the combination of KPT9274 and sotorasib enhances survival. In conclusion, this is the first study to demonstrate that KRASG12C inhibitors can synergize with the PAK4 inhibitor KPT9274 and combining KRASG12C inhibitors with KPT9274 can lead to remarkably enhanced antitumor activity and survival benefits, providing a novel combination therapy for patients with cancer who do not respond or develop resistance to KRASG12C inhibitor treatment.

Abstract To enhance the clinical utility of mass spectrometry (MS), lengthy dwell times on less informative regions of patient specimens (e.g., adipose tissue in breast) must be minimized. Additionally, a promising variant of MS known as picosecond infrared laser MS (PIRL-MS) faces further challenges, namely, lipid contamination when probing adipose tissue. Here we demonstrate on several thick non-sectioned resected human breast specimens (healthy and malignant) that reflection-mode polarimetric imaging can robustly guide PIRL-MS toward regions devoid of significant fat content to (1) avoid signal contamination and (2) shorten overall MS analysis times. Through polarimetric targeting of non-fat regions, PIRL-MS sampling revealed feature-rich spectral signatures including several known breast cancer markers. Polarimetric guidance mapping was enabled by circular degree-of-polarization (DOP) imaging via both Stokes and Mueller matrix polarimetry. These results suggest a potential synergistic hybrid approach employing polarimetry as a wide-field-imaging guidance tool to optimize efficient probing of tissue molecular content using MS.

The Karampuang Indigenous People are still actively carrying out rituals to worship the spirits of their ancestors as a form of thanksgiving and a wish for a better life. However, for some of the Karampuang Indigenous people, this ritual is only a form of gratitude and respect for traditional leaders. This research aims to explore and reveal how the Mappogau Sihanua ritual influences and shapes religious, social, and cultural values in Karampuang Indigenous peoples. This research was conducted using a qualitative descriptive method with the subject, namely the people in the location of the Karampuang Traditional Village, Tompobulu Village, Bulupoddo District, Sinjai Regency. Through the stages of analysis, including data reduction, data presentation, and data verification in the form of observation, interviews, and documentation, the findings reveal several efforts that can be made to preserve Karampuang Indigenous culture. This study shows that the ritual tradition of Mappogau Sihanua needs to be preserved by increasing inclusivity so that it can be accepted by the wider community, including people who do not understand myths that are considered sacred. The acknowledgment of various cultural identities in society is made possible by inclusivity. Within the Karampuang traditional community, maintaining the Mappogau Sihanua custom can symbolize acknowledging the plurality of cultures.

This research aims to describe the changes in the natural, physical, and social environment that occur in society and their influence on language. This research method uses a qualitative descriptive method. The data in this study are the speeches of speakers and community leaders regarding ecological and language changes in the Malay community in Riam Panjang, Kapuas Hulu. Data collection techniques were obtained through field observations, interviews, and documentation studies. The data analysis technique uses an ethnographic record analysis model by grouping thematically based on research objectives. After grouping, the data were described and interpreted, then concluded according to the focus of this research. The results of this study show that the natural, physical, and social environment has changed dramatically in the last three decades. The construction of the Southern Crossing Road linking Kapuas Hulu-Sintang (and Pontianak) and Malaysia in the northern crossing was a pivotal point of change. The population's relationship with the outside world has become more intense, while the relationship with the forest, fields, and rivers has become tenuous. The Malay language has shifted. The vocabulary of farming, games, rivers, fish and fishing gear, and river transportation has been abandoned. On the other hand, the previously monolingual society became a multilingual society. This research shows that changes in the natural and social environment greatly affect the shift in community language use. Abstrak Penelitian ini bertujuan untuk mendeskripsikan perubahan lingkungan alam, fisik, dan sosial yang terjadi dalam masyarakat dan pengaruhnya terhadap bahasa. Metode penelitian ini mengunakan metode deskriptif kualitatif. Data dalam penelitian ini tuturan penutur dan tokoh masyarakat berkenaan dengan perubahan ekologi dan bahasa dalam masyarakat Melayu di Riam Panjang, Kapuas Hulu. Teknik pengumpulan data diperoleh melalui observasi lapangan, wawancara, dan studi dokumentasi. Teknik analisis data menggunakan model analisis catatan etnografi dengan mengelompokkan secara tematik berdasarkan tujuan penelitian. Setelah dikelompokkan, selanjutnya data dideskripsikan dan diinterpretasikan, lalu disimpulkan sesuai fokus penelitian ini. Hasil penelitian ini memperlihatkan perubahan lingkungan alam, fisik, dan sosial terjadi drastis dalam tiga dekade terakhir ini. Pembangunan Jalan Lintas Selatan yang menghubungkan Kapuas Hulu-Sintang (dan Pontianak) serta Malaysia di lintas utara merupakan titik anjak perubahan. Hubungan penduduk dengan dunia luar semakin intens, sedangkan hubungan dengan hutan, ladang, dan sungai menjadi renggang. Bahasa Melayu mengalami pergeseran. Kosa kata perladangan, permainan, sungai, ikan dan alat tangkap, pengangkutan sungai telah ditinggalkan. Pada sisi lain, masyarakat yang sebelumnya monolingual menjadi masyarakat multilingual. Penelitian ini menunjukkan perubahan lingkungan alam dan sosial sangat memengaruhi pergeseran pemakaian bahasa masyarakat.

A tandem structure efficiently boosts solar cell efficiency because it uses a larger spectrum of solar radiation and minimizes photon energy thermalization. High-performance tandem solar cells have historically been difficult to produce due to a shortage of high-performance, low-bandgap cells. The proposed design is based on the CH3NH3GeI3 (1.9 eV) as a wide band gap absorber layer and FAMASnGeI3 (1.4 eV) as a narrow band gap perovskite layer with CZTSe as HTL. This research investigates the effect of different ETLs, perovskite layer thicknesses and their doping concentration on the device's photovoltaic parameters. Furthermore, the effect of tunnel junction thickness and front contact work function on the solar cell performance has also been simulated. It has been noted that the PCBM presents a better efficiency device than the other ETLs. The Voc of different ETLs has been related to Vbi. Moreover, the optimized thicknesses of both perovskite absorber layers are 450 nm and 400 nm for MAGeI3 and FAMASnGeI3, respectively. The optimal doping density is found to be E14 cm−3. It has been observed that the tunnel junction's thickness and the front contact's work function also play an important role in optimized device efficiency. The tunnel junction thickness is 4 nm for lead-free mixed cation perovskite/CZTSe tandem solar cells. However, the work function of the front electrode of 4.4 eV is optimum for this structure. The proposed lead-free mixed cation perovskite/CZTSe tandem device shows significant performance parameters, i.e., Voc= 0.970 V, Jsc = 28.46 mAcm−2, FF = 84.43 % and PCE= 23.32 %

The quantity of straw and rice husk waste remains a crucial problem to be solved, especially in Maggenrang Village, Bone Regency, South Sulawesi, so an alternative way for farmers to reduce it is through the combustion process that will add the problem of the impact of temporary air pollution but is harmful to the health of other residents. Therefore, community service is carried out to provide innovative solutions to the Eccengnge’ Farmer Group in Maggenrang Village by transforming rice straw and husk through the delignification process, which is continued by making animal feed pellets. The method of implementing this activity is carried out with three main stages: counseling, training, and mentoring to partners. The results showed an increase in partners' skills with three evaluation components, namely knowledge with a rise of 90% and production and supporting skills with an increase of 90% and 80%. Increasing skills for partners provides potential business opportunities by adding value to straw and rice husk waste into products with high commercial value, thus supporting the fulfillment of alternative, independent feed by the Maggenrang Village government based on local potential.

The potential of Maggenrang Village, Kahu Sub-district, Bone Regency as a center for plantation commodities is quite large, especially fruit plantations in the form of bananas. However, banana processing often leaves waste that is not properly processed. Therefore, the implementation of this Community Partnership Program (PKM) activity aims to empower the Pao Kalikie Farmer Group through diversification of processed bananas with a zero waste approach. The activity implementation method consists of three stages, namely counseling, training, and mentoring. The form of activity evaluation can be seen from the results of partner preferences using questionnaires and descriptive analysis. The results of the service showed an increase in partner knowledge and skills in processing bananas into high-value products, namely banana stems and fruits into chips, and the remaining stems and fronds into ecoenzyme. Partner knowledge after the implementation of the activity increased by 92%, and partner skills increased by 90%. This PKM has a positive impact in building the entrepreneurial spirit of partners.

Abstract Background Recent studies identified coronavirus disease 2019 (COVID-19) as a risk factor for invasive pulmonary aspergillosis (IPA) but produced conflicting data on IPA incidence and impact on patient outcomes. We aimed to determine the incidence and outcomes of COVID-19-associated pulmonary aspergillosis (CAPA) in mechanically ventilated patients. Methods We performed a multicenter retrospective observational cohort study in consecutive adults admitted to 15 French intensive care units (ICUs) in 2020 for COVID-19 requiring mechanical ventilation. CAPA was diagnosed and graded according to 2020 ECMM/ISHAM consensus criteria. The primary objective was to determine the incidence of proven/probable CAPA, and the secondary objectives were to identify risk factors for proven/probable CAPA and to assess associations between proven/probable CAPA and patient outcomes. Results The 708 included patients (522 [73.7%] men) had a mean age of 65.2 ± 10.8 years, a median mechanical ventilation duration of 15.0 [8.0–27.0] days, and a day-90 mortality rate of 28.5%. Underlying immunosuppression was present in 113 (16.0%) patients. Corticosteroids were used in 348 (63.1%) patients. Criteria for probable CAPA were met by 18 (2.5%) patients; no patient had histologically proven CAPA. Older age was the only factor significantly associated with probable CAPA (hazard ratio [HR], 1.04; 95% CI 1.00–1.09; P = 0.04). Probable CAPA was associated with significantly higher day-90 mortality (HR, 2.07; 95% CI 1.32–3.25; P = 0.001) but not with longer mechanical ventilation or ICU length of stay. Conclusion Probable CAPA is a rare but serious complication of severe COVID-19 requiring mechanical ventilation and is associated with higher day-90 mortality. Graphical Abstract

The Melawi Malay community has a rich tradition of medicine using oral literature in the form of mantras, passed down through generations. These medicine mantras incorporate elements of beautiful sound and reflect the ecological, customary, and cultural values of the Malay people. This research aims to unveil the sound patterns and describe the symbolism of the triadic ecological elements, namely nature, nurture, and culture. To achieve this, purposive sampling was employed to select key informants, with Su Usnah, a traditional healer from Bina Karya, Melawi, being a crucial source. Through interviews and field notes, six relevant data sets were extracted from a pool of 15 available medicine mantras for analysis. Using a qualitative descriptive approach, this research utilized stylistic protocols to categorize the data according to existing sound patterns and employed ecocriticism guidelines to reveal the presence of ecological elements within the Melawi Malay medicine mantras. The primary findings of this research disclose the existence of four sound patterns in these mantras: assonance, alliteration, consonance, and rhyme. The ecocritical perspective reveals that each mantra contains ecological elements, including nature, such as flora and natural elements; nurture, reflecting the relationship between nature and society, and human connections; and culture, as manifested in customary practices. This study deepens our understanding of the sound patterns and ecological elements present in these mantras, with the hope that further research, through exploration of mantras in the Melawi Regency, can contribute to the continuous conservation and promotion of oral literature. Enriching the global understanding of mantras from linguistic, literary, and ecological perspectives is vital in practising traditional medicine in Melawi and other regions in West Kalimantan.

This study compares the impact of pictorial health warning labels (HWLs) and their placements on waterpipe parts (device, tobacco and charcoal packages) on health communication outcomes between waterpipe smokers and nonsmokers in Lebanon. An online randomized crossover experimental study was conducted among young adults (n = 403, August 2021) who observed three conditions of HWLs: pictorial HWLs on the tobacco package, pictorial HWLs on all waterpipe's parts and text-only HWL on the tobacco package in random order. Participants completed post-exposure assessments of health communication outcomes after each image. Using linear mixed models, we examined the differences in the effect of HWL conditions on several outcomes (i.e. warning reactions) between waterpipe smokers and nonsmokers, controlling for confounders (i.e. age, sex). Nonsmokers reported greater attention ([beta] = 0.54 [95% confidence interval: 0.25-0.82]), cognitive elaboration (0.31 [0.05-0.58]) and social interaction (0.41 [0.18-0.65]) for pictorial HWLs on the tobacco packages than text-only compared with smokers. Pictorial HWLs on three parts versus one part elicited higher cognitive reactions and perceived message effectiveness in nonsmokers compared with waterpipe smokers. These findings provide valuable information for policymakers about the potential of implementing HWLs specific to waterpipes to prevent their use among young adults and limit tobacco-related morbidity and mortality in Lebanon.

This study aims to analyze the level of knowledge and understanding of the Sukadana Malay medicinal plant lexicon, especially among the school-age, early adults, and advanced adults population. The methods used in this research are qualitative and quantitative. Data collection involves observation, interviews, documentary study, and questionnaires, with age-divided respondents into three age groups: school-age, adult, and advanced adults. Data analysis comprises activities such as data reduction, presentation, and conclusion drawing, with specific techniques including organizing and reducing research data and analyzing the knowledge and use of different age groups. Based on the results of the analysis regarding the level of knowledge and use of Sukadana Malay medicinal plants, respondents of school age (14-17 years) have an average level of knowledge and use of Sukadana Malay medicinal plants as much as 26%, early adult respondents (21-45 years) have an average level of knowledge and use of Sukadana Malay medicinal plants as much as 58%, while advanced adults (46 years and over) have an average level of knowledge and use of Sukadana Malay medicinal plants as much as 81.4%. This study reveals the lexicon of medicinal plants that developed in the Sukadana Malay. It is necessary to involve local health practitioners to get their views on the use of medicinal plants and their potential in modern medical practice.

UNLABELLED: The identification of molecules that can bind covalently to KRAS G12C and lock it in an inactive GDP-bound conformation has opened the door to targeting KRAS G12C selectively. These agents have shown promise in preclinical tumor models and clinical trials. FDA has recently granted approval to sotorasib for KRAS G12C mutated non-small cell lung cancer (NSCLC). However, patients receiving these agents as monotherapy generally develop drug resistance over time. This necessitates the development of multi-targeted approaches that can potentially sensitize tumors to KRAS inhibitors. We generated KRAS G12C inhibitor-resistant cell lines and observed that they exhibit sensitivity toward selinexor, a selective inhibitor of nuclear export protein exportin1 (XPO1), as a single agent. KRAS G12C inhibitors in combination with selinexor suppressed the proliferation of KRAS G12C mutant cancer cell lines in a synergistic manner. Moreover, combined treatment of selinexor with KRAS G12C inhibitors resulted in enhanced spheroid disintegration, reduction in the number and size of colonies formed by G12C mutant cancer cells. Mechanistically, the combination of selinexor with KRAS G12C inhibitors suppressed cell growth signaling and downregulated the expression of cell cycle markers, KRAS and NF-kB as well as increased nuclear accumulation of tumor suppressor protein Rb. In an in vivo KRAS G12C cell-derived xenograft model, oral administration of a combination of selinexor and sotorasib was demonstrated to reduce tumor burden and enhance survival. In conclusion, we have shown that the nuclear transport protein XPO1 inhibitor can enhance the anticancer activity of KRAS G12C inhibitors in preclinical cancer models. SIGNIFICANCE: In this study, combining nuclear transport inhibitor selinexor with KRAS G12C inhibitors has resulted in potent antitumor effects in preclinical cancer models. This can be an effective combination therapy for cancer patients that do not respond or develop resistance to KRAS G12C inhibitor treatment.

This research explores the relationship between the school principal's leadership style and teachers' work discipline in State Senior High Schools Pekanbaru, Riau. The study adopts a quantitative approach with a survey method and correlation technique. Through random sampling, the research involves 40 teachers from eleven State Senior High Schools in Pekanbaru. Data collection is conducted using a questionnaire, which has been calibrated with validity testing using Pearson Product Moment and reliability coefficient with Cronbach's Alpha formula. The research results indicate a relationship between the leadership style of school principals and the discipline of teachers in State Senior High Schools in Pekanbaru. The significance testing of a correlation coefficient of 0.51 supports this relationship. It suggests a moderate connection between the principal's leadership style and teacher discipline. This study implies that enhancing teacher discipline can be achieved through the role of the school principal's leadership style. In other words, a correlation of 0.51 indicates that the principal's role in leading and guiding teachers can have a positive impact on their work discipline, and these efforts may be crucial in achieving a higher quality of education.

Abstract Background Out-of-hospital cardiac arrest (OHCA) is a heterogeneous entity with multiple origins and prognoses. An early, reliable assessment of the prognosis is useful to adapt therapeutic strategy, tailor intensity of care, and inform relatives. We aimed primarily to undertake a prospective multicentric study to evaluate predictive performance of the Cardiac Arrest Prognosis (CAHP) Score as compare to historical dataset systematically collected after OHCA (Utstein style criteria). Our secondary aim was to evaluate other dedicated scores for predicting outcome after OHCA and to compare them to Utstein style criteria. Methods We prospectively collected data from 24 French and Belgium Intensive Care Units (ICUs) between August 2020 and June 2022. All cases of non-traumatic OHCA (cardiac and non-cardiac causes) patients with stable return of spontaneous circulation (ROSC) and comatose at ICU admission (defined by Glasgow coma score ≤ 8) on ICU admission were included. The primary outcome was the modified Rankin scale (mRS) at day 90 after cardiac arrest, assessed by phone interviews. A wide range of developed scores (CAHP, OHCA, CREST, C-Graph, TTM, CAST, NULL-PLEASE, and MIRACLE2) were included, and their accuracies in predicting poor outcome at 90 days after OHCA (defined as mRS ≥ 4) were determined using the area under the receiving operating characteristic curve (AUROC) and the calibration belt. Results During the study period, 907 patients were screened, and 658 were included in the study. Patients were predominantly male (72%), with a mean age of 61 ± 15, most having collapsed from a supposed cardiac cause (64%). The mortality rate at day 90 was 63% and unfavorable neurological outcomes were observed in 66%. The performance (AUROC) of Utstein criteria for poor outcome prediction was moderate at 0.79 [0.76–0.83], whereas AUROCs from other scores varied from 0.79 [0.75–0.83] to 0.88 [0.86–0.91]. For each score, the proportion of patients for whom individual values could not be calculated varied from 1.4% to 17.4%. Conclusions In patients admitted to ICUs after a successfully resuscitated OHCA, most of the scores available for the evaluation of the subsequent prognosis are more efficient than the usual Utstein criteria but calibration is unacceptable for some of them. Our results show that some scores (CAHP, sCAHP, mCAHP, OHCA, rCAST) have superior performance, and that their ease and speed of determination should encourage their use. Trial registration https://clinicaltrials.gov/ct2/show/NCT04167891

Background: Waterpipe (WP) smoking has become a global public health problem in recent decades and growing evidence indicates that it can cause nicotine dependence. Most evidence on WP dependence to date has been derived from survey- or laboratory based studies. This study employed qualitative methods to explore WP users’ perceptions of dependence in Aleppo, Syria.Methods: A total of 15 focus groups were conducted with 64 adult WP smokers (51 males and 13 females) using a semi-structured interview. All focus group discussions were audiotaped, transcribed, and coded using directed content analysis. Findings: Several WP dependence features were consistent with those commonly reported by cigarette smokers. These included positively reinforced features, such as smoking’s association with social gatherings and cultural connectedness, and negatively reinforced features including relief of withdrawal symptoms, stress, and boredom. Although interest in quitting was low, many users perceived quitting WP to be difficult and an indicator of loss of control over smoking, a common marker of dependence. Several observed dependence features were specific to WP, including transitioning from social smoking to smoking alone, and adapting one’s behavior to the considerable effort normally required to engage in WP smoking despite inconvenience or cost, and often atthe expense of other reinforcers such as social interaction.Conclusion: The general and specific features of WP dependence need to be considered in developing instruments to measure WP dependence, in clinical assessment of WP dependence, and in developing cessation programs.

Tujuan kegiatan pengabdian kepada masyarakat ini adalah pendampingan kepada Kader Kesehatan Posyandu sebagai upaya peningkatan pengetahuan dan keterampilan pelaksanaan program kegiatan pelayanan kesehatan balita di Posyandu Maroanging Dusun Pakatto Caddi Desa Pakatto Kabupaten Gowa. Kader kesehatan merupakan ujung tombak pelaksanaan Posyandu untuk meningkatkan derajat kesehatan balita dan seluruh masyarakat di Desa Pakatto Kabupaten Gowa. Metode yang dilakukan adalah pendampingan kader kesehatan Posyandu dalam pelayanan kesehatan balita. Kegiatan pendampingan diantaranya 1) pengaturan sistem pendaftaran dan formulir pendaftaran serta dokumentasi dan pencatatan yang baik pada bayi dan balita yang berkunjung; 2) cara penimbangan berat badan, pengukuran tinggi badan, lingkar lengan atas dan lingkar kepala untuk mendeteksi antropometri bayi dan balita; 3) cara pengisian Kartu Menuju Sehat; 4) penyuluhan kesehatan sesuai kebutuhan balita; dan 5) jenis-jenis pelayanan kesehatan pada kegiatan Posyandu Balita. Hasil kegiatan ini telah terlaksana dengan baik dimana 5 kader kesehatan Posyandu Maroanging Dusun Pakatto Caddi Desa Pakatto Kecamatan Bontomarannu Kabupaten Gowa telah meningkat pengetahuan dan kemampuannya dalam memberikan pelayanan kesehatan balita di Posyandu. This community service aims to assist Posyandu Cadres in increasing their knowledge and skills in carrying out toddler health service activities at Posyandu Maroanging, Pakatto Caddi Hamlet, Pakatto Village, Gowa Regency. Posyandu cadres are the spearhead of implementing Posyandu activities to improve the health status of toddlers and the entire community in Pakatto Village, Gowa Regency. Method: Assistance of Posyandu health cadres in toddler health services include 1) preparation of registration systems and registration forms as well as proper documentation and recording of visits by infants and toddlers; 2) methods of weighing and measuring height, upper arm circumference, and head circumference to detect infant and toddler anthropometry; 3) how to fill out the health card (KMS); 4) health counseling according to the needs of toddlers; and 5) types of health services at Toddler Posyandu activities. Results: this activity has been implemented where 5 health cadres for Posyandu Maroanging Dusun Pakatto Caddi Pakatto Village, Bontomarannu District, Gowa Regency experienced increased knowledge and skills in providing toddler health services at Posyandu.

Abstract Background Response to prophylactic platelet transfusion is suspected to be inconsistent in critically ill patients questioning how to optimize transfusion practices. This study aimed to describe prophylactic platelet transfusion response, to identify factors associated with a suboptimal response, to analyse the correlation between corrected count increment and platelet count increment and to determine the association between poor platelet transfusion response and clinical outcomes. Methods This prospective multicentre observational study recruited patients who received at least one prophylactic platelet transfusion in one of the nine participating intensive care units for a period up to 16 months. Poor platelet transfusion response was defined as a corrected count increment (CCI) that adjusts for platelet dose and body surface area, less than 7 at 18–24 h after platelet transfusion. Factors associated with poor platelet transfusion response were assessed in a mixed-effect model. Sensitivity analyses were conducted in patients with and without haematology malignancy and chemotherapy. Results Poor platelet transfusion response occurred in 349 of the 472 (73.9%) prophylactic platelet transfusions and in 141/181 (77.9%) patients. The mixed-effect model identified haemoglobin at ICU admission (odds ratio (OR): 0.79 [95% confidence interval (CI) 0.7–0.89]) and body mass index (BMI) (OR: 0.93 [0.89–0.98]) being positively and independently associated with platelet transfusion response, while a haematological malignancy (OR 1.93 [1.09–3.43]), sepsis as primary ICU admission diagnosis (OR: 2.81 [1.57–5.03]), SOFA score (OR 1.10 [1.03; 1.17]) and maximum storage duration of platelet (OR: 1.24 [1.02–1.52]) were independently associated with a suboptimal platelet increment. Clinical outcomes did not differ between groups, nor the requirement for red blood cells. Poor platelet transfusion response was found in 93.5% of patients with haematology malignancy and chemotherapy. Conclusions In this study of critically ill patients, of whom more than half had bone marrow failure, almost three quarters of prophylactic platelet transfusions led to suboptimal platelet increment measured 18 to 24 h following platelet transfusion. Platelet storage duration was the only factor associated with poor platelet response that may be accessible to intervention. Trial registration in October 2017: ClinicalTrials.gov: NCT03325140.

Abstract Background Except in a few retrospective studies mainly including patients under chemotherapy, information regarding the impact of immunosuppressive therapy on the prognosis of patients admitted to the intensive care unit (ICU) for septic shock is scarce. Accordingly, the PACIFIC study aimed to asses if immunosuppressive therapy is associated with an increased mortality in patients admitted to the ICU for septic shock. Methods This was a retrospective epidemiological multicentre study. Eight high enroller centres in septic shock randomised controlled trials (RCTs) participated in the study. Patients in the “exposed” group were selected from the screen failure logs of seven recent RCTs and excluded because of immunosuppressive treatment. The “non-exposed” patients were those included in the placebo arm of the same RCTs. A multivariate logistic regression model was used to estimate the risk of death. Results Among the 433 patients enrolled, 103 were included in the “exposed” group and 330 in the “non-exposed” group. Reason for immunosuppressive therapy included organ transplantation (n = 45 [44%]) or systemic disease (n = 58 [56%]). ICU mortality rate was 24% in the “exposed” group and 25% in the “non-exposed” group (p = 0.9). Neither in univariate nor in multivariate analysis immunosuppressive therapy was associated with a higher ICU mortality (OR: 0.95; [95% CI 0.56–1.58]: p = 0.86 and 1.13 [95% CI 0.61–2.05]: p = 0.69, respectively) or 3-month mortality (OR: 1.13; [95% CI 0.69–1.82]: p = 0.62 and OR: 1.36 [95% CI 0.78–2.37]: p = 0.28, respectively). Conclusions In this study, long-term immunosuppressive therapy excluding chemotherapy was not associated with significantly higher or lower ICU and 3-month mortality in patients admitted to the ICU for septic shock.

Chronic obstructive pulmonary disease (COPD) and lung cancer represent formidable challenges in global health, characterized by intricate pathophysiological mechanisms and multifaceted disease progression. This comprehensive review integrates insights from diverse perspectives to elucidate the intricate roles of long non-coding RNAs (lncRNAs) in the pathogenesis of COPD and lung cancer, focusing on their diagnostic, prognostic, and therapeutic implications. In the context of COPD, dysregulated lncRNAs, such as NEAT1, TUG1, MALAT1, HOTAIR, and GAS5, emerge as pivotal regulators of genes involved in the disease pathogenesis and progression. Their identification, profiling, and correlation with the disease severity present promising avenues for prognostic and diagnostic applications, thereby shaping personalized disease interventions. These lncRNAs are also implicated in lung cancer, underscoring their multifaceted roles and therapeutic potential across both diseases. In the domain of lung cancer, lncRNAs play intricate modulatory roles in disease progression, offering avenues for innovative therapeutic approaches and prognostic indicators. LncRNA-mediated immune responses have been shown to drive lung cancer progression by modulating the tumor microenvironment, influencing immune cell infiltration, and altering cytokine production. Their dysregulation significantly contributes to tumor growth, metastasis, and chemo-resistance, thereby emphasizing their significance as therapeutic targets and prognostic markers. This review summarizes the transformative potential of lncRNA-based diagnostics and therapeutics for COPD and lung cancer, offering valuable insights into future research directions for clinical translation and therapeutic development.

5/6G is anticipated to address challenges such as low data speed and high latency in current cellular networks, particularly as the number of users overwhelms 4G and LTE capabilities. This paper proposes a microstrip patch antenna array comprising six radiating patches and utilizing a microstrip line feeding technique to facilitate the compact design crucial for 5G implementation. ROGER 3003, chosen for its advanced and environmentally friendly features, serves as the dielectric material, ensuring suitability for 5G and B5G applications. The designed antenna, evaluated at a resonating frequency of 28.8 GHz with a −10 dB impedance bandwidth of 1 GHz, offers a high gain of 9.19 dBi. Its compact array, cost-effectiveness, and broad impedance and radiation coverage position it as a viable candidate for 5G and future communication applications.

Epidemiological data suggest that moderate hyperoxemia may be associated with an improved outcome after traumatic brain injury. In a prospective, randomized investigation of long-term, resuscitated acute subdural hematoma plus hemorrhagic shock (ASDH + HS) in 14 adult, human-sized pigs, targeted hyperoxemia (200 < PaO2 < 250 mmHg vs. normoxemia 80 < PaO2 < 120 mmHg) coincided with improved neurological function. Since brain perfusion, oxygenation and metabolism did not differ, this post hoc study analyzed the available material for the effects of targeted hyperoxemia on cerebral tissue markers of oxidative/nitrosative stress (nitrotyrosine expression), blood–brain barrier integrity (extravascular albumin accumulation) and fluid homeostasis (oxytocin, its receptor and the H2S-producing enzymes cystathionine-β-synthase and cystathionine-γ-lyase). After 2 h of ASDH + HS (0.1 mL/kgBW autologous blood injected into the subdural space and passive removal of 30% of the blood volume), animals were resuscitated for up to 53 h by re-transfusion of shed blood, noradrenaline infusion to maintain cerebral perfusion pressure at baseline levels and hyper-/normoxemia during the first 24 h. Immediate postmortem, bi-hemispheric (i.e., blood-injected and contra-lateral) prefrontal cortex specimens from the base of the sulci underwent immunohistochemistry (% positive tissue staining) analysis of oxidative/nitrosative stress, blood–brain barrier integrity and fluid homeostasis. None of these tissue markers explained any differences in hyperoxemia-related neurological function. Likewise, hyperoxemia exerted no deleterious effects.

BACKGROUND: Nuclear protein transport is essential in guiding the traffic of important proteins and RNAs between the nucleus and cytoplasm. Export of proteins from the nucleus is mostly regulated by Exportin 1 (XPO1). In cancer, XPO1 is almost universally hyperactive and can promote the export of important tumor suppressors to the cytoplasm. Currently, there are no studies evaluating XPO1 amplifications and mutations in NSCLC and the impact on outcomes. METHODS: Tumor samples were analyzed using next-generation sequencing (NGS) (NextSeq, 592 Genes), immunohistochemistry (IHC), and whole transcriptome sequencing (WTS, NovaSeq) (Caris Life Sciences, Phoenix, AZ). Survival was extracted from insurance claims data and calculated from time of tissue collection to last contact using Kaplan-Meier estimate. RESULTS: Among 18,218 NSCLC tumors sequenced, 26 harbored XPO1 mutations and 24 had amplifications. XPO1 mutant tumors were more likely to have high TMB (79% vs. 52%, p = 0.007) and less likely to have high PD-L1 (32% vs. 68%, p = 0.03). KRAS co-mutations were seen in 19% (n = 5) and EGFR co-mutations were rare (n = 2). Among the 17,449 NSCLC tumors with clinical data, there were 24 XPO1 mutant. Comparison of survival between XPO1 mutant and WT showed a negative association with a hazard ratio (HR) of 1.932 (95% CI: 1.144-3.264 p = 0.012). XPO1 amplification was not associated with survival. CONCLUSIONS: XPO1 pathogenic mutations were associated with a poor survival in NSCLC. Although XPO1 mutations are rare in NSCLC, further studies to assess its associations with treatment responses are warranted.

Community Service: Training for Student Affairs Vice Principals' Work Program Development in Pekanbaru. This outreach activity was conducted by the faculty members of the Master's Program in Management at the Graduate School of Universitas Lancang Kuning. The participants included 18 vice principals from state high schools (SMAN), 10 from vocational schools (SMKN), and 4 from state Islamic schools (MAN), totaling 32 vice principals. The objective of this initiative was to enhance the competencies of student affairs vice principals in addressing and anticipating various teenage misbehaviors prevalent in today's society. The training aimed to foster the creation of effective work programs that would nurture students' character and creativity while promoting the development of scientific and technological knowledge that benefits the local community, nation, and country. The benefits derived from this program included the formulation of daily, weekly, monthly, and annual work programs for student affairs vice principals in SMAN, SMKN, and MAN throughout Pekanbaru, with a focus on character building, student behavior, and creativity, while also preserving Riau Malay Culture. Furthermore, the training aimed to proactively address the impact of media on adolescent behavior, especially among secondary school students. The anticipated outcomes of this training endeavor aimed to make a positive contribution to the local community, nation, and country at large.

Abstract Background Vascular leakage is a major feature of acute respiratory distress syndrome (ARDS). We aimed to evaluate the efficacy of FX06, a drug under development that stabilizes interendothelial cell junctions, at reducing vascular leakage during SARS-CoV-2-induced ARDS. Methods This multicenter, double-blinded, randomized trial included adults with COVID-19-associated ARDS who had received invasive mechanical ventilation for

With the increase in demand for high data rates and high bandwidth because of multiple users all over the globe, the technology has moved toward the next-generation of wireless communication. This rapid advancement of wireless communication technologies has led to the emergence of 5G networks, which promise significantly higher data rates, lower latency, and enhanced connectivity. Researchers believe that five essential techniques can enable 5G. Beamforming is one of those essentials, as it plays a vital role in achieving reliable and high-capacity communication. This review article portrays a comprehensive analysis of the 5G beamformer Microstrip Patch Antenna array techniques for communication systems. The paper comprises of a deep overview of the fundamental concepts and principles of beamforming, including analog, hybrid, and digital beamforming techniques. It explores the advantages and disadvantages of each approach and discusses their suitability for 5G applications. An in-depth examination of various beamforming techniques employed in 5G, encompassing traditional beamforming, massive Multiple-Input-Multiple-Output beamforming, hybrid beamforming, and adaptive beamforming. The discussion encompasses the strengths, weaknesses, and performance trade-offs of each technique, along with their applicability in diverse deployment scenarios and applications. The review of multiple couplers that are used for the feeding of the antenna is discussed with included hybrid coupler, Wilkinson power divider, branch line coupler, and butler matrix in beamformer smart antenna for 5G/6G communications. Numerous beamforming techniques are compared based on their merits, demerits, and applications. Moreover, the dielectric substrate utilized to design the beamformer was also reviewed. The findings presented in this paper serve as a valuable resource for the researcher, scholars, and engineers working in the field of 5G wireless communications and antenna designing, facilitating the development and deployment of efficient and robust beamforming solutions for future 5G networks.

Thymoquinone TQ, an active ingredient of Nigella Sativa, has been shown to inhibit COVID-19 symptoms in clinical trials. Thymoquinone Formulation (TQF or NP-101) is developed as a novel enteric-coated medication derivative from Nigella Sativa. TQF consists of TQ with a favorable concentration and fatty acids, including palmitic, oleic, and linoleic acids. In this study, we aimed to investigate the roles of individual ingredients of TQF on infection of SARS-CoV-2 variants in-vitro, by utilizing Murine Leukemia Virus (MLV) based pseudovirus particles. We demonstrated that NP-101, TQ, and other individual ingredients, including oleic, linoleic, and palmitic acids inhibited SARS-CoV-2 infection in the MLV-based pseudovirus model. A large, randomized phase 2 study of NP-101 is planned in outpatient COVID-19 patients.

Reprogramming human somatic cells into a pluripotent state, achieved through the activation of well-defined transcriptional factors known as OSKM factors, offers significant potential for regenerative medicine. While OSKM factors are a robust reprogramming method, efficiency remains a challenge, with only a fraction of cells undergoing successful reprogramming. To address this, we explored genes related to genomic integrity and cellular survival, focusing on iPSCs (A53T-PD1) that displayed enhanced colony stability. Our investigation had revealed three candidate genes CCN3, POSTN, and PTHLH that exhibited differential expression levels and potential roles in iPSC stability. Subsequent analyses identified various protein interactions for these candidate genes. POSTN, significantly upregulated in A53T-PD1 iPSC line, showed interactions with extracellular matrix components and potential involvement in Wnt signaling. CCN3, also highly upregulated, demonstrated interactions with TP53, CDKN1A, and factors related to apoptosis and proliferation. PTHLH, while upregulated, exhibited interactions with CDK2 and genes involved in cell cycle regulation. RT-qPCR validation confirmed elevated CCN3 and PTHLH expression in A53T-PD1 iPSCs, aligning with RNA-seq findings. These genes’ roles in preserving pluripotency and cellular stability require further exploration. In conclusion, we identified CCN3, POSTN, and PTHLH as potential contributors to genomic integrity and pluripotency maintenance in iPSCs. Their roles in DNA repair, apoptosis evasion, and signaling pathways could offer valuable insights for enhancing reprogramming efficiency and sustaining pluripotency. Further investigations are essential to unravel the mechanisms underlying their actions.

Railway infrastructure maintenance is critical for ensuring safe and efficient transportation networks. Railway track surface defects such as cracks, flakings, joints, spallings, shellings, squats, grooves pose substantial challenges to the integrity and longevity of the tracks. To address these challenges and facilitate further research, a novel dataset of railway track surface faults has been presented in this paper. It is collected using the EKENH9R cameras mounted on a railway inspection vehicle. This dataset represents a valuable resource for the railway maintenance and computer vision related scientific communities. This dataset includes a diverse range of real-world track surface faults under various environmental conditions and lighting scenarios. This makes it an important asset for the development and evaluation of Machine Learning (ML), Deep Learning (DL), and image processing algorithms. This paper also provides detailed annotations and metadata for each image class, enabling precise fault classification and severity assessment of the defects. Furthermore, this paper discusses the data collection process, highlights the significance of railway track maintenance, emphasizes the potential applications of this dataset in fault identification and predictive maintenance, and development of automated inspection systems. We encourage the research community to utilize this dataset for advancing the state-of-the-art research related to railway track surface condition monitoring.

Introduction Current guidelines on clinical nutrition of ventilated patients in the intensive care unit (ICU) recommend initiating continuous enteral nutrition within 48 hours of ICU admission when feasible. However, discontinuous feeding regimens, alternating feeding and fasting intervals, may have an impact on clinical and patient centred outcomes. The ongoing Impact of daily cyclic enteral nutrition versus standard continuous enteral nutrition in critically ill patients (DC-SCENIC) trial aims to compare standard continuous enteral feeding with daily cyclic enteral feeding over 10 hours to evaluate if implementing a fasting-mimicking diet can decrease organ failure in ventilated patients during the acute phase of ICU management.Methods and analysis DC-SCENIC is a randomised, controlled, multicentre, open-label trial comparing two parallel groups of patients 18 years of age or older receiving invasive mechanical ventilation and having an indication for enteral nutrition through a gastric tube. Enteral feeding is continuous in the control group and administered over 10 hours daily in the intervention group. Both groups receive isocaloric nutrition with 4 g of protein per 100 mL, and have the same 20 kcal/kg/day caloric target. The primary endpoint is the change in the Sequential Organ Failure Assessment score at 7 days compared with the day of inclusion in the study. Secondary outcomes include daily caloric and protein delivery, digestive, respiratory and metabolic tolerance as well as 28-day mortality, duration of mechanical ventilation and ventilator-free days. Outcomes will be analysed on an intention-to-treat basis. Recruitment started in June 2023 in 3 French ICU’s and a sample size of 318 patients is expected by February 2026.Ethics and dissemination This study received approval from the national ethics review board on 8 November 2022 (Comité de Protection des Personnes Sud-Est VI, registration number 2022-A00827-36). Patients are included after informed consent. Results will be submitted for publication in peer-reviewed journals.Trial registration number NCT05627167.

Introduction Fever treatment is commonly applied in patients with sepsis but its impact on survival remains undetermined. Patients with respiratory and haemodynamic failure are at the highest risk for not tolerating the metabolic cost of fever. However, fever can help to control infection. Treating fever with paracetamol has been shown to be less effective than cooling. In the SEPSISCOOL pilot study, active fever control by external cooling improved organ failure recovery and early survival. The main objective of this confirmatory trial is to assess whether fever control at normothermia can improve the evolution of organ failure and mortality at day 60 of febrile patients with septic shock. This study will compare two strategies within the first 48 hours of septic shock: treatment of fever with cooling or no treatment of fever.Methods and analysis SEPSISCOOL II is a pragmatic, investigator-initiated, adaptive, multicentre, open-label, randomised controlled, superiority trial in patients admitted to the intensive care unit with febrile septic shock. After stratification based on the acute respiratory distress syndrome status, patients will be randomised between two arms: (1) cooling and (2) no cooling. The primary endpoint is mortality at day 60 after randomisation. The secondary endpoints include the evolution of organ failure, early mortality and tolerance. The target sample size is 820 patients.Ethics and dissemination The study is funded by the French health ministry and was approved by the ethics committee CPP Nord Ouest II (Amiens, France). The results will be submitted for publication in peer-reviewed journals.Trial registration number NCT04494074.

IntroductionSupplementation with increased inspired oxygen fractions has been suggested to alleviate the harmful effects of tissue hypoxia during hemorrhagic shock (HS) and traumatic brain injury. However, the utility of therapeutic hyperoxia in critical care is disputed to this day as controversial evidence is available regarding its efficacy. Furthermore, in contrast to its hypoxic counterpart, the effect of hyperoxia on the metabolism of circulating immune cells remains ambiguous. Both stimulating and detrimental effects are possible; the former by providing necessary oxygen supply, the latter by generation of excessive amounts of reactive oxygen species (ROS). To uncover the potential impact of increased oxygen fractions on circulating immune cells during intensive care, we have performed a 13C-metabolic flux analysis (MFA) on PBMCs and granulocytes isolated from two long-term, resuscitated models of combined acute subdural hematoma (ASDH) and HS in pigs with and without cardiovascular comorbidity.MethodsSwine underwent resuscitation after 2 h of ASDH and HS up to a maximum of 48 h after HS. Animals received normoxemia (PaO2 = 80 – 120 mmHg) or targeted hyperoxemia (PaO2 = 200 – 250 mmHg for 24 h after treatment initiation, thereafter PaO2 as in the control group). Blood was drawn at time points T1 = after instrumentation, T2 = 24 h post ASDH and HS, and T3 = 48 h post ASDH and HS. PBMCs and granulocytes were isolated from whole blood to perform electron spin resonance spectroscopy, high resolution respirometry and 13C-MFA. For the latter, we utilized a parallel tracer approach with 1,2-13C2 glucose, U-13C glucose, and U-13C glutamine, which covered essential pathways of glucose and glutamine metabolism and supplied redundant data for robust Bayesian estimation. Gas chromatography-mass spectrometry further provided multiple fragments of metabolites which yielded additional labeling information. We obtained precise estimations of the fluxes, their joint credibility intervals, and their relations, and characterized common metabolic patterns with principal component analysis (PCA).Results13C-MFA indicated a hyperoxia-mediated reduction in tricarboxylic acid (TCA) cycle activity in circulating granulocytes which encompassed fluxes of glutamine uptake, TCA cycle, and oxaloacetate/aspartate supply for biosynthetic processes. We further detected elevated superoxide levels in the swine strain characterized by a hypercholesterolemic phenotype. PCA revealed cell type-specific behavioral patterns of metabolic adaptation in response to ASDH and HS that acted irrespective of swine strains or treatment group.ConclusionIn a model of resuscitated porcine ASDH and HS, we saw that ventilation with increased inspiratory O2 concentrations (PaO2 = 200 – 250 mmHg for 24 h after treatment initiation) did not impact mitochondrial respiration of PBMCs or granulocytes. However, Bayesian 13C-MFA results indicated a reduction in TCA cycle activity in granulocytes compared to cells exposed to normoxemia in the same time period. This change in metabolism did not seem to affect granulocytes’ ability to perform phagocytosis or produce superoxide radicals.

Abstract Background The majority of pancreatic ductal adenocarcinoma (PDAC) patients experience disease progression while on treatment with gemcitabine and nanoparticle albumin‐bound (nab)‐paclitaxel (GemPac) necessitating the need for a more effective treatment strategy for this refractory disease. Previously, we have demonstrated that nuclear exporter protein exportin 1 (XPO1) is a valid therapeutic target in PDAC, and the selective inhibitor of nuclear export selinexor (Sel) synergistically enhances the efficacy of GemPac in pancreatic cancer cells, spheroids and patient‐derived tumours, and had promising activity in a phase I study. Methods Here, we investigated the impact of selinexor–gemcitabine–nab‐paclitaxel (Sel‐GemPac) combination on LSL‐KrasG12D/+; LSL‐Trp53R172H/+; Pdx1‐Cre (KPC) mouse model utilising digital spatial profiling (DSP) and single nuclear RNA sequencing (snRNAseq). Results Sel‐GemPac synergistically inhibited the growth of the KPC tumour‐derived cell line. The Sel‐GemPac combination reduced the 2D colony formation and 3D spheroid formation. In the KPC mouse model, at a sub‐maximum tolerated dose (sub‐MTD) , Sel‐GemPac enhanced the survival of treated mice compared to controls (p

Liquid biopsy is now considered a valuable diagnostic tool for advanced metastatic non-small cell lung cancer (NSCLC). In NSCLC, circulating tumor DNA (ctDNA) analysis has been shown to increase the chances of identifying the presence of targetable mutations and has been adopted by many clinicians owing to its low risk. Serial monitoring of ctDNA may also help assess the treatment response or for monitoring relapse. As the presence of detectable plasma ctDNA post-surgery likely indicates residual tumor burden, studies have been performed to quantify plasma ctDNA to assess minimal residual disease (MRD) in early-stage resected NSCLC. Most data on utilizing liquid biopsy for monitoring MRD in early-stage NSCLC are from small-scale studies using ctDNA. Here, we review the recent research on liquid biopsy in NSCLC, not limited to ctDNA, and focus on novel methods such as micro RNAs (miRNA) and long non-coding (lncRNA).