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In this article, the authors evaluate the effects of a behavioral intervention for mothers with problem drinking who were infected with, or at risk for, HIV. They randomly selected 25 mothers from a larger longitudinal randomized controlled intervention trial for a qualitative interview. The authors found that mothers' participation in the program was facilitated by the development of a strong therapeutic alliance with the intervention facilitator and the use of a harm reduction approach toward alcohol and/or drug abuse. Mothers also reported that training in coping skills and the emphasis on parent-adolescent relationships were beneficial for program engagement and behavior change. The authors conclude from these results that treatment approaches that take into account the complexity of urban mothers' lives and substance use patterns can successfully engage and treat these women at high risk for adverse outcomes. [ABSTRACT FROM AUTHOR]

Abstract Background Attention-Deficit/Hyperactivity Disorder (ADHD) is a heterogeneous disorder from both clinical and pathogenic viewpoints. Executive function deficits are considered among the most important pathogenic pathways leading to ADHD and may index part of the heterogeneity in this disorder. Methods To investigate the relationship between the dopamine transporter gene (SLC6A3) 3'-UTR VNTR genotypes and executive function in children with ADHD, 196 children diagnosed with ADHD were sequentially recruited, genotyped, and tested using a battery of three neuropsychological tests aimed at assessing the different aspects of executive functioning. Results Taking into account a correction for multiple comparisons, the main finding of this study is a significant genotype effect on performances on the Tower of London (F = 6.902, p = 0.009) and on the Wechsler Intelligence Scale for Children, Third Edition (WISC-III) Freedom From Distractibility Index (F = 7.125, p = 0.008), as well as strong trends on Self Ordered Pointing Task error scores (F = 4,996 p = 0.026) and WISC-III Digit Span performance (F = 6.28, p = 0.023). Children with the 9/10 genotype exhibited, on average, a poorer performance on all four measures compared to children with the 10/10 genotype. No effect of genotype on Wisconsin Card Sorting Test measures of performance was detected. Conclusion Results are compatible with the view that SLC6A3 genotype may modulate components of executive function performance in children with ADHD.

Background: Acute respiratory distress syndrome (ARDS) is a severe and life-threatening condition that can occur in critically ill patients. Mechanical ventilation is a commonly used intervention with ARDS patients, but weaning patients off the ventilator can be challenging. An ARDSnet-like ventilator weaning protocol was implemented with the goal of reducing triggers for ventilator-associated events (VAEs)., Methods: The implementation of the new protocol was used to complete a retrospective investigation of patient outcomes for 1,233 ventilator periods. Periods were included between April and December 2022 for any ventilated patient lasting at least 4 days. National Health Care Safety Network VAE criteria were used to surveille the patient data. Triggers were based on the positive end-expiratory pressure increases or fraction of inspired oxygen (FiO₂) increases. The preset weaning criteria was a reduction by 2 cmH 2 O per 24 hours., Results: Of the total 1,233 individual ventilator periods, VAE criteria were met in 10%. Of the total 126 periods with VAE, 39.2% met the criteria for appropriate protocol implementation. There was a statistically significant relationship between VAE identification and implementation of the protocol., Conclusions: The implementation of a protocol for ventilator weaning affects the outcome of developing a VAE. The findings emphasize the importance of implementing the ARDS weaning protocol as a template to reduce the triggers for VAEs and improve overall patient outcomes., (Copyright © 2023 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Radical new possibilities of improved treatment of cancer are on offer from an advanced medical technology already demonstrating its significance: next-generation sequencing (NGS). This refined testing provides unprecedentedly precise diagnoses and permits the use of focused and highly personalized treatments. However, across regions globally, many cancer patients will continue to be denied the benefits of NGS as long as some of the yawning gaps in its implementation remain unattended. The challenges at the regional and national levels are linked because putting the solutions into effect is highly dependent on cooperation between regional- and national-level cooperation, which could be hindered by shortfalls in interpretation or understanding. The aim of the paper was to define and explore the necessary conditions for NGS and make recommendations for effective implementation based on extensive exchanges with policy makers and stakeholders. As a result, the European Alliance for Personalised Medicine (EAPM) developed a maturity framework structured around demand-side and supply-side issues to enable interested stakeholders in different countries to self-evaluate according to a common matrix. A questionnaire was designed to identify the current status of NGS implementation, and it was submitted to different experts in different institutions globally. This revealed significant variability in the different aspects of NGS uptake. Within different regions globally, to ensure those conditions are right, this can be improved by linking efforts made at the national level, where patients have needs and where care is delivered, and at the global level, where major policy initiatives in the health field are underway or in preparation, many of which offer direct or indirect pathways for building those conditions. In addition, in a period when consensus is still incomplete and catching up is needed at a political level to ensure rational allocation of resources-even within individual countries-to enable the best ways to make the necessary provisions for NGS, a key recommendation is to examine where closer links between national and regional actions could complement, support, and mutually reinforce efforts to improve the situation for patients.

Objectives: The introduction of Personalised Medicine (PM) into healthcare systems could benefit from a clearer understanding of the distinct national and regional frameworks around the world. Recent engagement by international regulators on maximising the use of real-world evidence (RWE) has highlighted the scope for improving the exploitation of the treasure-trove of health data that is currently largely neglected in many countries. The European Alliance for Personalised Medicine (EAPM) led an international study aimed at identifying the current status of conditions., Methods: A literature review examined how far such frameworks exist, with a view to identifying conducive factors - and crucial gaps. This extensive review of key factors across 22 countries and 5 regions revealed a wide variety of attitudes, approaches, provisions and conditions, and permitted the construction of a comprehensive overview of the current status of PM. Based on seven key pillars identified from the literature review and expert panels, the data was quantified, and on the basis of further analysis, an index was developed to allow comparison country by country and region by region., Results: The results show that United States of America is leading according to overall outcome whereas Kenya scored the least in the overall outcome., Conclusions: Still, common approaches exist that could help accelerate take-up of opportunities even in the less prosperous parts of the world., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Tackling cancer is a major challenge right on the global level. Europe is only the tip of an iceberg of cancer around the world. Prosperous developed countries share the same problems besetting Europe-and the countries and regions with fewer resources and less propitious conditions are in many cases struggling often heroically against a growing tide of disease. This paper offers a view on these geographically wider, but essentially similar, challenges, and on the prospects for and barriers to better results in this ceaseless battle. A series of panels have been organized by the European Alliance for Personalised Medicine (EAPM) to identify different aspects of cancer care around the globe. There is significant diversity in key issues such as NGS, RWE, molecular diagnostics, and reimbursement in different regions. In all, it leads to disparities in access and diagnostics, patients' engagement, and efforts for a better understanding of cancer.

Objective: Currently available treatments for neuropathic pain are only modestly efficacious when assessed in randomized clinical trials and work for only some patients in the clinic. Induced-pain or gain-of-function phenotypes have been shown to predict response to analgesics (vs placebos) in patients with neuropathic pain. However, the predictive value of these phenotypes has never been studied in post-traumatic neuropathic pain., Methods: Mixed-effects models for repeated measures were used to evaluate the efficacy of pregabalin vs placebo in subgroups with induced-pain phenotypes (i.e., hyperalgesia or allodynia) in data from a recent, multinational randomized clinical trial (N = 539) that identified phenotypic subgroups through the use of a structured clinical exam., Results: The difference in mean pain score between the active and placebo groups (i.e., delta) after 15 weeks of treatment for the subgroup with hyperalgesia was -0.76 (P = 0.001), compared with 0.19 (P = 0.47) for the subgroup that did not have hyperalgesia. The treatment-by-phenotype interaction, which tests whether subgroups have statistically different treatment responses, was significant (P = 0.0067). The delta for the subgroup with allodynia was -0.31 (P = 0.22), compared with -0.30 (P = 0.22) for the subgroup that did not have allodynia (treatment-by-phenotype interaction P = 0.98)., Conclusions: These data suggest that hyperalgesia, but not allodynia, predicts response to pregabalin in patients with chronic post-traumatic neuropathic pain. This study extends the growing data supporting the utility of induced-pain phenotypes to predict response to analgesics in post-traumatic neuropathic pain. Sensory phenotyping in large, multisite trials through the use of a structured clinical exam has the potential to accelerate the development of new analgesics and improve the generalizability of clinical trial results., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

During the development of a therapeutic protein, its quality attributes that pertain to the primary structure must be appropriately characterized, commonly by LC-MS/MS peptide mapping experiments. Extracting attribute information from LC-MS/MS data requires knowledge of the attribute of interest. Therefore, it is important to understand all potential modifications on the therapeutic proteins. In this work, we performed UV and visible light irradiation experiments on several therapeutic proteins, with or without the presence of a photosensitizer. Light-induced modifications were detected and characterized by tryptic digestion followed by LC-MS/MS analysis. A list of potential light-induced modifications, with their respective mass changes, was obtained. These modifications are primarily on methionine, tryptophan, histidine, cysteine, tyrosine and phenylalanine residues. Many of these modifications have not been previously reported on therapeutic proteins. Our findings therefore provide a database of potential light-induced modifications that would enable the routine characterization of light-induced modifications on therapeutic proteins., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

This report from ASCO's International Quality Steering Group summarizes early learnings on how the COVID-19 pandemic and its stresses have disproportionately affected cancer care delivery and its delivery systems across the world. This article shares perspectives from eight different countries, including Austria, Brazil, Ghana, Honduras, Ireland, the Philippines, South Africa, and the United Arab Emirates, which provide insight to their unique issues, challenges, and barriers to quality improvement in cancer care during the pandemic. These perspectives shed light on some key recommendations applicable on a global scale and focus on access to care, importance of expanding and developing new treatments for both COVID-19 and cancer, access to telemedicine, collecting and using COVID-19 and cancer registry data, establishing measures and guidelines to further enhance quality of care, and expanding communication among governments, health care systems, and health care providers. The impact of the COVID-19 pandemic on cancer care and quality improvement has been and will continue to be felt across the globe, but this report aims to share these experiences and learnings and to assist ASCO's international members and our global fight against the pandemic and cancer., Competing Interests: Giovanni BarianiConsulting or Advisory Role: LibbsResearch Funding: Mabxience, Merck Sharp & Dohme, Bristol Myers Squibb Shaheenah DawoodHonoraria: Novartis, Roche, Celgene, Janssen-Cilag, biocon, MSD, Pfizer, Bristol Myers Squibb, AbbVie, AstraZeneca, Caris Life SciencesConsulting or Advisory Role: MSD OncologySpeakers' Bureau: Pfizer, Roche/Genentech, AstraZenecaResearch Funding: MSD OncologyTravel, Accommodations, Expenses: Roche, MSD, Amgen, Pfizer, Bristol Myers Squibb Michael GnantEmployment: Sandoz (I)Honoraria: Amgen, Novartis, LillyConsulting or Advisory Role: Daiichi-Sankyo, Tolmar, LifeBrain, Lilly Roselle De GuzmanHonoraria: Novartis, Roche, AstraZeneca, Merck Serono, MSD Oncology, Boehringer IngelheimConsulting or Advisory Role: Roche, Novartis, AstraZeneca, Boehringer Ingelheim, AstraZenecaResearch Funding: Centus BiotherapeuticsTravel, Accommodations, Expenses: Hospira, Roche, Merck Sharp & Dohme, Eisai, Boehringer Ingelheim, AstraZeneca, Lilly¸ Novartis Deirdre O'MahonyConsulting or Advisory Role: Genomic Health/Exact SciencesTravel, Accommodations, Expenses: Roche, Novartis Ireland Ltd, Roche Paul RuffEmployment: TeladocStock and Other Ownership Interests: TeladocSpeakers' Bureau: Amgen, Mylan, MSDResearch Funding: Janssen Oncology, Roche, AstraZeneca, Novartis, PfizerTravel, Accommodations, Expenses: Merck Serono, MSD Oncology, Pfizer, Dr Reddy's Laboratories, AstraZeneca, Roche Arif KamalEmployment: Prepped Health, Acclivity Health, Private Diagnostic ClinicLeadership: Prepped Health, Acclivity HealthStock and Other Ownership Interests: Acclivity HealthConsulting or Advisory Role: Medtronic, Huron Therapeutics, New Century Health, Compassus, AstraZeneca, United Health Group¸ Janssen Oncology, Care4ward, United Health GroupTravel, Accommodations, Expenses: Janssen OncologyNo other potential conflicts of interest were reported.

Background: Pregnant and lactating women were excluded from initial coronavirus disease 2019 vaccine trials; thus, data to guide vaccine decision making are lacking., Objective: This study aimed to evaluate the immunogenicity and reactogenicity of coronavirus disease 2019 messenger RNA vaccination in pregnant and lactating women compared with: (1) nonpregnant controls and (2) natural coronavirus disease 2019 infection in pregnancy., Study Design: A total of 131 reproductive-age vaccine recipients (84 pregnant, 31 lactating, and 16 nonpregnant women) were enrolled in a prospective cohort study at 2 academic medical centers. Titers of severe acute respiratory syndrome coronavirus 2 spike and receptor-binding domain immunoglobulin G, immunoglobulin A, and immunoglobulin M were quantified in participant sera (n=131) and breastmilk (n=31) at baseline, at the second vaccine dose, at 2 to 6 weeks after the second vaccine, and at delivery by Luminex. Umbilical cord sera (n=10) titers were assessed at delivery. Titers were compared with those of pregnant women 4 to 12 weeks from the natural infection (n=37) by enzyme-linked immunosorbent assay. A pseudovirus neutralization assay was used to quantify neutralizing antibody titers for the subset of women who delivered during the study period. Postvaccination symptoms were assessed via questionnaire. Kruskal-Wallis tests and a mixed-effects model, with correction for multiple comparisons, were used to assess differences among groups., Results: Vaccine-induced antibody titers were equivalent in pregnant and lactating compared with nonpregnant women (pregnant, median, 5.59; interquartile range, 4.68-5.89; lactating, median, 5.74; interquartile range, 5.06-6.22; nonpregnant, median, 5.62; interquartile range, 4.77-5.98, P=.24). All titers were significantly higher than those induced by severe acute respiratory syndrome coronavirus 2 infection during pregnancy (P<.0001). Vaccine-generated antibodies were present in all umbilical cord blood and breastmilk samples. Neutralizing antibody titers were lower in umbilical cord than maternal sera, although this finding did not achieve statistical significance (maternal sera, median, 104.7; interquartile range, 61.2-188.2; cord sera, median, 52.3; interquartile range, 11.7-69.6; P=.05). The second vaccine dose (boost dose) increased severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G, but not immunoglobulin A, in maternal blood and breastmilk. No differences were noted in reactogenicity across the groups., Conclusion: Coronavirus disease 2019 messenger RNA vaccines generated robust humoral immunity in pregnant and lactating women, with immunogenicity and reactogenicity similar to that observed in nonpregnant women. Vaccine-induced immune responses were statistically significantly greater than the response to natural infection. Immune transfer to neonates occurred via placenta and breastmilk., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Current agents for the intravascular embolization of traumatic hemorrhage are used off-label and have been minimally studied with respect to their performance under differing coagulation conditions. We studied the hemorrhage control efficacy of a novel, liquid, polyethylene glycol-based hydrogel delivered as two liquid precursors that polymerize within the target vessel in a unique animal model of severe solid organ injury with and without dilutional coagulopathy., Methods: Anesthetized swine (n = 36, 45 ± 3 kg) had laparotomy and splenic externalization. Half underwent 50% isovolemic hemodilution with 6% hetastarch and cooling to 33°C-35°C (coagulopathic group). All animals had controlled 20 mL/kg hemorrhage and endovascular proximal splenic artery access with a 4F catheter via a right femoral sheath. Splenic transection and 5-minute free bleeding were followed by treatment (n = 5/group) with 5 mL of gelfoam slurry, three 6-mm coils, up to 6 mL of hydrogel, or no treatment (n = 3, control). Animals received 15 mL/kg plasma and were monitored for 6 hours with continuous blood loss measurement., Results: Coagulopathy was successfully established, with coagulopathic animals having greater pretreatment blood loss and earlier mean time to death regardless of the treatment group. All control animals died within 100 minutes. Overall survival without coagulopathy was 5/5 for hydrogel, 4/5 for coil, and 3/5 for gelfoam. With coagulopathy, one hydrogel animal survived to the end of the experiment, with 2/4 hydrogel deaths occurring in the final hour of observation. In noncoagulopathic animals, hydrogel demonstrated improved survival time ( P  < .01) and post-treatment blood loss (1.46 ± 0.8 mL/kg) over controls (18.8 ± 0.7, P  = .001), gelfoam (4.7 ± 1.3, P > .05), and coils (4.6 ± 1.5, P > .05). In coagulopathic animals, hydrogel had improved survival time ( P  = .003) and decreased blood loss (4.2 ± 0.8 mL/kg) compared with control (20.4 ± 4.2, P  = .003)., Conclusions: The hydrogel demonstrated equivalent hemorrhage control performance to standard treatments under noncoagulopathic conditions and improved performance in the face of dilutional coagulopathy. This agent should be explored as a potential preferable treatment for the embolization of traumatic solid organ and other injuries. (JVS-Vascular Science 2021;2:43-51.)., Clinical Relevance: In a translational model of severe solid organ injury hemorrhage with and without coagulopathy, a novel hydrogel transarterial embolization agent demonstrated equivalent hemorrhage control performance to standard agents under noncoagulopathic conditions and improved performance in the face of dilutional coagulopathy. This agent represents a promising future treatment for the embolization of traumatic solid organ and other injuries.

Background: Endovascular embolization is increasingly used in treating traumatic hemorrhage and other applications. No endovascular-capable translational large animal models exist and coagulopathy's effect on embolization techniques is unknown. We developed a coagulation-adaptable solid organ hemorrhage model in swine for investigation of embolization techniques., Methods: Anesthetized swine (n = 26, 45 ± 3 kg) had laparotomy and splenic externalization. Half underwent 50% isovolemic hemodilution with 6% hetastarch and cooling to 33-35°C (COAG group). All had controlled 20 mL/kg hemorrhage and endovascular access to the proximal splenic artery with a 4F catheter via a right femoral sheath. Splenic transection and 5 min free bleeding were followed by treatment (n = 5/group) with 5 mL gelfoam slurry, three 6-mm coils, or no treatment (n = 3, control). Animals received 15 mL/kg plasma resuscitation and were monitored for 6 hr. Splenic blood loss was continuously measured and angiograms were performed at specified times., Results: Coagulopathy was successfully established in COAG animals. Pre-treatment blood loss was greater in COAG (11 ± 6 mL/kg) than non-COAG (7 ± 3 mL/kg, P = 0.04) animals. Splenic hemorrhage was universally fatal without treatment. Non-COAG coil survival was 4/5 (326 ± 75 min) and non-COAG Gelfoam 3/5 (311 ± 67 min) versus non-COAG Control 0/3 (82 ± 18 min, P < 0.05 for both). Neither COAG Coil (0/5, 195 ± 117 min) nor COAG Gelfoam (0/5, 125 ± 32 min) treatment improved survival over COAG Control (0/3, 56 ± 19 min). Post-treatment blood loss was 4.6 ± 3.4 mL/kg in non-COAG Coil and 4.6 ± 2.9 mL/kg in non-COAG Gelfoam, both lower than non-COAG Control (18 ± 1.3 mL/kg, P = 0.05). Neither COAG Coil (8.4 ± 5.4 mL/kg) nor COAG Gelfoam (15 ± 11 ml/kg) had significantly less blood loss than COAG Control (20 ± 1.2 mL/kg). Both non-COAG treatment groups had minimal blood loss during observation, while COAG groups had ongoing slow blood loss. In the COAG Gelfoam group, there was an increase in hemorrhage between 30 and 60 min following treatment., Conclusions: A swine model of coagulation-adaptable fatal splenic hemorrhage suitable for endovascular treatment was developed. Coagulopathy had profound negative effects on coil and gelfoam efficacy in controlling bleeding, with implications for trauma and elective embolization procedures., (Published by Elsevier Inc.)

Antibody-dependent cell-mediated cytotoxicity (ADCC) has been identified as one of the potentially critical effector functions underlying the clinical efficacy of some therapeutic immunoglobin G1 (IgG1) antibodies. It has been well established that higher levels of afucosylated N-linked glycan structures on the Fc region enhance the IgG binding affinity to the FcγIIIa receptor and lead to increased ADCC activity. However, whether terminal galactosylation of an IgG1 impacts its ADCC activity is less understood. Here, we used a new strategy for glycan enrichment and remodeling to study the impact of terminal galactose on ADCC activity for therapeutic IgG1s. Our results indicate that the degree of influence of terminal galactose on in vitro ADCC activity depends on the presence or absence of the core fucose, which is typically linked to the first N-acetyl glucosamine residue of an N-linked glycosylation core structure. Specifically, terminal galactose on afucosylated IgG1 mAbs enhanced ADCC activity with impact coefficients (ADCC%/Gal%) more than 20, but had minimal influence on ADCC activity on fucosylated structures with impact coefficient in the range of 0.1-0.2. Knowledge gained here can be used to guide product and process development activities for biotherapeutic antibodies that require effector function for efficacy, and also highlight the complexity in modulating the immune response through N-linked glycosylation of antibodies., (© 2020 American Institute of Chemical Engineers.)

Background: The new guidelines for prehospital care of combat casualties in shock recommend administration of whole blood or blood components to increase blood pressure to a permissible hypotensive level (i.e., hypotensive resuscitation [HR]). We investigated if 2 h of HR using limited volumes of whole blood, plasma, or albumin would lead to full recovery and long-term survival of rabbits subjected to severe hemorrhagic shock (HS)., Methods: Following instrumentation, laparotomy was performed on IV-anesthetized spontaneously breathing New Zealand white rabbits (3.0 kg -3.5 kg). Next, ∼40% of rabbits' blood volume was removed producing HS (mean arterial pressure [MAP]∼20 mm Hg). Fifteen minutes later, rabbits were resuscitated with a limited volume (12.5 mL/kg) of rabbit whole blood (fresh whole blood [FWB]), rabbit fresh frozen plasma (FFP), or 5% human albumin (ALB) to a target pressure (MAP) of 60 mm Hg (n=8/grp) and monitored for 2 h. Liver bleeding time was measured at baseline and 10 min after HR. Subsequently, animals were fully resuscitated (blood + lactated Ringer [LR]), surgically repaired, and recovered for 8 days. An untreated group (n = 6) was also included., Results: Following HS, lactate and base deficit levels were increased to 8.2 ± 1.6 and 12.9 ± 3.1 mM respectively with no difference among groups. A lower volume of FWB volume was required to reach the target MAP (P < 0.05 vs. ALB) but MAP declined during the HR period (P < 0.01 vs. ALB). FWB provided higher hematocrit and platelets but it did not reduce lactate level faster than other fluids. Beside higher fibrinogen, no differences were found in hemostatic or resuscitative effects of FFP versus ALB. Bleeding time was prolonged with ALB and FFP fluids but unchanged with FWB. Untreated rabbits died during shock or shortly after. All treated rabbits except one recovered and lived for 8 days with normal blood tests and similar tissue histology., Conclusions: Two hours of HR using a limited volume of FWB, FFP, or ALB led to full recovery and long-term survival of rabbits subjected to HS. Apart from bleeding time, no clinically significant differences were found among the three fluids. Five percent human albumin solutions are isotonic, iso-oncotic, ready-to-use, stable, and compatible with all blood types and should be considered for prehospital resuscitation where blood products are not available or not accepted.

RNA-binding protein Musashi-1 (MSI1) is a key regulator of several stem cell populations. MSI1 is involved in tumor proliferation and maintenance, and it regulates target mRNAs at the translational level. The known mRNA targets of MSI1 include Numb , APC , and P21 WAF-1 , key regulators of Notch/Wnt signaling and cell cycle progression, respectively. In this study, we aim to identify small molecule inhibitors of MSI1-mRNA interactions, which could block the growth of cancer cells with high levels of MSI1. Using a fluorescence polarization (FP) assay, we screened small molecules from several chemical libraries for those that disrupt the binding of MSI1 to its consensus RNA. One cluster of hit compounds is the derivatives of secondary metabolites from Aspergillus nidulans . One of the top hits, Aza-9, from this cluster was further validated by surface plasmon resonance and nuclear magnetic resonance spectroscopy, which demonstrated that Aza-9 binds directly to MSI1, and the binding is at the RNA binding pocket. We also show that Aza-9 binds to Musashi-2 (MSI2) as well. To test whether Aza-9 has anti-cancer potential, we used liposomes to facilitate Aza-9 cellular uptake. Aza-9-liposome inhibits proliferation, induces apoptosis and autophagy, and down-regulates Notch and Wnt signaling in colon cancer cell lines. In conclusion, we identified a series of potential lead compounds for inhibiting MSI1/2 function, while establishing a framework for identifying small molecule inhibitors of RNA binding proteins using FP-based screening methodology.

Tobacco use has detrimental effects in the Western Pacific Region. The World Health Organization (WHO) Framework Convention on Tobacco Control (FCTC) came into effect in 2005 to address the global tobacco epidemic, and WHO introduced the MPOWER measures to facilitate implementation of key demand-reduction measures of the WHO FCTC at the country level. This paper provides an overview of progress made by countries within the Region since the introduction of the MPOWER measures 12 years ago, and examines challenges and threats hindering their further implementation.

Coronavirus or COVID-19 is caused by severe acute respiratory syndrome coronavirus 2. The COVID-19 pandemic has resulted in social and economic disruption throughout the entire world. Each country is being challenged. Although much of the world's focus has been on the rapid spread in Italy, Spain, and the United States, the potential impact on the world's poor, a majority of whom are living in Asia, could be devastating. Asia has the world's most densely populated cities, and its developing countries are facing challenges in their socioeconomic and health care systems. COVID-19 is quickly overwhelming the fragile and overstretched health systems of low- and low- to middle-income countries. With its aging population having chronic diseases and the growing burden of cancer, Asia is facing the dual challenge of controlling the spread of COVID-19 and at the same time providing and maintaining cancer care.

Recovery housing is a promising way to augment the substance use continuum of care, but we know little about the experiences of members of the lesbian, gay, bisexual, transgender, and queer (LGBTQ) community who live in them or about residences specifically for them. Within the LGBTQ community, gay, bisexual, and other men who have sex with men (MSM) often experience co-occurring syndemic conditions (e.g., trauma, depression, HIV) that present unique recovery challenges. Using qualitative data gathered from residents living in a recovery residence specifically for gay and bisexual men and from community key informants, we examine the experiences of men living in the home and factors that facilitate operating it. Findings highlight the need for residences that can address syndemic burden among gay and bisexual men in recovery and identify programmatic and community-level factors critical to operating residences for this population.

Background: Prognostic modeling in health care has been predominantly statistical, despite a rapid growth of literature on machine-learning approaches in biological data analysis. We aim to assess the relative importance of variables in predicting overall survival among patients with non-small cell lung cancer using a Variable Importance (VIMP) approach in a machine-learning Random Survival Forest (RSF) model for posttreatment planning and follow-up., Methods: A total of 935 non-small cell lung cancer patients were randomly and equally divided into 2 training and testing cohorts in an RFS model. The prognostic variables included age, sex, race, the TNM Classification of Malignant Tumors (TNM) stage, smoking history, Eastern Cooperative Oncology Group performance status, histologic type, treatment category, maximum standard uptake value of whole-body tumor (SUVmaxWB), whole-body metabolic tumor volume (MTVwb), and Charlson Comorbidity Index. The VIMP was calculated using a permutation method in the RSF model. We further compared the VIMP of the RSF model to that of the standard Cox survival model. We examined the order of VIMP with the differential functional forms of the variables., Results: In both the RSF and the standard Cox models, the most important variables are treatment category, TNM stage, and MTVwb. The order of VIMP is more robust in RSF model than in Cox model regarding the differential functional forms of the variables., Conclusions: The RSF VIMP approach can be applied alongside with the Cox model to further advance the understanding of the roles of prognostic factors, and improve prognostic precision and care efficiency.

Background: Resuscitative endovascular balloon occlusion of the aorta (REBOA) and Abdominal Aortic and Junctional Tourniquet (AAJT) have received much attention in recent as methods for temporary control of junctional hemorrhage. Previous studies typically used the animal's shed blood for resuscitation. With current interest in moving REBOA to prehospital environment, this study aimed to evaluate the hemodynamic and metabolic responses to different resuscitation fluids used with these devices., Methods: In swine (Sus scrofa), shock was induced using a controlled hemorrhage, femur fracture, and uncontrolled hemorrhage from the femoral artery. Infrarenal REBOA or AAJT was deployed for 60 min during which the arterial injury was repaired. Animals were resuscitated with 15 mL/kg of shed whole blood (SWB) or fresh frozen plasma (FFP) or 30 mL/kg of a balanced crystalloid (PlasmaLyte)., Results: Animals in the AAJT and REBOA groups did not show any measurable differences in hemodynamics, metabolic responses, or survival with AAJT or REBOA treatment; hence, the data are pooled and analyzed among the three resuscitative fluids. SWB, FFP, and PlasmaLyte groups did not have a difference in survival time or overall survival. The animals in the SWB and FFP groups maintained higher blood pressure after resuscitation, (P < 0.001) and required significantly less norepinephrine to maintain blood pressure than those in the PlasmaLyte group (P < 0.001). The PlasmaLyte resuscitation prolonged prothrombin time and decreased thromboelastography maximum amplitude., Conclusions: After 60 min, infrarenal REBOA or AAJT aortic occlusion SWB and FFP resuscitation provided better blood pressure support with half of the resuscitative volume of PlasmaLyte. Swine resuscitated with SWB and FFP also had a more favorable coagulation profile. These data suggest that whole blood or component therapy should be used for resuscitation in conjunction with REBOA or AAJT, and administration of these fluids should be considered if prehospital device use is pursued., (Published by Elsevier Inc.)

Background: Junctional hemorrhage is a leading contributor to battlefield mortality. The Abdominal Aortic and Junctional Tourniquet (AAJT) and infrarenal (zone III) resuscitative endovascular balloon occlusion of the aorta (REBOA) are emerging strategies for controlling junctional hemorrhage, with AAJT currently available in select forward deployed settings and increasing interest in applying REBOA in the military prehospital environment. This study compared the hemostatic, hemodynamic, and metabolic effects of these devices used for junctional hemorrhage control., Methods: Shock was induced in anesthetized, mechanically ventilated swine with a controlled hemorrhage (20 mL/kg) and closed femur fracture followed by uncontrolled hemorrhage from a partial femoral artery transection (40% total hemorrhage volume). Residual femoral hemorrhage was recorded during 60-minute AAJT (n = 10) or zone III REBOA (n = 10) deployment, and the arterial injury was repaired subsequently. Animals were resuscitated with 15 mL/kg autologous whole blood and observed for 6 hours., Results: One animal in each group died during observation. Both devices achieved hemostasis with mean residual femoral blood loss in the AAJT and REBOA groups of 0.38 ± 0.59 mL/kg and 0.10 ± 0.07 mL/kg (p = 0.16), respectively, during the 60-minute intervention. The AAJT and REBOA augmented proximal blood pressure equally with AAJT allowing higher distal pressure than REBOA during intervention (p < 0.01). Following device deflation, AAJT animals had transiently lower mean arterial blood pressure than REBOA pigs (39 ± 6 vs. 54 ± 11 mm Hg p = 0.01). Both interventions resulted in similar degrees of lactic acidemia which resolved during observation. Similar cardiac and renal effects were observed between AAJT and REBOA., Conclusion: The AAJT and REBOA produced similar hemostatic, resuscitative, and metabolic effects in this model of severe shock with junctional hemorrhage. Both interventions may have utility in future military medical operations.

Objective: Laryngopharyngeal Reflux (LPR) is a disease characterized by the presence of symptoms, signs and tissue alterations in the aero-digestive upper tract as a consequence of the gastric contents retrograde movement. In most cases diagnosis is clinical and it is established by the presence of symptoms and endoscopic laryngeal signs. The aim of the study was to determine the sensitivity, specificity, positive and negative Likelihood Ratio (LR) of the salivary pepsin assay (PEP-test, RD Biomed, Hull, UK) as diagnostic tool of LPR., Study Design: Diagnostic Accuracy Study., Method: 221 subjects aged between 26 and 68 years were recruited. All subjects completed the Reflux Symptom Index scale. PEP-test was carried out on fasting subjects, and a second test was performed one hour after the main meal, only on those subjects with a fasting negative result., Results: Fasting PEP-test showed a 98% specificity, 40% sensitivity, positive LR of 16.4 and negative LR of 0.61. The use of both PEP-test showed a 95% specificity, 48% sensitivity, positive LR of 9.61 and negative LR of 0.55., Conclusions: The PEP-test is a simple, inexpensive, non-invasive and easily reproducible test that should be considered as an alternative diagnosis tool for LPR diagnosis. When there is a clinical suspicion of LPR disease, a positive result on the test could be considered diagnostic, but on subjects with negative results it should be complemented with more complex tests such as the 24-hour dual-channel pH-metry., (Copyright © 2018 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is accepted as a resuscitation adjunct and bridge to definitive hemostasis. The ischemic burden of REBOA may be mitigated by a partial REBOA (P-REBOA) strategy permitting longer occlusion times and military use for combat trauma. We evaluated REBOA and P-REBOA in a swine multiple trauma model with uncontrolled solid organ hemorrhage and delayed resuscitation and surgical hemostasis., Methods: Anesthetized swine (51.9 ± 2.2 kg) had 20 mL/kg hemorrhage and closed femur fracture. Splenic transection was performed and free bleeding permitted for 10 minutes. Controls (n = 5) were hemorrhaged but had no REBOA, REBOA (n = 8) had 60 minutes complete zone 1 occlusion, P-REBOA (n = 8) had 15 minutes complete occlusion and 45 minutes 50% occlusion. Splenectomy was performed and plasma (15 mL/kg) resuscitation initiated 5 minutes prior to deflation. Resuscitation goal was 80 mm Hg systolic with epinephrine as needed. Animals were monitored for 6 hours., Results: An initial study with 120-minute occlusion had universal fatality in three REBOA (upon deflation) and three P-REBOA animals (after 60 minutes inflation). With 60-minute occlusion, mortality was 100%, 62.5%, and 12.5% in the control, REBOA, and P-REBOA groups, respectively (p < 0.05). Survival time was shorter in controls (120 ± 89 minutes) than REBOA and P-REBOA groups (241 ± 139, 336 ± 69 minutes). Complete REBOA hemorrhaged less during inflation (1.1 ± 0.5 mL/kg) than Control (5.6 ± 1.5) and P-REBOA (4.3 ± 1.4), which were similar. Lactate was higher in the REBOA group compared with the P-REBOA group after balloon deflation, remaining elevated. Potassium increased in REBOA after deflation but returned to similar levels as P-REBOA by 120 minutes., Conclusion: In a military relevant model of severe uncontrolled solid organ hemorrhage 1-hour P-REBOA improved survival and mitigated hemodynamic and metabolic shock. Two hours of partial aortic occlusion was not survivable using this protocol due to ongoing hemorrhage during inflation. There is potential role for P-REBOA as part of an integrated minimally invasive field-expedient hemorrhage control and resuscitation strategy.

The world has been witnessing more frequent and greater intensity weather-related disasters. Natural disasters hit every continent in the world. Asia has borne the brunt in terms of frequency and the total numbers of people affected. This is mainly because of Asia's increasing population and its large and varied landmass, with multiple river basins, mountains, flood plains, and active seismic and volcanic zones. The Union for International Cancer Control New Global Cancer Date: GLOBOCAN 2018 has estimated the global cancer burden to have risen to 18.1 million new cases and 9.6 million deaths. Asia constitutes roughly 60% of the world's population. The region contributes nearly one half of new cancer cases and more than one half of cancer deaths worldwide. This increase in the regional burden of cancer is largely a result of socioeconomic growth and the increasing size and aging of the population. In addition to the increasing cancer cases, the string of natural disasters will cause heavy damage and a great human toll in Asia. Medical care for disaster-affected populations is focused traditionally on the management of immediate trauma and acute infections. For people with noncommunicable diseases, this presents a significant risk. Patients with cancer are especially susceptible to the disruptions that natural disasters can cause. Their special needs are largely neglected. There is a need to refocus and expand disaster risk reduction strategies and resources to include patients with noncommunicable diseases such as cancer, because these conditions are generating the bulk of disability, ill health, and premature death around the globe. Having the world's biggest burden of cancer, Asia will definitely be facing these challenges.

Persons in the U.S. who are incarcerated for drug offenses are increasingly being released into the community as a way to decrease prison and jail overcrowding. One challenge is finding housing that supports compliance with probation and parole requirements, which often includes abstinence from drugs and alcohol. Sober living houses (SLHs) are alcohol- and drug-free living environments that are increasingly being used as housing options for probationers and parolees. Although a few studies have reported favorable outcomes for residents of SLHs, little is known about resident experiences or the factors that are experienced as helpful or counterproductive. This study conducted qualitative interviews with 28 SLH residents on probation or parole to understand their experiences living in the houses, aspects of the houses that facilitated recovery, ways residence in a SLH affected compliance with probation and parole, and ways the houses addressed HIV risk, a widespread problem among this population. Interviews were audiotaped and coded for dominant themes. Study participants identified housing as a critically important need after incarceration. For residents nearing the end of their stay in the SLHs, there was significant concern about where they might live after they left. Residents emphasized that shared experiences and goals, consistent enforcement of rules (especially the requirement of abstinence), and encouragement from probation and parole officers as particularly helpful. There was very little focus in HIV issues, even though risk behaviors were common. For some residents, inconsistent enforcement of house rules was experienced as highly problematic. Research is needed to identify the organizational and operational procedures that enhance factors experienced as helpful. This paper is the first to document the views and experiences of persons on probation or parole who reside in sober living recovery houses. These data can be used by SLH operators to develop houses that are responsive to factors experienced as helpful and counterproductive. The significance of this paper is evident in the trend toward decreasing incarceration in the U.S. of persons convicted of drug offenses and the need for alcohol- and drug-free alternative living environments., Competing Interests: Declarations: No Conflict of Interest to Report.

Epidemiologic studies have consistently found elevated rates of alcohol and other substance use among sexual minority women (SMW), and despite calls for "LGBT-specific" services and culturally-tailored interventions, few such services exist. This study involved qualitative interviews with directors from substance use treatment programs (N=10) about how they addressed the needs of SMW. Strategies implemented primarily focused on creating a safe and welcoming environment for sexual minority clients. Findings highlight challenges involved in meeting the treatment needs of SMW and provide guidance to researchers and service providers on how to improve the quality of care for them.