1,1'-Diarylethylene as a Key Additive for the Visible Light Synthesis of Bioactive Dihydrobenzo[a]phenanthridine Compounds.

This study introduces a straightforward synthetic approach for generating 7,8-dihydrobenzo[a]phenanthridine analogs through visible-light-induced cyclization, showing promise as antitumor agents. Unexpectedly, the incorporation of 1,1'-diarylethylene as an additive significantly boosts yield. Through mechanistic investigations, we uncover its crucial role as a trap for the methyl radical formed after the N-O bond cleavage of O-acetyl oxime, promoting intramolecular cyclization of a nitrogen-centered imine radical. These insights into the mechanism pave the way for transformative advancements in this synthesis strategy.

Oral care interventions for autistic individuals: A systematic review.

LAY ABSTRACT: Oral care-related challenges are well documented in the autistic community; dental care remains one of the most prevalent unmet health needs among autistic individuals. This review examined interventions designed to improve oral health in autistic individuals from children and adult populations. Through a systematic process, 36 studies were identified. These studies focused on improving home-based oral care skills and routines and reducing fear, anxiety, and/or negative behaviors in the dental clinic. Studies incorporated different types of techniques for facilitating oral care practice, including preparatory interventions to support home-based hygiene activities or improve an approaching dental encounter (n = 29), most often using visual aids, and/or strategies to manage behavioral difficulties exhibited in the dental office (n = 17). Some studies used both approaches (n = 10), combining visual aids prior to a visit with behavior management. Using an evidence-based rubric, we reviewed the methodological quality of the studies and found that most were only "adequate" (n = 8) or "weak" (n = 23) in reporting their evidence. This review has two key findings: (1) there is support for preparatory home-based visual interventions to improve toothbrushing and/or ready patients for dental visits; and (2) distraction or sensory-reducing interventions may also improve experiences in the dental clinic. Only one study purposefully recruited autistic adults, and no studies included intervention elements tailored to race/ethnicity, culture, and/or socioeconomic status. This review highlights the need for more studies investigating the impact of oral care-related interventions for autistic individuals of all ages and identifies a gap in interventions for autistic adults and those from minoritized populations.

Leveraging in situ N-tosylhydrazones as diazo surrogates for efficient access to pyrazolo-[1,5-c]quinazolinone derivatives.

We developed a transition metal-free methodology for the construction of pyrazoloquinazolinone derivatives. The strategy involves a one-pot reaction wherein the N-tosylhydrazone and its corresponding diazo derivative are generated in situ, followed by an intramolecular 1,3-dipolar cycloaddition-ring expansion to provide the pyrazolo-[1,5-c]quinazolinone motif. This approach enables straightforward access to a diverse range of highly functionalized N-heterocyclic compounds in good yields (up to 92%).

MSA: scalable DNA methylation screening BeadChip for high-throughput trait association studies.

The Infinium DNA Methylation BeadChips have significantly contributed to population-scale epigenetics research by enabling epigenome-wide trait association discoveries. Here, we design, describe, and experimentally verify a new iteration of this technology, the Methylation Screening Array (MSA), to focus on human trait screening and discovery. This array utilizes extensive data from previous Infinium platform-based epigenome-wide association studies (EWAS). It incorporates knowledge from the latest single-cell and cell type-resolution whole genome methylome profiles. The MSA is engineered to achieve scalable screening of epigenetics-trait association in an ultra-high sample throughput. Our design encompassed diverse human trait associations, including those with genetic, cellular, environmental, and demographical variables and human diseases such as genetic, neurodegenerative, cardiovascular, infectious, and immune diseases. We comprehensively evaluated this array's reproducibility, accuracy, and capacity for cell-type deconvolution and supporting 5-hydroxymethylation profiling in diverse human tissues. Our first atlas data using this platform uncovered the complex chromatin and tissue contexts of DNA modification variations and genetic variants linked to human phenotypes.

Association of risk analysis index with 90-day failure to rescue following major abdominal surgery in geriatric patients.

BACKGROUND: Failure to rescue (FTR) is a quality metric defined as mortality after potentially preventable complications after surgery. Predicting patients who are at the highest risk of mortality after a complication may aid in preventing deaths. Thirty-day follow-up period inadequately captures postoperative deaths; alternatively, a 90-day follow-up period has been advocated. This study aimed to examine the association of a validated frailty metric, the risk analysis index (RAI), with 90-day FTR (FTR-90). METHODS: Patients aged ≥65 years who underwent a major abdominal operation between 2014 and 2020 at a quaternary care center were abstracted. Institutional data were merged with the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) and Geriatric Surgery Research File variables. The association between RAI and FTR-90 was evaluated using multivariable logistic regression. RESULTS: A total of 398 patients with postoperative complications were included. Fifty-two patients (13.1%) died during the 90-day follow-up. The FTR-90 group was older (median age: 76 vs 73 years, respectively; P = .002), had a greater preoperative American Society of Anesthesiologists classification score (P < .001), and had a higher ACS NSQIP estimated risk of morbidity (0.33% vs 0.20%, P < .001) and mortality (0.067% vs 0.012%, P < .001). The FTR-90 group had a greater median RAI score (23 vs 19; P = .002). The RAI score was independently associated with FTR-90 (odds ratio, 1.04; 95% CI, 1.0042-1.0770; P = .028) but not with FTR-30 (P = .13). CONCLUSION: Preoperative frailty, as defined by RAI, is independently associated with FTR at 90-day follow-up. FTR-90 captured nearly 60% more deaths than did FTR-30. Frailty has major implications beyond the typical 30-day follow-up period, and a longer follow-up period must be considered.

Cancer-oocyte SAS1B protein is expressed at the cell surface of multiple solid tumors and targeted with antibody-drug conjugates.

BACKGROUND: Sperm acrosomal SLLP1 binding (SAS1B) protein is found in oocytes, which is necessary for sperm-oocyte interaction, and also in uterine and pancreatic cancers. Anti-SAS1B antibody-drug conjugates (ADCs) arrested growth in these cancers. However, SAS1B expression in cancers and normal tissues has not been characterized. We hypothesized that SAS1B is expressed on the surface of other common solid cancer cells, but not on normal tissue cells, and might be selectively targeted therapeutically. METHODS: SAS1B expression in human normal and cancer tissues was determined by immunohistochemistry, and complementary DNA (cDNA) libraries were employed to PCR amplify human SAS1B and its transcripts. Monoclonal antibodies (mAbs) to human SAS1B were generated using mouse hybridomas. SAS1B deletion constructs were developed to map SAS1B's epitope, enabling the creation of a blocking peptide. Indirect immunofluorescence (IIF) of human transfected normal and cancer cells was performed to assess SAS1B expression. SAS1B intracellular versus surface expression in normal and tumor tissues was evaluated by flow cytometry after staining with anti-SAS1B mAb, with specificity confirmed with the blocking peptide. Human cancer lines were treated with increasing mAb and ADC concentrations. ATP was quantitated as a measure of cell viability. RESULTS: SAS1B expression was identified in a subset of human cancers and the cytoplasm of pancreatic islet cells. Two new SAS1B splice variants were deduced. Monoclonal antibodies were generated to SAS1B splice variant A. The epitope for mAbs SB2 and SB5 is between SAS1B amino acids 32-39. IIF demonstrated intracellular SAS1B expression in transfected kidney cells and on the cell surface of squamous cell lung carcinoma. Flow cytometry demonstrated intracellular SAS1B expression in all tumors and some normal cells. However, surface expression of SAS1B was identified only on cancer cells. SB2 ADC mediated dose-dependent cytotoxic killing of multiple human cancer lines. CONCLUSION: SAS1B is a novel cancer-oocyte antigen with cell surface expression restricted to cancer cells. In vitro, it is an effective target for antibody-mediated cancer cell lysis. These findings support further exploration of SAS1B as a potential therapeutic cancer target in multiple human cancers, either with ADC or as a chimeric antigen receptor-T (CAR-T) cell target.

US South Asian Youths' Perspectives on the Use of Complementary and Alternative Medicine (CAM).

Complementary and alternative medicine (CAM) includes varied medical and healthcare systems, healing practices, and products that are outside of allopathy/biomedicine. The aim of this study was to examine US South Asian youths' beliefs, practices, decision-making, and experiences of using CAM. Ten focus group discussions with 36 participants were conducted. Data were coded deductively and inductively by four coders, working in pairs. Thematic analysis was performed. Disagreements were resolved through consensus. The results showed that CAM was appealing because of its often low cost, ease of access, family traditions to use CAM, and the perception that it was safe to use. Participants exercised pluralistic health choices. Some responses suggested a hierarchy wherein allopathy was used for serious, acute issues, and CAM for much of the remaining issues. The high use of and trust in CAM among young US South Asians raises important issues (e.g., provider support and integration to prevent potential interactions and avoid delaying allopathic treatment). More exploration is needed about the decision-making processes of US South Asian youth, including the perceived benefits/limitations of allopathy and CAM. US healthcare practitioners should familiarize themselves with South Asian social and cultural beliefs about healing to provide culturally-appropriate services and enhance patient care.

Curriculum mapping of accredited pharmacy programs in the United States.

INTRODUCTION: No current guidance exists to inform the content area credit hours for doctor of pharmacy (PharmD) programs in the United States (US). METHODS: Public websites were accessed for all Accreditation Council for Pharmacy Education (ACPE) accredited PharmD programs in the US to record the credit hours devoted to drug therapy, clinical skills, experiential learning, scholarship, social and administrative sciences, physiology/pathophysiology, pharmacogenomics, medicinal chemistry, pharmacology, pharmaceutics, and pharmacokinetics/pharmacodynamics in the didactic curricula. Due to the high prevalence of programs that integrate drug therapy, pharmacology, and medicinal chemistry into a single course, we subdivided programs based upon whether drug therapy courses were "integrated" or "non-integrated." A regression analyses was conducted to explore the relationship between each content area and North American Pharmacist Licensure Examination (NAPLEX) pass rates and residency match rates. RESULTS: Data were available for 140 accredited PharmD programs. Drug therapy had the highest credit hours in programs with both integrated and non-integrated drug therapy courses. Programs with integrated drug therapy courses had significantly more credit hours in experiential and scholarship and fewer credit hours in stand-alone courses for pathophysiology, medicinal chemistry, and pharmacology. Credit hours in content areas did not predict NAPLEX pass rate nor residency match success rate. CONCLUSIONS: This is the first comprehensive description of all ACPE accredited pharmacy schools with credit hours broken down by content areas. While content areas did not directly predict success criteria, these results may still be useful to describe curricular norms or inform the design of future pharmacy curricula.

Catalyst-Free Synthesis of Functionalized 4-Substituted-4H-Benzo[d][1,3]oxazines via Intramolecular Cyclization of ortho-Amide-N-tosylhydrazones.

Functionalized 4-aryl-4H-benzo[d][1,3]oxazines are synthesized under transition-metal-free conditions using ortho-amide-N-tosylhydrazones. This synthetic method uses readily available N-tosylhydrazones as the diazo compound precursors and involves an intramolecular ring closure reaction mediated by a protic polar additive (iPrOH). A wide range of functionalized oxazines are obtained by this straightforward method in good to excellent yields. Furthermore, the viability of our strategy is illustrated by the gram-scale elaboration of a bromo-substituted 4H-benzo[d][1,3]oxazine and its post-functionalization by palladium-catalyzed cross-couplings.

Intratumoral IFN-γ or topical TLR7 agonist promotes infiltration of melanoma metastases by T lymphocytes expanded in the blood after cancer vaccine.

BACKGROUND: Immune-mediated melanoma regression relies on melanoma-reactive T cells infiltrating tumor. Cancer vaccines increase circulating melanoma-reactive T cells, but little is known about vaccine-induced circulating lymphocytes (viCLs) homing to tumor or whether interventions are needed to enhance infiltration. We hypothesized that viCLs infiltrate melanoma metastases, and intratumoral interferon (IFN)-γ or Toll-like receptor 7 (TLR7) agonism enhances infiltration. METHODS: Patients on two clinical trials (Mel51 (NCT00977145), Mel53 (NCT01264731)) received vaccines containing 12 class I major histocompatibility complex-restricted melanoma peptides (12MP). In Mel51, tumor was injected with IFN-γ on day 22, and biopsied on days 1, 22, and 24. In Mel53, dermal metastases were treated with topical imiquimod, a TLR7 agonist, for 12 weeks, and biopsied on days 1, 22, and 43. For patients with circulating T-cell responses to 12MP by IFN-γ ELISpot assays, DNA was extracted from peripheral blood mononuclear cells (PBMCs) pre-vaccination and at peak T-cell response, and from tumor biopsies, which underwent T-cell receptor sequencing. This enabled identification of clonotypes induced in PBMCs post-vaccination (viCLs) and present in tumor post-vaccination, but not pre-vaccination. RESULTS: Six patients with T-cell responses post-vaccination (Mel51 n = 4, Mel53 n = 2) were evaluated for viCLs and vaccine-induced tumor infiltrating lymphocytes (viTILs). All six patients had viCLs, five of whom were evaluable for viTILs in tumor post-vaccination alone. Mel51 patients had viTILs identified in day 22 tumors, post-vaccination and before IFN-γ (median = 2, range = 0-24). This increased in day 24 tumors after IFN-γ (median = 30, range = 4-74). Mel53 patients had viTILs identified in day 22 tumors, post-vaccination plus imiquimod (median = 33, range = 2-64). Three of five evaluable patients across both trials had viTILs with vaccination alone. All five had enhancement of viTILs with tumor-directed therapy. viTILs represented 0.0-2.9% of total T cells after vaccination alone, which increased to 0.6-8.7% after tumor-directed therapy. CONCLUSION: Cancer vaccines induce expansion of new viCLs, which infiltrate melanoma metastases in some patients. Our findings identify opportunities to combine vaccines with tumor-directed therapies to enhance T-cell infiltration and T cell-mediated tumor control. These combinations hold promise in improving the therapeutic efficacy of antigen-specific therapies for solid malignancies.

The significance of vertical platform discrepancies and splinting on marginal bone levels for adjacent dental implants.

OBJECTIVE: The aim of this retrospective study was to investigate the influence of vertical platform discrepancies for splinted and non-splinted adjacent implants on radiographic marginal bone loss (RMBL). METHODS: Data from January 2000 to February 2021 were collected from the electronic charts of 156 patients with 337 implants at the UCSF School of Dentistry. Five different implant restoration categories were evaluated for radiographic evidence of proximal RMBL. Patients with (1) two adjacent single crowns, (2) two adjacent splinted crowns, (3) three-unit bridges supported by two implants, (4) three adjacent single crowns, and (5) three adjacent splinted crowns. Inclusion required baseline radiograph taken at the time of prosthesis delivery or final impression, and follow-up radiographs at least 12 months after restorations have been in function. Measurements assessed included vertical distance between adjacent implant platforms and proximal RMBL around implants. Odds ratios (ORs) and 95% confidence interval (95% CI) of implants with ≥1 mm RMBL between different type of restorations were calculated. RESULTS: In general, prostheses supported by splinted adjacent implants demonstrated a significant association with the presence of ≥1 mm RMBL (OR = 2.55, 95% CI = 1.17-5.17, p = 0.018) when compared to prostheses supported by non-splinted adjacent implants. In addition, prostheses with a vertical platform discrepancy ≥0.5 mm demonstrated a significant association with the presence of ≥1 mm RMBL (OR = 4.30, 95% CI = 1.85 to 10.01, p = 0.007) when compared to prostheses with a vertical platform discrepancy <0.5 mm. When adjacent implants had ≥0.5 mm vertical platform discrepancy, the majority (66.67%) of three splinted adjacent crowns had at least one implant with ≥1 mm RMBL. This was followed by two splinted adjacent crowns (58.97%), three-unit bridge (25.93%), two single adjacent crowns (24.24%), and three single adjacent crowns (18.18%). When adjacent implants had ≥1 mm vertical platform discrepancy, there was an increased percentage of implants with ≥1 mm RMBL. The restorative design associated with the highest percent of implants with bone loss was three splinted adjacent crowns (70%), two splinted adjacent crowns (61.11%), three single adjacent crowns (40%), and three-unit bridge and two single adjacent implants (21.05%). Three splinted adjacent crowns were significantly associated with ≥1 mm RMBL when compared to three-unit bridge (OR 6.56, 95% CI 1.59-27.07). Similarly, two splinted crowns were significantly associated with ≥1 mm RMBL when compared to two single crowns (OR = 2.50, 95% CI = 1.08-5.79). CONCLUSION: Two or three adjacent implants placed with a vertical platform discrepancy, when splinted together, are associated with higherincidence of ≥1 mm RMBL than non-splinted restorations.

Incision-free, coronally advanced flap with subepithelial connective tissue graft placed by the molar or canine access (MOCA) technique: 13 case series.

INTRODUCTION: Root coverage procedures are not always predictable, and outcomes depend on several factors. This technique provides a predictable alternative to managing facial gingival recessions. CASE SERIES: A new grafting technique is introduced that requires no incisions at the recipient site, thereby preserving the integrity of the local blood supply to optimize the healing process. The graft is placed through the gingival sulcus via a molar or canine access (MOCA) approach, and there is minimal tension on the coronally advanced flap through use of suspension sutures. Thirteen non-smoking patients, between the ages of 27 and 57, with Cairo RT1 facial recession were studied, with a follow-up period of 1-60 weeks. This paper explains the step-by-step technique and highlights 13 cases. CONCLUSION: Complete root coverage was achieved in all 13 cases, although one case showed initial altered healing. While MOCA is technique sensitive, it provides optimal root coverage results. With no incisions at the recipient site, there is no uneven texture or scar formation, and healing proceeds with minimal interruption. Why is this case series new information? MOCA is a unique approach to introduce grafts into non-incised sites of recession that can be one, two, or three teeth away at molars or canines. Non-incised approach minimizes interruption to blood supply. Coronally advanced flaps are secured in place with composite-fastened suspension sutures for tension-free flap closure. What are the keys to successful management of these cases? Good quality and quantity of connective tissue graft Early diagnosis and treatment of recession Expert surgical technique What are the key limitations to the success of these cases? The quality of the donor site is variable among patients. A technique-sensitive approach Advanced recession might warrant a second surgery.

Addressing CAUTIs with an External Female Catheter.

BACKGROUND: Catheter-associated urinary tract infections (CAUTIs) can lead to complications that prolong hospital stays and result in patient discomfort as well as increased health care costs and mortality. At our academic medical center in New York City, in 2016-17, 21 of 87 CAUTI cases (24%) were in bedbound female patients in whom indwelling catheters were used for incontinence. Although condom catheters were available as an alternative to indwelling urinary catheters for male patients, there was a lack of effective products for female patients. METHODS: A team of clinical nurse specialists (CNSs) conducted a literature search, reviewed internal data on CAUTI rates and catheter use, and searched for available catheter alternatives that would meet the needs of bedbound female patients. The team identified two different external female urinary catheters and piloted both with a focus on efficacy as well as stakeholder satisfaction. RESULTS: In 2019-20, external female catheters were used in 1,195 unique patients. Approximately 90% of external female catheter use was to avoid using an indwelling urinary catheter. With a cost avoidance of $13,786 per patient, $16,473,912 in costs to the organization were avoided. CAUTI rates in bedbound female patients decreased after implementation of the external female catheters. CONCLUSION: This initiative demonstrates that external female urinary catheters can be used at other hospitals to decrease indwelling urinary catheter use and CAUTI rates in bedbound female patients.

Bruck Syndrome: Beyond the Obvious.

INTRODUCTION: Bruck syndrome is a rare autosomal recessive disease characterized by multiple joint contractures, bone fragility, and fractures. Two genes have been associated with Bruck syndrome, FKBP10 and PLOD2, though they are phenotypically indistinguishable. CASE PRESENTATION: We present a prenatally diagnosed case of Bruck syndrome in a young multiparous woman, with no notable personal, family or obstetric history. A 12-week ultrasound raised the suspicion of short long bones, subsequently confirmed at 16 weeks. In addition, bilateral fixed flexion of the elbow, wrist, and knee joints as well as talipes was observed. Chromosomal SNP microarray analysis (0.2 Mb) detected a homozygous deletion at chromosome 3, band q24, involving a part of PLOD2 to a part of PLSCR4. At mid-trimester morphology, bilateral intrauterine fractures of the humerus and femur were evident. In the late third trimester, a fetal echocardiogram noted enlargement of the right heart with severe tricuspid regurgitation in combination with pulmonary insufficiency and a restrictive arterial duct. The potential risk of premature closure of the ductus arteriosus near term led to delivery by emergency caesarean section. CONCLUSION: To our knowledge, this is the first case of Bruck syndrome prenatally confirmed by chromosomal microarray analysis and the second reported case with an extra-skeletal abnormality. This case highlights the importance of comprehensive fetal morphological assessment during pregnancy as diagnosis of an additional abnormality has the potential to impact both management and prognosis.

Design, synthesis and biological evaluation of quinoline-2-carbonitrile-based hydroxamic acids as dual tubulin polymerization and histone deacetylases inhibitors.

A series of quinoline and quinazoline analogs were designed and synthesized as new tubulin polymerization (TP) and histone deacetylases (HDAC) inhibitors. Compounds 12a and 12d showed the best cytotoxicity activities against a panel of human cancer cell lines with an averaged IC50 value of 0.6 and 0.7 nM, respectively. Furthermore, these lead compounds showed good activities against CA-4-resistant colon-carcinoma and multidrug-resistant leukemia cells. In addition, compounds 12a and 12d induced HT29 cell cycle arrest in the G2/M phase and produced caspase-induced apoptosis of HT29 cells through mitochondrial dysfunction. Also, 12a and 12d inhibited HDAC8, 6, and 11 activities. Furthermore, lead compound 12a exhibited higher metabolic stability than isoCA-4 and was highly potent in suppressing tumor growth in the fibrosarcoma MCA205 tumor model. Collectively, these studies suggest that 12a represents a new dual inhibitor of TP and HDAC activities, which makes it a suitable candidate for further investigations in clinical development.

Synthesis of Benzo[c][2,7]naphthyridinones and Benzo[c][2,6]naphthyridinones via Ruthenium-Catalyzed [2+2+2] Cycloaddition between 1,7-Diynes and Cyanamides.

A convenient method for the ruthenium-catalyzed synthesis of benzo[c]naphthyridinone derivatives is reported. The [2+2+2] cycloaddition from various mono- and disubstituted 1,7-diynes and cyanamides provided benzo[c][2,7]naphthyridinones as major products and benzo[c][2,6]naphthyridinones as minor ones in yields of ≤79% and regioselectivities of ≤99:1. This method is amenable to internal and terminal diynes and a number of cyanamides with diverse functional group tolerance.

Recent Developments in the Photochemical Synthesis of Functionalized Imidazopyridines.

Imidazopyridines constitute one of the most important scaffolds in medicinal chemistry, as their skeleton could be found in a myriad of biologically active molecules. Although numerous strategies were elaborated for imidazopyridine preparation in the 2010s, novel eco-compatible synthetic approaches have emerged, conscious of climate change concerns. In this framework, photochemical methods have been promoted to conceive this heterocyclic motif over the last decade. This review covers the recently published works on synthesizing highly functionalized imidazopyridines by light induction.

Adherence to lipid monitoring and its impact on treat intensification of LDL-C lowering therapies at an urban academic medical center.

BACKGROUND: Lipid monitoring is recommended by treatment guidelines to assess efficacy and adherence to lipid lowering therapy, but the available data is mostly limited to integrated health delivery systems with less diverse populations. OBJECTIVE: To determine the proportion of patients that completed appropriate lipid monitoring at an urban academic medical center and whether lipid monitoring is associated with treatment intensification. METHODS: Adults prescribed ≥1 LDL-C lowering therapy and with ≥1 outpatient encounter during 2018 and 2019 were included. Appropriate lipid monitoring was defined as ≥1 lipid panel obtained during the 12 month follow up period. Treatment intensification was defined as a dose increase, change to a higher intensity statin, or addition of a new LDL-C lowering therapy. The association between lipid monitoring and treatment intensification were assessed using regression models. RESULTS: Of the 12,332 patients on LDL-C lowering therapy, 88% had ≥1 lipid panel. The average patient was 60 years of age, 50% were female, and 50% identified as black or African American. On regression analysis (odds ratio [OR], 95% confidence interval [CI]), lipid monitoring occurred less frequently in adults >75 years of age (0.63, 0.44 to 0.90), black or African American individuals (0.78, 0.69 to 0.89), and those insured by Medicaid (0.72, 0.61 to 0.86). The odds of treatment intensification steadily increased with the number of lipid panels compared to those without lipid monitoring. CONCLUSION: Lipid monitoring is associated with treatment intensification but occurs less frequently in adults >75 years of age, black or African American individuals, and those insured by Medicaid.