Hydrogen-Bonded Thiol Undergoes Unconventional Excited-State Intramolecular Proton-Transfer Reactions.

The chapter on the thiol-related hydrogen bond (H-bond) and its excited-state intramolecular proton-transfer (ESIPT) reaction was recently opened where compound 4'-diethylamino-3-mercaptoflavone (3NTF) undergoes ESIPT in both cyclohexane solution and solid, giving a 710 nm tautomer emission with an anomalously large Stokes shift of 12,230 cm-1. Considering the thiol H-bond to be unconventional compared to the conventional Pauling-type -OH or -NH H-bond, it is thus essential and timely to probe its fundamental difference between their ESIPT. However, thiol-associated ESIPT tends to be nonemissive due to the dominant nπ* character of the tautomeric lowest excited state. Herein, based on the 3-mercaptoflavone scaffold and π-elongation concept, a new series of 4'-substituted-7-diethylamino-3-mercaptoflavones, NTFs, was designed and synthesized with varied H-bond strength and 690-720 nm tautomeric emission upon ultraviolet (UV) excitation in cyclohexane. The order of their H-bonding strength was experimentally determined to be N-NTF < O-NTF < H-NTF < F-NTF, while the rate of -SH ESIPT measured by fluorescence upconversion was F-NTF (398 fs)-1 < H-NTF (232 fs)-1 < O-NTF (123 fs)-1 < N-NTF (101 fs)-1 in toluene. Unexpectedly, the strongest H-bonded F-NTF gives the slowest ESIPT, which does not conform to the traditional ESIPT model. The results are rationalized by the trend of carbonyl oxygen basicity rather than -SH acidity. Namely, the thiol acidity relevant to the H-bond strength plays a minor role in the driving force of ESIPT. Instead, the proton-accepting strength governs ESIPT. That is to say, the noncanonical thiol H-bonding system undergoes an unconventional type of ESIPT.

Ensemble of kernel ridge regression-based small molecule-miRNA association prediction in human disease.

MicroRNAs (miRNAs) play crucial roles in human disease and can be targeted by small molecule (SM) drugs according to numerous studies, which shows that identifying SM-miRNA associations in human disease is important for drug development and disease treatment. We proposed the method of Ensemble of Kernel Ridge Regression-based Small Molecule-MiRNA Association prediction (EKRRSMMA) to uncover potential SM-miRNA associations by combing feature dimensionality reduction and ensemble learning. First, we constructed different feature subsets for both SMs and miRNAs. Then, we trained homogeneous base learners based on distinct feature subsets and took the average of scores obtained from these base learners as SM-miRNA association score. In EKRRSMMA, feature dimensionality reduction technology was employed in the process of construction of feature subsets to reduce the influence of noisy data. Besides, the base learner, namely KRR_avg, was the combination of two classifiers constructed under SM space and miRNA space, which could make full use of the information of SM and miRNA. To assess the prediction performance of EKRRSMMA, we conducted Leave-One-Out Cross-Validation (LOOCV), SM-fixed local LOOCV, miRNA-fixed local LOOCV and 5-fold CV based on two datasets. For Dataset 1 (Dataset 2), EKRRSMMA got the Area Under receiver operating characteristic Curves (AUCs) of 0.9793 (0.8871), 0.8071 (0.7705), 0.9732 (0.8586) and 0.9767 ± 0.0014 (0.8560 ± 0.0027). Besides, we conducted four case studies. As a result, 32 (5-Fluorouracil), 19 (17ß-Estradiol), 26 (5-Aza-2'-deoxycytidine) and 11 (cyclophosphamide) out of top 50 predicted potentially associated miRNAs were confirmed by database or experimental literature. Above evaluation results demonstrated that EKRRSMMA is reliable for predicting SM-miRNA associations.

The Association of Oxygen Delivery and Transfusion on Cardiopulmonary Bypass with Acute Kidney Injury.

OBJECTIVES: To estimate whether the association of transfusion and acute kidney injury (AKI) has a threshold of oxygen delivery below which transfusion is beneficial but above which it is harmful. DESIGN: Retrospective study SETTING: Cardiovascular operating room and intensive care unit PARTICIPANTS: Patients undergoing cardiac surgery with continuous oxygen delivery monitoring during cardiopulmonary bypass INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS: Logistic regression was used to estimate the associations between oxygen delivery (mean, cumulative deficit, and bands of oxygen delivery), transfusion, and their interaction and AKI. A subgroup analysis of transfused and nontransfused patients with exact matching on cumulative oxygen deficit and time on bypass with adjustment for propensity to receive a transfusion using logistic regression. Nine hundred ninety-one of 4,203 patients developed AKI within 7 days. After adjustment for confounders, lower mean oxygen delivery (odds ratio [OR], 0.968; 95% confidence interval [CI], 0.949-0.988; p = 0.002) and transfusions (OR, 1.442; 95% CI, 1.077, 1.932; p = 0.014) were associated with increased odds of AKI by 7 days. As oxygen delivery decreased, the risk of AKI increased, with the slope of the OR steeper at <160 mL/m2/min. In the subgroup analysis, matched transfused patients were more likely than matched nontransfused patients to develop AKI (45% [n = 145] v 31% [n = 101]; p < 0.001). However, after propensity score adjustment, the difference was nonsignificant (OR, 1.181; 95% CI, 0.796-1.752; p = 0.406). CONCLUSIONS: We found a nonlinear relationship between oxygen delivery and AKI. We found no level of oxygen delivery at which transfusion was associated with a decreased risk of AKI.

Pre-exposure prophylaxis (PrEP) use history in people with antiretroviral resistance at HIV diagnosis: Findings from New York City HIV surveillance and partner services, 2015-2022.

BACKGROUND: Drug resistance may be acquired in people starting HIV pre-exposure prophylaxis (PrEP) during undiagnosed infection. Population-based estimates of PrEP-related resistance are lacking. METHODS: We used New York City surveillance and partner services data to measure the effect of PrEP use (tenofovir disoproxil fumarate/tenofivir alafenamide fumarate with emtricitabine) history on baseline prevalence of M184I/V mutations in people diagnosed with HIV, 2015-2022. PrEP use was categorized as "Recent" defined as PrEP stopped ≤ 90 days before diagnosis, "Past" as PrEP stopped >90 days before diagnosis, and "No known use". Resistance associated mutations were determined using the Stanford Algorithm. We used log binomial regression to generate adjusted relative risk (aRR) of M184I/V by PrEP use history in people with and without acute HIV infection (AHI). RESULTS: Of 4,246 newly diagnosed people with a genotype ≤30 days of diagnosis, 560 (13%) had AHI, 136 (3%) reported recent, and 124 (35%) past PrEP use; 98 (2%) harbored M184I/V. In people with AHI, recent PrEP use was associated with 6 times greater risk of M184I/V than no known use (aRR: 5.86; 95% confidence interval [CI]: 2.49-13.77). In people without AHI, risk of M184I/V in recent users was 7 times (aRR:7.26; 95% CI: 3.98-13.24), and in past users, 4 times that of people with no known use (aRR: 4.46; 95% CI: 2.15-9.24). CONCLUSIONS: PrEP use was strongly associated with baseline M184I/V in NYC, regardless of AHI. Ordering a nucleic acid test when indicated after assessment of exposure, antiretroviral history and AHI symptoms can decrease PrEP initiation in people with undetected infection.

Photoinduced Aryl Transfer from Imidazolyl-Quinoline π-Conjugated Systems.

Aryl transfer between heteroatoms was photochemically available through radical initiation followed by a bimolecular reaction. However, such an excited-state reaction has rarely been reported through a photoinduced intramolecular pathway in the π-conjugated systems. Herein, we found, for the first time, a clean photoinduced intramolecular aryl shift for imidazolyl-quinoline derivatives 2NQ (imidazophenanthrene) and 4NQX (imidazophenanthroline), of which the photoproducts are thermally reversible. Upon light irradiation of the studied compounds in solution, an appreciable blue fluorescence along with a gradual change in color appearance was observed, the photoluminescence and photoconversion quantum yields of which were shown to be competitive in the same excited state. We were able to harness the photoconversion quantum yields of the NQ compounds with facile electronic modifications. These, in combination with time-resolved studies on the NQ compounds, gave an oxygen-insensitive aryl transfer rate within 1-100 ns. The anomalously slow intramolecular reaction rates were further proven to be associated with the ∼5.0 kcal/mol transition free energy. The photoproducts NQ_rs were isolated, identified by X-ray analyses, and also shown to demonstrate anti-Vavilov reverse reactions back to the NQ compounds in the higher-lying excited state. The discovery of photoinduced intramolecular aryl transfer paves a new pathway in the synthetic field, which may also be extended and far-reaching to solar-chemical storage under an appropriate design strategy.

Rational Design of Asymmetric Polymethines to Attain NIR(II) Bioimaging at >1100 nm.

Organic molecules having emission in the NIR(II) region are emergent and receiving enormous attention. Unfortunately, attaining accountable organic emission intensity around the NIR(II) region is hampered by the dominant internal conversion operated by the energy gap law, where the emission energy gap and the associated internal reorganization energy λint play key roles. Up to the current stage, the majority of the reported organic NIR(II) emitters belong to those polymethines terminated by two symmetric chromophores. Such a design has proved to have a small λint that greatly suppresses the internal conversion. However, the imposition of symmetric chromophores is stringent, limiting further development of organic NIR(II) dyes in diversity and versatility. Here, we propose a new concept where as far as the emissive state of the any asymmetric polymethines contains more or less equally transition density between two terminated chromophores, λint can be as small as that of the symmetric polymethines. To prove the concept, we synthesize a series of new polymethines terminated by xanthen-9-yl-benzoic acid and 2,4-diphenylthiopyrylium derivatives, yielding AJBF1112 and AEBF1119 that reveal emission peak wavelength at 1112 and 1119 nm, respectively. The quantum yield is higher than all synthesized symmetric polymethines of 2,4-diphenylthiopyrylium derivatives (SC1162, 1182, 1185, and 1230) in this study. λint were calculated to be as small as 6.2 and 7.3 kcal/mol for AJBF1112 and AEBF1119, respectively, proving the concept. AEBF1119 was further prepared as a polymer dot to demonstrate its in vitro specific cellular imaging and in vivo tumor/bone targeting in the NIR(II) region.

Systematic evaluation of machine learning methods for identifying human-pathogen protein-protein interactions.

In recent years, high-throughput experimental techniques have significantly enhanced the accuracy and coverage of protein-protein interaction identification, including human-pathogen protein-protein interactions (HP-PPIs). Despite this progress, experimental methods are, in general, expensive in terms of both time and labour costs, especially considering that there are enormous amounts of potential protein-interacting partners. Developing computational methods to predict interactions between human and bacteria pathogen has thus become critical and meaningful, in both facilitating the detection of interactions and mining incomplete interaction maps. In this paper, we present a systematic evaluation of machine learning-based computational methods for human-bacterium protein-protein interactions (HB-PPIs). We first reviewed a vast number of publicly available databases of HP-PPIs and then critically evaluate the availability of these databases. Benefitting from its well-structured nature, we subsequently preprocess the data and identified six bacterium pathogens that could be used to study bacterium subjects in which a human was the host. Additionally, we thoroughly reviewed the literature on 'host-pathogen interactions' whereby existing models were summarized that we used to jointly study the impact of different feature representation algorithms and evaluate the performance of existing machine learning computational models. Owing to the abundance of sequence information and the limited scale of other protein-related information, we adopted the primary protocol from the literature and dedicated our analysis to a comprehensive assessment of sequence information and machine learning models. A systematic evaluation of machine learning models and a wide range of feature representation algorithms based on sequence information are presented as a comparison survey towards the prediction performance evaluation of HB-PPIs.

Deep-belief network for predicting potential miRNA-disease associations.

MicroRNA (miRNA) plays an important role in the occurrence, development, diagnosis and treatment of diseases. More and more researchers begin to pay attention to the relationship between miRNA and disease. Compared with traditional biological experiments, computational method of integrating heterogeneous biological data to predict potential associations can effectively save time and cost. Considering the limitations of the previous computational models, we developed the model of deep-belief network for miRNA-disease association prediction (DBNMDA). We constructed feature vectors to pre-train restricted Boltzmann machines for all miRNA-disease pairs and applied positive samples and the same number of selected negative samples to fine-tune DBN to obtain the final predicted scores. Compared with the previous supervised models that only use pairs with known label for training, DBNMDA innovatively utilizes the information of all miRNA-disease pairs during the pre-training process. This step could reduce the impact of too few known associations on prediction accuracy to some extent. DBNMDA achieves the AUC of 0.9104 based on global leave-one-out cross validation (LOOCV), the AUC of 0.8232 based on local LOOCV and the average AUC of 0.9048 ± 0.0026 based on 5-fold cross validation. These AUCs are better than other previous models. In addition, three different types of case studies for three diseases were implemented to demonstrate the accuracy of DBNMDA. As a result, 84% (breast neoplasms), 100% (lung neoplasms) and 88% (esophageal neoplasms) of the top 50 predicted miRNAs were verified by recent literature. Therefore, we could conclude that DBNMDA is an effective method to predict potential miRNA-disease associations.

Identification of miRNA-disease associations via multiple information integration with Bayesian ranking.

In recent years, increasing microRNA (miRNA)-disease associations were identified through traditionally biological experiments. These associations contribute to revealing molecular mechanism of diseases and preventing and curing diseases. To improve the efficiency of miRNA-disease association discovery, some calculation methods were developed as auxiliary tools for researchers. In the current study, we raised a novel model named Bayesian Ranking for MiRNA-Disease Association prediction (BRMDA) by improving Bayesian Personalized Ranking from three aspects: (i) taking advantage of similarity of diseases and miRNAs; (ii) incorporating miRNA bias for miRNAs associated with different number of diseases; and (iii) implementing neighborhood-based approach for new miRNAs and diseases. For each investigated disease, BRMDA used the set of triples (i.e. disease, labeled miRNA, unlabeled miRNA) that reflected association preference of the disease to miRNAs as training set, which made full use of unknown samples rather than simply considering them as negative samples. To investigate the predictive performance of BRMDA, we employed leave-one-out cross-validation and obtained Area Under the Curve of 0.8697, which outperformed many classical methods. Besides, we further implemented three distinct classes of case studies for three common Neoplasms. As a result, there are 44 (Colon Neoplasms), 49 (Esophageal Neoplasms) and 49 (Lung Neoplasms) among the top 50 predicted miRNAs validated through experiments. In short, BRMDA would be a trustable tool for inferring valuable associations.

Two Models for Increasing the Scope and Activities of Human Immunodeficiency Virus Partner Services Programs: Preliminary Findings From the Fast Track Project.

BACKGROUND: We sought to develop a novel strategy for expanding an existing human immunodeficiency virus (HIV) partner services (PS) model to provide comprehensive sexual health services, including sexually transmitted infection testing, a virtual telemedicine visit, and access to immediate start medication (antiretroviral treatment, preexposure or postexposure prophylaxis). Fast Track was a National Institutes of Health-funded implementation science trial in New York City to pilot and refine the new strategy, and examine its feasibility, acceptability, and impact. METHODS: Over the course of 1 year, health department staff collaborated with the academic research team to develop Fast Track protocols and workflows, create a cloud-based database to interview and track patients, and train disease intervention specialists to deliver the new program. The initial field-based program (Fast Track 1.0) was piloted March to December 2019. A modified telephone-based program (Fast Track 2.0) was developed in response to COVID-19 pandemic constraints and was piloted August 2020 to March 2021. RESULTS: These 2 pilots demonstrate the feasibility and acceptability of integrating comprehensive sexual health services into HIV PS programs. Disease intervention specialists were successfully trained to conduct comprehensive sexual health visits, and clients reported that the availability of comprehensive sexual health services made them more willing to engage with PS. Key lessons for scale-up include managing collaboration with a licensed provider, navigating technical and technological issues, and challenges in client engagement and retention. CONCLUSIONS: The success of this integrated strategy suggests that telehealth visits may be a critical gateway to care engagement for PS clients. This model is an innovative strategy for increasing engagement with HIV testing, prevention, and treatment for underserved populations.

Quest for singlet fission of organic sulfur-containing systems in the higher lying singlet excited state: application prospects of anti-Kasha's rule.

In this study, we explore the possibilities of the deactivating pathways of organic thione containing systems through first-principles calculations. We particularly pay attention to the second lying singlet excited state, S2, due to its large energy difference from the lowest lying S1 state in the sulfur-containing systems. Several theoretical models including the previously synthesized thiones and the strategically designed molecules are investigated to search for the basic conjugation unit that exhibits the prospect of S2 fission. Various molecular motifs and different substituents are combined to maneuver the relative alignment of the relevant low excited energy states. The results lead us to conclude that the thione derivatives, under rational and delicate molecular designs, may be engineered to possess a sufficiently high S2-S1 energy gap as high as 2 eV and that these systems may exhibit S2 fission to triplet excitons in the red to near infrared region.

Metabolism, pharmacokinetics and excretion of [14C]dimethyl fumarate in healthy volunteers: an example of xenobiotic biotransformation following endogenous metabolic pathways.

Delayed-release dimethyl fumarate (DMF), Tecfidera®, is approved globally for treating relapsing-remitting multiple sclerosis. The disposition of DMF was determined in humans after administration of a single oral dose of [14C]DMF, and the total recovery was estimated to be between 58.4% to 75.0%, primarily through expired air.The absorption of [14C]DMF-derived radioactivity was rapid, with Tmax at 1h postdose. Glucose was the predominant circulating metabolite, accounting for ∼60% of the total extractable radioactivity. Cysteine and N-acetylcysteine conjugates of mono- or di-methyl succinate were found to be the major urinary metabolites.In vitro studies showed that [14C]DMF was mainly metabolised to MMF, and fumarase exclusively converted fumaric acid to malic acid and did not catalyse the conversion of fumaric acid esters to malic acid. DMF was observed to bind with human serum albumin through Michael addition to the Cys-34 residue when exposed to human plasma.These findings indicate that DMF undergoes metabolism via hydrolysis, GSH conjugation, and the TCA cycle, leading to the formation of citric acid, CO2, and water. These ubiquitous and well-conserved metabolism pathways minimise the risk of drug-drug interactions and reduce variability related to pharmacogenetics and ethnicity.

Evaluating a scalable ARCHES (Addressing Reproductive Coercion in Health Settings) model in government health facilities in Uasin Gishu county, Kenya: study protocol for a cluster-randomized controlled trial.

BACKGROUND: Since 2013, the World Health Organization has recommended that reproductive coercion (RC) and intimate partner violence (IPV) be addressed within reproductive health services and, in 2018, the Lancet Commission on Sexual and Reproductive Health and Rights found that RC and IPV were significant contributors to unmet need for family planning (FP) and unintended pregnancy. In Kenya, the Ministry of Health (MOH) has made reduction of unintended pregnancy and gender-based violence a primary objective. Despite this need and guidance, no clinic-based intervention models outside of the U.S. (apart from the one described here) have demonstrated efficacy to improve FP use and reduce IPV or RC thereby reducing unintended pregnancy. ARCHES (Addressing Reproductive Coercion in Health Settings) is a brief, clinic-based intervention delivered by existing FP providers aiming to: (1) Increase women's ability to use FP without interference, (2) Provide a safe and supportive environment for IPV disclosure and referral to support services, and (3) Improve quality of FP counseling, including addressing RC and IPV. The objective of this study is to generate evidence on scaling integrated FP services (including FP, RC, and IPV) in public sector health facilities in Uasin Gishu county, Kenya via adaptation and implementation of ARCHES in partnership with the Kenya MOH. METHODS: A cluster-randomized controlled trial paired with concurrent implementation science assessments will test effectiveness of the ARCHES model, adapted for scale by the Kenya MOH, in reducing unintended pregnancy. Female FP clients aged 15-49 years at selected sites will complete baseline surveys (immediately prior to receiving care), immediately post-visit exit surveys, and 6-month follow-up surveys. Provider surveys will assess changes in gender-equitable attitudes and self-efficacy to address violence reported by their clients. Costs associated with scaling ARCHES will be tracked and utilized in combination with results of the effectiveness trial to assess costs and cost-effectiveness relative to the standard of care. DISCUSSION: This study will provide evidence of the effectiveness of a facility-based intervention to address RC and IPV within public sector FP services at scale, as adapted and implemented in Uasin Gishu county, Kenya. Trial registration Trial registered on 28 September 2023 with clinicaltrials.gov NCT06059196.

This study will document evidence of the effectiveness of the ARCHES intervention, a brief, clinic-based counselling intervention demonstrated to reduce intimate partner violence and reproductive coercion and promote women's reproductive health, as scaled in government health facilities in Kenya. ARCHES aims to (1) decrease unintended pregnancy, (2) increase family planning uptake and use/continuation, (3) decrease experiences of reproductive coercion and intimate partner violence of women and girls aged 15­49 years seeking family planning services, and to (4) improve quality of care, (5) increase gender equitable attitudes, and (6) increase self-efficacy to provide comprehensive family planning counseling among providers trained in ARCHES.

Integrating Contact Tracers Into Point-of-Care Testing Workflow to Accelerate the Tracing of People With Exposure to COVID-19, August-December 2020, New York City.

OBJECTIVES: We assessed the timeliness of contact tracing following rapid-positive COVID-19 test result at point-of-care testing (POCT) sites in New York City (NYC). DESIGN: Interviewed case-patients to elicit exposed contacts and conducted COVID-19 exposure notifications. SETTINGS: Twenty-two COVID-19 POCT sites in NYC, the 2 NYC international airports, and 1 ferry terminal. PARTICIPANTS: Case-patients with rapid-positive COVID-19 test results and their named contacts. MAIN OUTCOME MEASURES: We quantified the proportions of interviewed individuals with COVID-19 and notified contacts and assessed the timeliness between the dates of the rapid-positive COVID-19 test results and the interviews or notifications. RESULTS: In total, 11 683 individuals with rapid-positive COVID-19 test results were referred for contact tracing on the day of their diagnosis; 8878 (76) of whom were interviewed within 1 day of diagnosis, of whom 5499 (62%) named 11 486 contacts. A median of 1.24 contacts were identified from each interview. The odds of eliciting contacts were significantly higher among individuals reporting COVID-19 symptoms than among persons with no symptoms (51% vs 36%; adjusted odds ratio [aOR] = 1.37; 95% confidence interval [CI], 1.11-1.70) or living with 1 or more persons than living alone (89% vs 38%; aOR = 12.11; 95% CI, 10.73-13.68). Among the 8878 interviewed case-patients, 8317 (94%) were interviewed within 1 day of their rapid-positive COVID-19 test results and 91% of contact notifications were completed within 1 day of contact identification. The median interval from test result to interview date and from case investigation interview to contact notification were both 0 days (IQR = 0). CONCLUSIONS: The integration of contact tracers into COVID-19 POCT workflow achieved timely case investigation and contact notification. Accelerated contact tracing can be used to curb COVID-19 transmission during local outbreaks.

Self-Assembled Monolayers of Bi-Functionalized Porphyrins: A Novel Class of Hole-Layer-Coordinating Perovskites and Indium Tin Oxide in Inverted Solar Cells.

Self-assembled monolayers (SAMs) offer the advantage of facile interfacial modification, leading to significant improvements in device performance. In this study, we report the design and synthesis of a new series of carboxylic acid-functionalized porphyrin derivatives, namely AC-1, AC-3, and AC-5, and present, for the first time, a strategy to exploit the large π-moiety of porphyrins as a backbone for interfacing the indium tin oxide (ITO) electrode and perovskite active layer in an inverted perovskite solar cell (PSC) configuration. The electron-rich nature of porphyrins facilitates hole transfer and the formation of SAMs, resulting in a dense surface that minimizes defects. Comprehensive spectroscopic and dynamic studies demonstrate that the double-anchored AC-3 and AC-5 enhance SAMs on ITO, passivate the perovskite layer, and function as conduits to facilitate hole transfer, thus significantly boosting the performance of PSCs. The champion inverted PSC employing AC-5 SAM achieves an impressive solar efficiency of 23.19 % with a high fill factor of 84.05 %. This work presents a novel molecular engineering strategy for functionalizing SAMs to tune the energy levels, molecular dipoles, packing orientations to achieve stable and efficient solar performance. Importantly, our comprehensive investigation has unraveled the associated mechanisms, offering valuable insights for future advancements in PSCs.

Comprehensive Thione-Derived Perylene Diimides and Their Bio-Conjugation for Simultaneous Imaging, Tracking, and Targeted Photodynamic Therapy.

In this study, the chromophore 3,4,9,10-perylenetetracarboxylic diimide (PDI) is anchored with phenyl substituents at the imide N site, followed by thionation, yielding a series of thione products 1S-PDI-D, 2S-cis-PDI-D, 2S-trans-PDI-D, 3S-PDI-D, and 4S-PDI-D, respectively, with n = 1, 2, 3, and 4 thione. The photophysical properties are dependent on the number of anchored thiones, where the observed prominent lower-lying absorption is assigned to the S0 → S2(ππ*) transition and is red-shifted upon increasing the number of thiones; the lowest-lying excited state is ascribed to a transition-forbidden S1(nπ*) configuration. All nS-PDIs are non-emissive in solution but reveal an excellent two-photon absorption cross-section of >800 GM. Supported by the femtosecond transient absorption study, the S1(nπ*) → T1(ππ*) intersystem crossing (ISC) rate is > 1012 s-1, resulting in ∼100% triplet population. The lowest-lying T1(ππ*) energy is calculated to be in the order of 1S-PDI-D > 2S-cis-PDI-D ∼ 2S-trans-PDI-D > 3S-PDI-D > 4S-PDI-D, where the T1 energy of 1S-PDI-D (1.10 eV) is higher than that (0.97 eV) of the 1O2 1Δg state. 1S-PDI-D is further modified by either conjugation with peptide FC131 on the two terminal sides, forming 1S-FC131, or linkage with peptide FC131 and cyanine5 dye on each terminal, yielding Cy5-1S-FC131. In vitro experiments show power of 1S-FC131 and Cy5-1S-FC131 in recognizing A549 cells out of other three lung normal cells and effective photodynamic therapy. In vivo, both molecular composites demonstrate outstanding antitumor ability in A549 xenografted tumor mice, where Cy5-1S-FC131 shows superiority of simultaneous fluorescence tracking and targeted photodynamic therapy.

What to expect when girls are expecting: psychosocial support challenges and opportunities in the context and aftermath of teenage pregnancy in Kenya.

BACKGROUND: An understanding of the psychosocial support challenges and opportunities in the context of teenage pregnancy is important for developing appropriate interventions for pregnant and parenting girls. This qualitative study was conducted in Homa Bay County, Kenya, to examine the experience of teenage pregnancy and the resultant psychosocial support needs from the perspectives of both pregnant/parenting girls and their own parents, who are typically expected to provide various forms of support. METHODS: The study used a descriptive case study design, drawing on counseling case notes documented by psychologists who held counseling sessions with 20 pregnant or parenting girls and 6 of their parents as part of a psychosocial support intervention. The counseling case notes formed a qualitative data set, which was analyzed thematically. RESULTS: Emerging master themes were related to pregnant and parenting girls' experience of sexual violence and adverse childbirth outcomes; psychological trauma confronted by girls and their parents alike; parental need for support in communicating with pregnant/parenting girls about sex and sexuality; and the availability of family support as a resource for teenage mothers. CONCLUSION: Pregnant and parenting teenage girls require a range of psychosocial support responses that recognize the realities of sexual violence and other challenges in the lives of the girls themselves, as well as in the lives of their parents and caregivers. While parents and other caregivers can serve as an important resource for supporting affected girls, they often need assistance as well, in order to support pregnant/parenting girls effectively. These realities need to be taken into account to maximize the effectiveness of health and development programs for pregnant and parenting girls. Furthermore, emerging themes from actual counseling sessions with affected girls and parents can provide important insights into the potential psychosocial support needs of the broader population of pregnant and parenting girls.

This study looked into the lives of pregnant and parenting girls in Kenya by examining case notes that were written up by psychologists during the counseling sessions they held with 20 different teenage girls who were pregnant, or already had children, and 6 of their parents. The case notes provided an understanding of the kind of support pregnant and parenting girls need, including mental health care to deal with the trauma of sexual violence (and other issues) that some had experienced. It also helped put a spotlight on the traumas that parents of affected girls face after a teenage pregnancy occurs. These issues need to be addressed in order to ensure that health and development professionals who work with pregnant and parenting girls are as helpful to them as possible.

Invited commentary: Total anomalous pulmonary venous connection remains a challenging pediatric disease.

Cervantes-Salazar and colleagues report the long-term surgical outcomes of 414 patients with total anomalous pulmonary venous connection (TAPVC) from January 2003 to June 2019. With an overall survival rate of 87.2% from 2003 to 2019, the authors found that an increased mortality risk was associated with infracardiac TAPVC, pulmonary venous obstruction, and postoperative mechanical ventilation. Their comprehensive study with a large sample size of varying age groups, and patients with late referrals for surgery, provide valuable insight into TAPVC surgical outcomes. Improved survival for these patients continues to be a major goal of clinical teams striving to transform treatment paradigms. The promising result of the study reported by Cervantes-Salazar and colleagues gives our field hope for a better future for these patients.

Functional analysis of Clostridium difficile sortase B reveals key residues for catalytic activity and substrate specificity.

Most of Gram-positive bacteria anchor surface proteins to the peptidoglycan cell wall by sortase, a cysteine transpeptidase that targets proteins displaying a cell wall sorting signal. Unlike other bacteria, Clostridium difficile, the major human pathogen responsible for antibiotic-associated diarrhea, has only a single functional sortase (SrtB). Sortase's vital importance in bacterial virulence has been long recognized, and C. difficile sortase B (Cd-SrtB) has become an attractive therapeutic target for managing C. difficile infection. A better understanding of the molecular activity of Cd-SrtB may help spur the development of effective agents against C. difficile infection. In this study, using site-directed mutagenesis, biochemical and biophysical tools, LC-MS/MS, and crystallographic analyses, we identified key residues essential for Cd-SrtB catalysis and substrate recognition. To the best of our knowledge, we report the first evidence that a conserved serine residue near the active site participates in the catalytic activity of Cd-SrtB and also SrtB from Staphylococcus aureus The serine residue indispensable for SrtB activity may be involved in stabilizing a thioacyl-enzyme intermediate because it is neither a nucleophilic residue nor a substrate-interacting residue, based on the LC-MS/MS data and available structural models of SrtB-substrate complexes. Furthermore, we also demonstrated that residues 163-168 located on the ß6/ß7 loop of Cd-SrtB dominate specific recognition of the peptide substrate PPKTG. The results of this work reveal key residues with roles in catalysis and substrate specificity of Cd-SrtB.

Gastrostomy Tube for Nutrition and Malignant Bowel Obstruction in Patients With Cancer.

BACKGROUND: Gastrostomy tubes (G-tubes) are invaluable clinical tools that play a role in palliation and nutrition in patients with cancer. This study aimed to better understand the risks and benefits associated with the placement and maintenance of G-tubes. METHODS: Patients who underwent placement of a G-tube for cancer from January 2013 through December 2017 at a tertiary care center were considered for inclusion. Clinical data were retrospectively collected from medical records. RESULTS: A total of 242 patients with cancer, whose average age at diagnosis was 61 years (range, 21-94 years), underwent G-tube placement for nutrition (76.4%), decompression (22.7%), or both (0.8%). Successful insertion was achieved in 96.8%, but 8 patients required >1 attempted method of insertion. In the decompression group, minor postplacement complications were less common (23.6% vs 53.5%; P<.001) and survival was shorter (P<.001) compared with the nutrition group. For those with decompressive G-tubes, 45.5% had a palliative care consult; 56.4% were seen by social workers; and 46.3% went to hospice. The frequency of hospice discharge was higher in patients who had consults (53.7% vs 23.1%; P=.01). CONCLUSIONS: Half of the patients who received decompressive G-tubes presented with stage IV disease and died within 1 month of placement. Those with >1 consult were more likely to be discharged to hospice. Patients with G-tubes for nutrition saw no change in functionality, complication rate, or survival, regardless of adjunct chemotherapy status. These findings illustrate the need for a tool to allow a better multidisciplinary approach and interventional decision-making for patients with cancer.