Evidence-based recommendations for gene-specific ACMG/AMP variant classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.

The ENIGMA research consortium develops and applies methods to determine clinical significance of variants in hereditary breast and ovarian cancer genes. An ENIGMA BRCA1/2 classification sub-group, formed in 2015 as a ClinGen external expert panel, evolved into a ClinGen internal Variant Curation Expert Panel (VCEP) to align with Food and Drug Administration recognized processes for ClinVar contributions. The VCEP reviewed American College of Medical Genetics and Genomics/Association of Molecular Pathology (ACMG/AMP) classification criteria for relevance to interpreting BRCA1 and BRCA2 variants. Statistical methods were used to calibrate evidence strength for different data types. Pilot specifications were tested on 40 variants and documentation revised for clarity and ease of use. The original criterion descriptions for 13 evidence codes were considered non-applicable or overlapping with other criteria. Scenario of use was extended or re-purposed for eight codes. Extensive analysis and/or data review informed specification descriptions and weights for all codes. Specifications were applied to pilot variants with pre-existing ClinVar classification as follows: 13 uncertain significance or conflicting, 14 pathogenic and/or likely pathogenic, and 13 benign and/or likely benign. Review resolved classification for 11/13 uncertain significance or conflicting variants and retained or improved confidence in classification for the remaining variants. Alignment of pre-existing ENIGMA research classification processes with ACMG/AMP classification guidelines highlighted several gaps in the research processes and the baseline ACMG/AMP criteria. Calibration of evidence strength was key to justify utility and strength of different data types for gene-specific application. The gene-specific criteria demonstrated value for improving ACMG/AMP-aligned classification of BRCA1 and BRCA2 variants.

How difficult is titanium plate and screw implant removal? A retrospective case series.

INTRODUCTION: Titanium implants are commonly used for surgical fixation in orthopedic trauma, and have many benefits compared to stainless steel implants. Despite these benefits, some orthopedic surgeons remain hesitant to use titanium implants due to concerns of difficulty with future implant removal, given concerns with cold-welding and screw strippage. The objective of this study was to assess difficulties associated with titanium plate and screw implant removal. METHODS: This is a retrospective case series from a large hospital system. Patients were identified using Current Procedural Terminology (CPT) code 20,680 from 2017 to 2020. Patients were included if they had removal of titanium plate and screws from the upper or lower extremity, were at least18 years of age, and considered skeletally mature. The ease of titanium plate/screw removal was determined by assessing for implant cold-welding, broken screws, stripped screws, and the need for advanced tools (screw removal set, trephine, burr). RESULTS: 157 patients were identified, with a mean age of 54 years and 59 % female. In total 1274 screws were removed: 14 (1.1 %) were stripped, 8 (0.6 %) were cold-welded, 42 (3.3 %) were loose, and 13 (1.0 %) were broken. 183 plates were removed in total, and 15 (8.2 %) had bone overgrowth that required removal. 12 (7.6 %) procedures were complicated and required the use of advanced tools. Complicated implant removal operations occurred after significantly longer in vivo implant time (mean of 3.7 vs. 1.1 years, p = 0.036), were associated with a younger age, were more likely to occur in lower extremity procedures (p = 0.034), and took significantly longer time for removal (95 vs. 42 min, p < 0.001). CONCLUSIONS: Despite concerns with titanium implants, we found a low rate of screw strippage, breakage, and cold welding during the removal process. However, 7.6 % of the 157 surgeries required additional tools other than just a screwdriver, and needed additional operative time. This information allows treating surgeons to plan for implant removal when titanium implants have been used for fixation. LEVEL OF EVIDENCE: IV.

Urinary Incontinence Medications: Patient-Initiated Concerns in Primary Care.

IMPORTANCE: Guideline-recommended medications for overactive bladder and urge urinary incontinence (OAB/UUI) are effective but have high costs and side effects. Little is known about patient concerns regarding these medications when prescribed by their primary care providers (PCPs). OBJECTIVE: The aim of the study was to describe PCP-patient interactions when prescribing medications for OAB/UUI, specifically clinical concerns, cost and authorization issues, and mode of communication for these interactions. STUDY DESIGN: Using electronic health records, we identified a retrospective cohort of women aged 18-89 years who were prescribed a medication for OAB/UUI during a primary care office visit from 2017 to 2018. We examined the electronic health record from initial prescription through 15 subsequent months for documentation of prior authorization requests and patient concerns about cost, side effects, or ineffectiveness. The association of patient demographics, comorbidity, and medication class with these concerns was examined with logistic regression models. RESULTS: Overall, 46.2% of patients (n = 123) had 1 or more OAB/UUI medication concerns, and 52 reported outside an office visit. Only higher comorbidity was associated with reduced concern of any type. Although the overall percent age of patients reporting concerns was similar by medication type, the patterns of concern type varied. Compared with those taking short-acting antimuscarinics, patients taking long-acting antimuscarinics other than oxybutynin were less likely to have side effect concerns (adjusted odds ratio 0.35, 95% CI 0.16-0.78) and more likely to have cost concerns (adjusted odds ratio 5.10, 95% CI 1.53-17.03). CONCLUSIONS: Patient concerns regarding OAB/UUI medications were common in primary care practices and frequently reported outside of office visits. However, the patterns of concerns (cost vs side effects) varied between medication classes.

Developing a urinary incontinence primary care pathway: a mixed methods study.

BACKGROUND: While nearly 50% of adult women report at least one episode of urinary incontinence (UI), most never receive treatment. OBJECTIVE: To better integrate primary and specialty UI care, we conducted (i) an environmental scan to assess the availability of key pathway resources in primary care, (ii) interviews with primary care providers to understand barriers to care, and (iii) a pilot UI care pathway intervention. METHODS: Environmental scan: Clinic managers from all primary care clinics within a Midwestern healthcare system were invited to participate in an interview covering the availability of clinic resources. Provider interviews: Primary care providers were invited to participate in an interview covering current practices and perceived barriers to UI care. Pilot UI care pathway: Patients who screened positive for UI were provided resources for first-line behavioral management. Pilot patients completed questionnaires at baseline, 8 weeks, and 6 months. RESULTS: While many clinics had point-of-care urinalysis (17/21, 81%), most did not have a working bladder ultrasound (14/21, 67%) or on-site pelvic floor physical therapy (18/21, 86%). Providers (n = 5) described barriers to completing almost every step of diagnosis and treatment for UI. The most persistent barrier was lack of time. Patients (n = 15) reported several self-treatment strategies including avoiding bladder irritants (7/15, 47%) and performing Kegel exercises (4/15, 27%). Five patients (33%) requested follow-up care. At 6 months, patients reported small improvements in UI symptoms. CONCLUSION: Promising results from a novel UI care pathway pilot indicate that streamlining UI care may assist primary care providers in the first-line treatment of UI.

Although the majority of women will experience urine leakage at some point during their lives, most will never receive treatment. To better understand this discrepancy, we embarked on a multimodal investigation into the barriers to care and trialed a new treatment pathway in the primary care setting within a large academic medical system in the Midwest. Speaking with the clinic managers from 21 primary care clinics, we determined that many clinics lacked the tools to perform the steps outlined in the professional society guidelines for urinary incontinence diagnosis. Additionally, there was limited access to pelvic floor physical therapy, a proven treatment strategy. Interviews with five primary care providers revealed barriers, most notably lack of time during clinic visits, to almost every step of diagnosis and treatment. Finally, we trialed a care pathway for primary care providers to make it easier to provide patients with self-management education or to refer them to specialist care. Fifteen patients participated in a pilot study, about half reported trying self-management, and about 1/3 requested follow-up care. Streamlining urinary incontinence care at the primary care level may alleviate some of the barriers to patients receiving care.

Pain and Post-traumatic Stress Disorder Symptoms: Dyadic Relationships Between Canadian Armed Forces Members/Veterans With Chronic Pain and Their Offspring.

Chronic pain and mental health issues occur at higher rates in Veterans than the general population. One widely recognized mental health issue faced by Veterans is post-traumatic stress disorder (PTSD). Trauma symptoms and pain frequently co-occur and are mutually maintained due to shared mechanisms. Many Veterans are also parents. Parental physical and mental health issues significantly predict children's chronic pain and related functioning, which can continue into adulthood. Only 1 U.S.-based study has examined pain in the offspring of Veterans, suggesting a heightened risk for pain. Research to date has not examined the associations between trauma and pain and the dyadic influences of these symptoms, among Veterans, and their children. The current study aimed to describe pain characteristics in Canadian Armed Forces Members/Veterans with chronic pain and their offspring (youth and adult children aged 9-38). Cross-lagged panel models were conducted to examine dyadic relationships between pain interference and trauma symptoms of Canadian Armed Forces Members/Veterans and their offspring. Over half of adult offspring and over one-quarter of youth offspring reported chronic pain. Results revealed effects between one's own symptoms of PTSD and pain interference. No significant effects of parents on offspring or offspring on parents were found. The findings highlight the interconnection between pain and PTSD consistent with mutual maintenance models and a lack of significant interpersonal findings suggestive of resiliency in this unique population. PERSPECTIVE: We characterized chronic pain in the offspring of Canadian Armed Forces Members/Veterans with chronic pain and examined dyadic relationships between PTSD symptoms and chronic pain interference. Findings revealed that PTSD symptoms and pain interference were related within Veterans and offspring, but no dyadic relationships were found, which could reflect resiliency.

IMPROVER (Involving Men with Prostate Cancer in Engaged Research): Assessing Patient Experience With Testing, Diagnosis, And Surveillance.

BACKGROUND: Our understanding of patient experiences with prostate cancer testing for diagnosis and surveillance is limited. The aim of this study was to collaborate with patients and clinicians to understand their lived experience and unmet needs around the early detection, diagnosis and monitoring (active surveillance) of prostate cancer. METHODS: Two focus groups were held with patients (n = 20) and healthcare professionals (n = 16), to identify the main challenges in prostate cancer detection, diagnosis, and monitoring. This information formed the basis of an online questionnaire for broader dissemination. RESULTS: A total of 1138 analyzable responses were obtained from people tested for prostate cancer (69% tested positive) in Europe and the US. Only 29 healthcare professionals completed the survey. Almost one-third of people reported knowing very little/nothing about prostate cancer prior to testing. Prior disease awareness was significantly higher in those who tested negative (P < .0001). Most respondents (n = 857; 75%) felt informed about the steps involved in testing. Receiving written information was a key factor; 91% of those who felt uninformed were not given any written information. Overall, most people felt "satisfied" with the typical prostate cancer tests: PSA, DRE, mpMRI, and biopsy. However, dissatisfaction for prostate biopsy (12%) was almost double that of other tests (P < .0001). Most patients understood why each test was done, and felt that their results and next steps were clearly explained to them; though PSA scored lowest in all of these fields. Apart from PSA, test satisfaction was lower when used repeatedly for surveillance, compared to once-off detection/diagnosis. CONCLUSIONS: Greater public awareness and education around prostate cancer, as well as clear and accessible written information for patients at the beginning of their cancer journey is needed. Further research is needed into alternative, less invasive tests, particularly when used repeatedly in the surveillance population.

Parametric investigation of ultrashort pulsed laser surface texturing on aluminium alloy 7075 for hydrophobicity enhancement.

Hydrophobicity plays a pivotal role in mitigating surface fouling, corrosion, and icing in critical marine and aerospace environments. By employing ultrafast laser texturing, the characteristic properties of a material's surface can be modified. This work investigates the potential of an advanced ultrafast laser texturing manufacturing process to enhance the hydrophobicity of aluminium alloy 7075. The surface properties were characterized using goniometry, 3D profilometry, SEM, and XPS analysis. The findings from this study show that the laser process parameters play a crucial role in the manufacturing of the required surface structures. Numerical optimization with response surface optimization was conducted to maximize the contact angle on these surfaces. The maximum water contact angle achieved was 142º, with an average height roughness (Sa) of 0.87 ± 0.075 µm, maximum height roughness (Sz) of 19.4 ± 2.12 µm, and texture aspect ratio of 0.042. This sample was manufactured with the process parameters of 3W laser power, 0.08 mm hatch distance, and a 3 mm/s scan speed. This study highlights the importance of laser process parameters in the manufacturing of the required surface structures and presents a parametric modeling approach that can be used to optimize the laser process parameters to obtain a specific surface morphology and hydrophobicity. Supplementary Information: The online version contains supplementary material available at 10.1007/s00170-024-12971-8.

Challenges and approaches to calibrating patient phenotype as evidence for cancer gene variant classification under ACMG/AMP guidelines.

Since first publication of the American College of Medical Genetics and Genomics/Association for Medical Pathology (ACMG/AMP) variant classification guidelines, additional recommendations for application of certain criteria have been released (https://clinicalgenome.org/docs/), to improve their application in the diagnostic setting. However, none have addressed use of the PS4 and PP4 criteria, capturing patient presentation as evidence towards pathogenicity. Application of PS4 can be done through traditional case-control studies, or "proband counting" within or across clinical testing cohorts. Review of the existing PS4 and PP4 specifications for Hereditary Cancer Gene Variant Curation Expert Panels revealed substantial differences in the approach to defining specifications. Using BRCA1, BRCA2 and TP53 as exemplar genes, we calibrated different methods proposed for applying the "PS4 proband counting" criterion. For each approach, we considered limitations, non-independence with other ACMG/AMP criteria, broader applicability, and variability in results for different datasets. Our findings highlight inherent overlap of proband-counting methods with ACMG/AMP frequency codes, and the importance of calibration to derive dataset-specific code weights that can account for potential between-dataset differences in ascertainment and other factors. Our work emphasizes the advantages and generalizability of logistic regression analysis over simple proband-counting approaches to empirically determine the relative predictive capacity and weight of various personal clinical features in the context of multigene panel testing, for improved variant interpretation. We also provide a general protocol, including instructions for data formatting and a web-server for analysis of personal history parameters, to facilitate dataset-specific calibration analyses required to use such data for germline variant classification.

Structural Optimization and Anticancer Activity of Polo-like Kinase 1 (Plk1) Polo-Box Domain (PBD) Inhibitors and Their Prodrugs.

Polo-like kinase 1 (Plk1), a mitotic kinase whose activity is widely upregulated in various human cancers, is considered an attractive target for anticancer drug discovery. Aside from the kinase domain, the C-terminal noncatalytic polo-box domain (PBD), which mediates the interaction with the enzyme's binding targets or substrates, has emerged as an alternative target for developing a new class of inhibitors. Various reported small molecule PBD inhibitors exhibit poor cellular efficacy and/or selectivity. Here, we report structure-activity relationship (SAR) studies on triazoloquinazolinone-derived inhibitors, such as 43 (a 1-thioxo-2,4-dihydrothieno[2,3-e][1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-one) that effectively block Plk1, but not Plk2 and Plk3 PBDs, with improved affinity and drug-like properties. The range of prodrug moieties needed for thiol group masking of the active drugs has been expanded to increase cell permeability and mechanism-based cancer cell (L363 and HeLa) death. For example, a 5-thio-1-methyl-4-nitroimidazolyl prodrug 80, derived from 43, showed an improved cellular potency (GI50 4.1 µM). As expected, 80 effectively blocked Plk1 from localizing to centrosomes and kinetochores and consequently induced potent mitotic block and apoptotic cell death. Another prodrug 78 containing 9-fluorophenyl in place of the thiophene-containing heterocycle in 80 also induced a comparable degree of anti-Plk1 PBD effect. However, orally administered 78 was rapidly converted in the bloodstream to parent drug 15, which was shown be relatively stable toward in vivo oxidation due to its 9-fluorophenyl group in comparison to unsubstituted phenyl. Further derivatization of these inhibitors, particularly to improve the systemic prodrug stability, could lead to a new class of therapeutics against Plk1-addicted cancers.

Alteration in Levels of Specific miRNAs and Their Potential Protein Targets between Human Pancreatic Cancer Samples, Adjacent Normal Tissue, and Xenografts Derived from These Tumors.

Herein, we describe the global comparison of miRNAs in human pancreatic cancer tumors, adjacent normal tissue, and matched patient-derived xenograft models using microarray screening. RNA was extracted from seven tumor, five adjacent normal, and eight FI PDX tumor samples and analyzed by Affymetrix GeneChip miRNA 4.0 array. A transcriptome analysis console (TAC) was used to generate comparative lists of up- and downregulated miRNAs for the comparisons, tumor vs. normal and F1 PDX vs. tumor. Particular attention was paid to miRNAs that were changed in the same direction in both comparisons. We identified the involvement in pancreatic tumor tissue of several miRNAs, including miR4534, miR3154, and miR4742, not previously highlighted as being involved in this type of cancer. Investigation in the parallel mRNA and protein lists from the same samples allowed the elimination of proteins where altered expression correlated with corresponding mRNA levels and was thus less likely to be miRNA regulated. Using the remaining differential expression protein lists for proteins predicted to be targeted for differentially expressed miRNA on our list, we were able to tentatively ascribe specific protein changes to individual miRNA. Particularly interesting target proteins for miRs 615-3p, 2467-3p, 4742-5p, 509-5p, and 605-3p were identified. Prominent among the protein targets are enzymes involved in aldehyde metabolism and membrane transport and trafficking. These results may help to uncover vulnerabilities that could enable novel approaches to treating pancreatic cancer.

Impact of the COVID-19 pandemic on cancer care in Ireland - Perspectives from a COVID-19 and Cancer Working Group.

Upon the COVID-19 pandemic onset in Ireland, cancer service disruptions occurred due to prioritisation of COVID-19 related care, redeployment of staff, initial pausing of screening, diagnostic, medical and surgical oncology procedures, staff shortages due to COVID-19 infection and impacts on the physical and mental health of cancer healthcare workers. This was coupled with reluctance among people with symptoms suspicious for cancer to attend for clinical evaluation, due to concerns of contracting the virus. This was further compounded by a cyber-attack on national health service IT systems on May 14th 2021. The Irish Cancer Society, a national cancer charity with a role in advocacy, research and patient supports, convened a multi-disciplinary stakeholder group (COVID-19 and Cancer Working Group) to reflect on and understand the impact of the pandemic on cancer patients and services in Ireland, and discuss potential mitigation strategies. Perspectives on experiences were gathered across domains including timeliness of data acquisition and its conversion into intelligence, and the resourcing of cancer care to address cancer service impacts. The group highlighted aspects for future research to understand the long-term pandemic impact on cancer outcomes, while also highlighting potential strategies to support cancer services, build resilience and address delayed diagnosis. Additional measures include the need for cancer workforce recruitment and retention, increased mental health supports for both patients and oncology professionals, improvements to public health messaging, a near real-time multimodal national cancer database, and robust digital and physical infrastructure to mitigate impacts of the current pandemic and future challenges to cancer care systems.

Area-Selective Deposition of AlOx and Al-Silicate for Fully Self-Aligned Via Integration.

The rush for better-performing electronics, and manufacturing processes that heavily rely on "top-down" patterning techniques, is making the integration of "self-aligned" fabrication methods, such as area-selective deposition (ASD), a critical objective for continued device scaling. The fully self-aligned via (FSAV) scheme is broadly proposed as a "killer application" to determine whether ASD can shift from an R&D process to high-volume manufacturing. Nevertheless, the lack of a suitable low-κ deposition process has prevented the realization of FSAV by dielectric-on-dielectric ASD. This is primarily due to the high temperature and/or strong oxidizers employed during low-κ dielectric deposition and their unsuitability in the presence of organic masks, such as self-assembled monolayers (SAMs), used to prevent material nucleation during ASD. In this work, AlOx and Al-silicate atomic layer deposition (ALD) processes are studied to provide suitable materials for ASD-enabled FSAV. Dimethylaluminum isopropoxide and H2O are utilized to deposit the metal oxide, whereas Al-silicate is grown by adding 2,2-dimethoxy-1,6-diaza-2-silacyclooctane (DMDAcO) pulses to the AlOx ALD cycle. The selectivity of such processes is demonstrated on 50 nm Cu/SiO2 structures, using octadecanethiol-derived SAMs to inhibit material nucleation on the metal lines. Scanning and transmission electron microscopies are employed to assess the quality of the ASD processes and investigate the mechanisms behind defect generation on a nongrowth surface. X-ray photoelectron spectroscopy measurements show the high purity of the AlOx film, whereas DMDAcO-ligand incorporation into the Al-silicate matrix is observed. Planar capacitor structures are used to assess the electrical properties of both ASD films, revealing that the silicate film exhibits a relatively low κ-value (5.3 ± 0.2), with a high acceleration field factor (32.4 ± 1.4) and a dielectric breakdown voltage of 6.0 ± 0.3 V at 100 °C.

Investigation of Two Zr-p-NO2Bn-DOTA Isomers via NMR and Quantum Chemical Studies.

A combination of NMR studies and quantum chemical calculations were employed to investigate the structure and energetics of Zr4+ chelates of pNO2Bn-DOTA. We have demonstrated that two discrete regioisomeric chelates are generated during the complex formation. The nitrobenzyl substituent can adopt either an equatorial corner or side position on the macrocyclic ring. These regioisomers are incapable of interconversion and were isolated by HPLC. The corner isomer is more stable than the side, and the SAP conformer of both regioisomers is energetically more favorable than the corresponding TSAP conformer.

Structure-Activity Studies of 1H-Imidazo[4,5-c]quinolin-4-amine Derivatives as A3 Adenosine Receptor Positive Allosteric Modulators.

We previously reported 1H-imidazo[4,5-c]quinolin-4-amines as A3 adenosine receptor (A3AR) positive allosteric modulators (PAMs). A3AR agonists, but not PAMs, are in clinical trials for inflammatory diseases and liver conditions. We synthesized new analogues to distinguish 2-cyclopropyl antagonist 17 (orthosteric interaction demonstrated by binding and predicted computationally) from PAMs (derivatives with large 2-alkyl/cycloalkyl/bicycloalkyl groups). We predicted PAM binding at a hydrophobic site on the A3AR cytosolic interface. Although having low Caco-2 permeability and high plasma protein binding, hydrophobic 2-cyclohept-4-enyl-N-3,4-dichlorophenyl, MRS7788 18, and 2-heptan-4-yl-N-4-iodophenyl, MRS8054 39, derivatives were orally bioavailable in rat. 2-Heptan-4-yl-N-3,4-dichlorophenyl 14 and 2-cyclononyl-N-3,4-dichlorophenyl 20 derivatives and 39 greatly enhanced Cl-IB-MECA-stimulated [35S]GTPγS binding Emax, with only 12b trending toward decreasing the agonist EC50. A feasible route for radio-iodination at the p-position of a 4-phenylamino substituent suggests a potential radioligand for allosteric site binding. Herein, we advanced an allosteric approach to developing A3AR-activating drugs that are potentially event- and site-specific in action.

Fabrication of High-κ Dielectric Metal Oxide Films on Topographically Patterned Substrates: Polymer Brush-Mediated Depositions.

Fabrication of ultrathin films of dielectric (with particular reference to materials with high dielectric constants) materials has significance in many advanced technological applications including hard protective coatings, sensors, and next-generation logic devices. Current state-of-the-art in microelectronics for fabricating these thin films is a combination of atomic layer deposition and photolithography. As feature size decreases and aspect ratios increase, conformality of the films becomes paramount. Here, we show a polymer brush template-assisted deposition of highly conformal, ultrathin (sub 5 nm) high-κ dielectric metal oxide films (hafnium oxide and zirconium oxide) on topographically patterned silicon nitride substrates. This technique, using hydroxyl terminated poly-4-vinyl pyridine (P4VP-OH) as the polymer brush, allows for conformal deposition with uniform thickness along the trenches and sidewalls of the substrate. Metal salts are infiltrated into the grafted monolayer polymer brush films via solution deposition. Tailoring specific polymer interfacial chemistries for ion infiltration combined with subsequent oxygen plasma treatment enabled the fabrication of high-quality sub 5 nm metal oxide films.

Approaches to Safety Evaluation of Baby Wipes.

Disposable baby wipes manufactured by Procter & Gamble, soft sheets bearing lotion that is balanced to maintain natural skin pH, are convenient for cleaning the diaper area and a quick cleanup on baby's face and hands. Objective: Develop a rigorous safety assessment process to ensure that baby wipes are safe and gentle to skin. This process is built-in from the start of product research and development. Methods: A systematic, iterative approach that includes (1) exposure-based safety assessment of all raw materials for systemic and local effects, which are consistent with established risk assessment paradigms; (2) when needed, testing of finished wipes in in vitro and/or clinical studies for skin and eye irritation, contact sensitization, or mechanical effects on skin in comparison to benchmark products that have a long history of wipe safety in marketplace; (3) prospective and randomized in-use studies in babies; and (4) in-market monitoring that is an integral part of the on-going product safety assessment. Results: Individual approaches and/or their combination show mildness of the test wipes. Further, in-market monitoring is testimony to baby skin compatibility of baby wipes. Conclusion: The approaches that have been developed demonstrate the skin compatibility and/or benefits of baby wipes relative to other modes of cleaning if needed. This article describes our safety assurance program, exposure-based safety assessment, and the range of robust testing strategies and approaches that can be employed to assure the safety of baby wipes.

2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

AIM: This clinical practice guideline for the evaluation and diagnosis of chest pain provides recommendations and algorithms for clinicians to assess and diagnose chest pain in adult patients. METHODS: A comprehensive literature search was conducted from November 11, 2017, to May 1, 2020, encompassing randomized and nonrandomized trials, observational studies, registries, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Collaboration, Agency for Healthcare Research and Quality reports, and other relevant databases. Additional relevant studies, published through April 2021, were also considered. STRUCTURE: Chest pain is a frequent cause for emergency department visits in the United States. The "2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain" provides recommendations based on contemporary evidence on the assessment and evaluation of chest pain. This guideline presents an evidence-based approach to risk stratification and the diagnostic workup for the evaluation of chest pain. Cost-value considerations in diagnostic testing have been incorporated, and shared decision-making with patients is recommended.

Prioritising Informed Health Choices Key Concepts for those impacted by cancer: a protocol.

Background: Few areas of health have been as insidiously influenced by misinformation as cancer. Thus, interventions that can help people impacted by cancer reduce the extent to which they are victims of misinformation are necessary. The Informed Health Choices (IHC) initiative has developed Key Concepts that can be used in the development of interventions for evaluating the trustworthiness of claims about the effects of health treatments. We are developing an online education programme called Informed Health Choices-Cancer (IHC-C) based on the IHC Key Concepts. We will provide those impacted by cancer with the knowledge and skills necessary to think critically about the reliability of health information and claims and make informed choices. Methods: We will establish a steering group (SG) of 12 key stakeholders, including oncology specialists and academics. In addition, we will establish a patient and public involvement (PPI) panel of 20 people impacted by cancer. After training the members on the Key Concepts and the prioritisation process, we will conduct a two-round prioritisation process. In the first round, 12 SG members and four PPI panel members will prioritise Key Concepts for inclusion. In the second round, the remaining 16 PPI members will undertake the prioritisation based on the prioritised Key Concepts from the first round. Participants in both rounds will use a structured judgement form to rate the importance of the Key Concepts for inclusion in the online IHC-C programme. A consensus meeting will be held, where members will reach a consensus on the Key Concepts to be included and rank the order in which the prioritised Key Concepts will be addressed in the IHC-C programme. Conclusions: At the end of this process, we will identify which Key Concepts should be included and the order in which they should be addressed in the IHC-C programme.

Lentzeacins A-E, New Bacterial-Derived 2,5- and 2,6-Disubstituted Pyrazines from a BGC-Rich Soil Bacterium Lentzea sp. GA3-008.

Pyrazines (1,4-diazirines) are an important group of natural products that have tremendous monetary value in the food and fragrance industries and can exhibit a wide range of biological effects including antineoplastic, antidiabetic and antibiotic activities. As part of a project investigating the secondary metabolites present in understudied and chemically rich Actinomycetes, we isolated a series of six pyrazines from a soil-derived Lentzea sp. GA3-008, four of which are new. Here we describe the structures of lentzeacins A-E (1, 3, 5 and 6) along with two known analogues (2 and 4) and the porphyrin zincphyrin. The structures were determined by NMR spectroscopy and HR-ESI-MS. The suite of compounds present in Lentzea sp. includes 2,5-disubstituted pyrazines (compounds 2, 4, and 6) together with the new 2,6-disubstituted isomers (compounds 1, 3 and 5), a chemical class that is uncommon. We used long-read Nanopore sequencing to assemble a draft genome sequence of Lentzea sp. which revealed the presence of 40 biosynthetic gene clusters. Analysis of classical di-modular and single module non-ribosomal peptide synthase genes, and cyclic dipeptide synthases narrows down the possibilities for the biosynthesis of the pyrazines present in this strain.

2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

AIM: This executive summary of the clinical practice guideline for the evaluation and diagnosis of chest pain provides recommendations and algorithms for clinicians to assess and diagnose chest pain in adult patients. METHODS: A comprehensive literature search was conducted from November 11, 2017, to May 1, 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Collaboration, Agency for Healthcare Research and Quality reports, and other relevant databases. Additional relevant studies, published through April 2021, were also considered. STRUCTURE: Chest pain is a frequent cause for emergency department visits in the United States. The "2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain" provides recommendations based on contemporary evidence on the assessment and evaluation of chest pain. These guidelines present an evidence-based approach to risk stratification and the diagnostic workup for the evaluation of chest pain. Cost-value considerations in diagnostic testing have been incorporated and shared decision-making with patients is recommended.