Efficacy of a Digital Mental Health Biopsychosocial Transdiagnostic Intervention With or Without Therapist Assistance for Adults With Anxiety and Depression: Adaptive Randomized Controlled Trial.

BACKGROUND: Digital mental health (DMH) interventions incorporating elements that adapt to the evolving needs of consumers have the potential to further our understanding of the optimal intensity of therapist assistance and inform stepped-care models. OBJECTIVE: The primary objective was to compare the efficacy of a transdiagnostic biopsychosocial DMH program, with or without therapist assistance for adults with subthreshold symptoms or a diagnosis of anxiety or depression. METHODS: In a randomized adaptive clinical trial design, all participants had access to the DMH program, with eligibility to have their program augmented with therapist assistance determined by program engagement or symptom severity. Participants who met stepped-care criteria were randomized to have their treatment program augmented with either low-intensity (10 min/week of video chat support for 7 weeks) or high-intensity (50 min/week of video chat support for 7 weeks) therapist assistance. A total of 103 participants (mean age 34.17, SD 10.50 years) were assessed before (week 0), during (weeks 3 and 6), and after the intervention (week 9) and at the 3-month follow-up (week 21). The effects of 3 treatment conditions (DMH program only, DMH program+low-intensity therapist assistance, and DMH program+high-intensity therapist assistance) on changes in the 2 primary outcomes of anxiety (7-item Generalized Anxiety Disorder Scale [GAD-7]) and depression (9-item Patient Health Questionnaire [PHQ-9]) were assessed using the Cohen d, reliable change index, and mixed-effects linear regression analyses. RESULTS: There were no substantial differences in the outcome measures among intervention conditions. However, there were significant time effect changes in most outcomes over time. All 3 intervention conditions demonstrated strong and significant treatment effect changes in GAD-7 and PHQ-9 scores, with absolute Cohen d values ranging from 0.82 to 1.79 (all P<.05). The mixed-effects models revealed that, in the Life Flex program-only condition at week 3, mean GAD-7 and PHQ-9 scores significantly decreased from baseline by 3.54 and 4.38 (all P<.001), respectively. At weeks 6, 9, and 21, GAD-7 and PHQ-9 scores significantly decreased from baseline by at least 6 and 7 points (all P<.001), respectively. Nonresponders at week 3 who were stepped up to therapist assistance increased program engagement and treatment response. At the postintervention time point and 3-month follow-up, 67% (44/65) and 69% (34/49) of the participants, respectively, no longer met diagnostic criteria for anxiety or depression. CONCLUSIONS: The findings highlight that early detection of low engagement and non-treatment response presents an opportunity to effectively intervene by incorporating an adaptive design. Although the study findings indicate that therapist assistance was no more effective than the DMH intervention program alone for reducing symptoms of anxiety or depression, the data highlight the potential influence of participant selection bias and participant preferences within stepped-care treatment models. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12620000422921; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378317&isReview=true. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/45040.

A Fully Automated Self-help Biopsychosocial Transdiagnostic Digital Intervention to Reduce Anxiety and/or Depression and Improve Emotional Regulation and Well-being: Pre-Follow-up Single-Arm Feasibility Trial.

BACKGROUND: Anxiety disorders and depression are prevalent disorders with high comorbidity, leading to greater chronicity and severity of symptoms. Given the accessibility to treatment issues, more evaluation is needed to assess the potential benefits of fully automated self-help transdiagnostic digital interventions. Innovating beyond the current transdiagnostic one-size-fits-all shared mechanistic approach may also lead to further improvements. OBJECTIVE: The primary objective of this study was to explore the preliminary effectiveness and acceptability of a new fully automated self-help biopsychosocial transdiagnostic digital intervention (Life Flex) aimed at treating anxiety and/or depression, as well as improving emotional regulation; emotional, social, and psychological well-being; optimism; and health-related quality of life. METHODS: This was a real-world pre-during-post-follow-up feasibility trial design evaluation of Life Flex. Participants were assessed at the preintervention time point (week 0), during intervention (weeks 3 and 5), at the postintervention time point (week 8), and at 1- and 3-month follow-ups (weeks 12 and 20, respectively). RESULTS: The results provided early support for the Life Flex program in reducing anxiety (Generalized Anxiety Disorder 7), depression (Patient Health Questionnaire 9), psychological distress (Kessler 6), and emotional dysregulation (Difficulties in Emotional Regulation 36) and increasing emotional, social, and psychological well-being (Mental Health Continuum-Short Form); optimism (Revised Life Orientation Test); and health-related quality of life (EQ-5D-3L Utility Index and Health Rating; all false discovery rate [FDR]<.001). Large within-group treatment effect sizes (range |d|=0.82 to 1.33) were found for most variables from pre- to postintervention assessments and at the 1- and 3-month follow-up. The exceptions were medium treatment effect sizes for EQ-5D-3L Utility Index (range Cohen d=-0.50 to -0.63) and optimism (range Cohen d=-0.72 to -0.79) and small-to-medium treatment effect size change for EQ-5D-3L Health Rating (range Cohen d=-0.34 to -0.58). Changes across all outcome variables were generally strongest for participants with preintervention clinical comorbid anxiety and depression presentations (range |d|=0.58 to 2.01) and weakest for participants presenting with nonclinical anxiety and/or depressive symptoms (|d|=0.05 to 0.84). Life Flex was rated as acceptable at the postintervention time point, and participants indicated that they enjoyed the transdiagnostic program and biological, wellness, and lifestyle-focused content and strategies. CONCLUSIONS: Given the paucity of evidence on fully automated self-help transdiagnostic digital interventions for anxiety and/or depressive symptomatology and general treatment accessibility issues, this study provides preliminary support for biopsychosocial transdiagnostic interventions, such as Life Flex, as a promising future mental health service delivery gap filler. Following large-scale, randomized controlled trials, the potential benefits of fully automated self-help digital health programs, such as Life Flex, could be considerable. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12615000480583; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368007.

Evaluation of Various Support Intensities of Digital Mental Health Treatment for Reducing Anxiety and Depression in Adults: Protocol for a Mixed Methods, Adaptive, Randomized Clinical Trial.

BACKGROUND: Anxiety and depression are leading causes of disease worldwide, requiring timely access to evidence-based treatment. Digital mental health (dMH) interventions increase accessibility to evidence-based psychological services delivered in a variety of web-based formats (eg, self-help and therapist-assisted interventions). Robust and rigorous studies of adaptive web-based intervention designs are scarce. No identified randomized clinical trial has investigated the efficacy of a 2-stage adaptive design, whereby the program-only condition or no support dMH treatment program is augmented by either low or high therapist assistance, if a participant does not improve or engage in the program-only condition. OBJECTIVE: The primary objective is to assess whether low or high therapist-assisted support delivered via video chat is more effective in reducing anxiety and depressive symptoms compared with a dMH program-only condition. The secondary objective is to evaluate the role of motivation; self-efficacy; and preferences in participant engagement, adherence, and clinical outcomes (anxiety and depression symptoms) among the 3 treatment conditions (program only, low-intensity therapist assistance, and high-intensity therapist assistance). A mixed methods analysis of factors affecting participant attrition, participant reasons for nonengagement and withdrawal, and therapist training and implementation of dMH interventions will be completed. Qualitative data regarding participant and therapist experiences and satisfaction with video chat assessment and treatment will also be analyzed. METHODS: Australian adults (N=137) with symptoms or a diagnosis of anxiety or depression will be screened for eligibility and given access to the 8-module Life Flex dMH treatment program. On day 15, participants who meet the augmentation criteria will be stepped up via block randomization to receive therapist assistance delivered via video chat for either 10 minutes (low intensity) or 50 minutes (high intensity) per week. This adaptive trial will implement a mixed methods design, with outcomes assessed before the intervention (week 0), during the intervention (weeks 3 and 6), after the intervention (week 9), and at the 3-month follow-up (week 21). RESULTS: The primary outcome measures are for anxiety (Generalized Anxiety Disorder-7) and depression severity (Patient Health Questionnaire-9). Measures of working alliance, health status, health resources, preferences, self-efficacy, and motivation will be used for secondary outcomes. Qualitative methods will be used to explore participant and therapist experiences of video chat assessment and treatment, participant reasons for withdrawal and nonengagement, and therapist training and implementation experiences. Data collection commenced in November 2020 and was completed at the end of March 2022. CONCLUSIONS: This is the first mixed methods adaptive trial to explore the comparative efficacy of different intensity levels of self-help and a therapist-assisted dMH intervention program delivered via video chat for adults with anxiety or depression. Anticipated results may have implications for the implementation of dMH interventions. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry 12620000422921; https://tinyurl.com/t9cyu372. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/45040.

Cervical bleeding with cervical stabilization during IUD placement: allis clamp versus single-tooth tenaculum, a randomized control trial.

OBJECTIVE: To evaluate whether the use of an atraumatic Allis clamp will result in less bleeding than the standard single-tooth tenaculum for cervical stabilization during intrauterine device (IUD) placement. METHODS: A single-blinded randomized controlled trial was conducted during insertions of IUDs between March 2017 and March 2018. University of Kentucky Institutional Review Board (IRB 16-1110-P3K) approval was obtained. Physicians were randomized to use either an Allis clamp or a single-tooth tenaculum for cervical stabilization. A post-procedure questionnaire was used to collect outcome measures as well as demographic and obstetric-related factors. RESULTS: Of the ninety-five participants, there was no difference in age, self-identified race/ethnicity, or the evaluated obstetric factors between the groups. Bleeding was present after clamp removal in 3 (6.3%) insertions using an Allis clamp and 26 (55.3%) insertions using a single-tooth tenaculum (RR = 0.113, CI = [0.037, 0.3481], p < 0.0001). There was no difference in IUD insertion success rates between the two clamps. There was no difference in the number of interventions needed to obtain hemostasis including indirect pressure, silver nitrate, monsel's solution, or stitch for hemostasis. Pain scores did not differ based on clamp type or age of patient, but were significantly different based on parity (p < 0.001) and IUD type (p < 0.003). CONCLUSION: Decreased incidence of bleeding from cervical stabilization device, with unchanged insertion success using the Allis clamp can be an alternative to the single tooth tenaculum in the procedure of IUD insertion. TRIAL REGISTRATION NUMBER: The trial was retrospectively registered on 1/11/22 (trial registration number NCT05187078).

The association between smoking status and post-operative complications in pelvic organ prolapse corrective surgeries.

INTRODUCTION AND HYPOTHESIS: Tobacco is a known risk factor for pelvic organ prolapse (POP) as well as postoperative complications in general surgery procedures. Very little is known regarding the impact of tobacco use on postoperative outcomes in POP-correcting procedures, however. We hypothesize that tobacco use will be associated with an increased risk of postoperative complications in these procedures. METHODS: This study utilized the National Surgical Quality Improvement Program (NSQIP) database for the years 2012-2020. Patients who underwent POP-correcting procedures were identified using current procedural terminology (CPT) codes. Baseline characteristics between the patient populations were compared using chi-square and one-way ANOVA tests as indicated. Binary logistic regression was used to evaluate the incidence of postoperative complications based on smoking status while controlling for demographic and clinical factors. RESULTS: This study included 43,406 total patients, 39,614 non-smokers and 3792 smokers. Postoperative complications including deep wound infections (P < 0.001), intraperitoneal infections (P = 0.003), wound dehiscence (P = 0.014), urinary tract infections (P = 0.029), and hospital readmissions (P < 0.001) were significantly higher in patients who smoke than those who do not. Further evaluation of patients who did not undergo mesh placement intraoperatively and those who solely underwent vaginal procedures showed similar trends. CONCLUSIONS: This study demonstrates a higher incidence of postoperative complications after POP-correcting procedures in patients with who smoke. Wound complications, urinary tract infections, and hospital readmission confer a considerable amount of risk to patient outcomes in addition to significant healthcare cost. Consideration should be given to smoking status in preoperative evaluation and counseling before these procedures.

Comparison of the Role of Protein Dynamics in Catalysis by Dihydrofolate Reductase from E. coli and H. sapiens.

Dihydrofolate reductase (DHFR) is a well-studied, clinically relevant enzyme known for being highly dynamic over the course of its catalytic cycle. However, the role dynamic motions play in the explicit hydride transfer from the nicotinamide cofactor to the dihydrofolate substrate remains unclear because reaction initiation and direct spectroscopic examination on the appropriate time scale for such femtosecond to picosecond motions is challenging. Here, we employ pre-steady-state kinetics to observe the hydride transfer as directly as possible in two different species of DHFR: Escherichia coli and Homo sapiens. While the hydride transfer has been well-characterized in DHFR from E. coli, improvements in time resolution now allow for sub-millisecond dead times for stopped-flow spectroscopy, which reveals that the maximum rate is indeed faster than previously recorded. The rate in the human enzyme, previously only estimated, is also able to be directly observed using cutting-edge stopped-flow instrumentation. In addition to the pH dependence of the hydride transfer rates for both enzymes, we examine the primary H/D kinetic isotope effect to reveal a temperature dependence in the human enzyme that is absent from the E. coli counterpart. This dependence, which appears above a temperature of 15 °C is a shared feature among other hydride transfer enzymes and is also consistent with computational work suggesting the presence of a fast promoting-vibration that provides donor-acceptor compression on the time scale of catalysis to facilitate the chemistry step.

Impact of Race and Ethnicity on Perioperative Outcomes During Hysterectomy for Endometriosis.

STUDY OBJECTIVE: To assess whether complications incurred during hysterectomy for the treatment of endometriosis differ among racial-ethnic groups. DESIGN: Retrospective cohort study. SETTING: American College of Surgeons National Surgical Quality Improvement Program database from 2014 to 2019. This database is a robust, comprehensive, multi-institutional database with nearly 700 participating hospitals. PATIENTS: Patients with a diagnosis of endometriosis or with an endometriosis-associated symptom as the primary indication for surgery and surgical intraoperative documentation of endometriosis. INTERVENTIONS: Compare perioperative complications based on patient race and ethnicity. MEASUREMENTS AND MAIN RESULTS: A total of 5639 patients underwent hysterectomy for endometriosis; of these, 4368 were White patients (77.5%), 528 Black patients (9.4%), 491 Hispanic patients (8.7%), 252 Asian patients (4.5%). There was no association between location of endometriosis and patient race and ethnicity. However, White patients had highest rate, and Asian patients had the lowest rate of laparoscopic hysterectomy, 85.3% vs 69.8%, respectively (p <.01). In addition, there were differences in concomitant procedures performed at time of hysterectomy based on race and ethnicity, with White patients having the highest rates of adnexal/peritoneal surgery at 12.5% (p <.01) compared with patients of the other racial and ethnic groups. Asian patients had the highest rate of ureteral surgery at 6.8% (p <.01) and highest rate of intestinal surgery at 16.3% (p <.01) compared with patients of other racial and ethnic groups. There was no association of rates of concomitant bladder surgery, appendectomy, or rectal surgery with patient race and ethnicity. Black patients had the highest rate of minor complications at 13.5% (p <.01) and the highest rate of major complications at 6.6% (p <.01) compared with patients of other racial and ethnic groups. After multivariable analysis, Black patients still had increased odds of having a major complication compared with patients of other racial and ethnic groups even after controlling for patient characteristics and perioperative factors such as endometriosis lesion location, surgical approach, and concomitant procedures (odds ratio 1.64; 95% confidence interval, 1.10-2.45). CONCLUSION: Endometriosis lesion location did not differ with patient race and ethnicity. However, patient race and ethnicity did have an impact on the surgical approach and the concomitant surgical procedures performed at time of hysterectomy. Black patients had the highest odds of major complications.

Perioperative Myomectomy Outcomes Based on the Current Coding Rules: Comparing Leiomyoma Burden and Surgical Approach.

OBJECTIVE: To assess postoperative outcomes based on surgical approach for myomectomies with increasing leiomyoma burden. METHODS: We conducted a retrospective analysis using the American College of Surgeons National Surgical Quality Improvement Program database from 2014 to 2019 of benign myomectomy procedures. These cases were categorized into "smaller" and "larger" procedures based on leiomyoma burden. Smaller myomectomies included leiomyomas weighing less than 250 g or with one-four leiomyomas (Current Procedural Terminology [CPT] codes 58545 and 58140); larger myomectomies included leiomyomas weighing 250 g or more or with five or more leiomyomas (CPT codes 58546 and 58146). Postoperative complications estimated using the Clavien-Dindo classification system were compared based on surgical approach. RESULTS: Of 8,363 total myomectomy procedures, 3,117 (37.3%) were performed using minimally invasive surgery (MIS) and 5,246 (62.7%) were performed using laparotomy. Among MIS cases, 2,080 (66.7%) were categorized as smaller myomectomies and 1,037 (33.3%) cases as larger myomectomies. Among laparotomy cases, 2,587 (49.3%) were smaller myomectomies, and 2,659 (50.7%) were larger myomectomies. Regardless of myomectomy size, MIS was associated with a lower perioperative blood transfusion rate than laparotomy (1.63% vs 8.93%, respectively, P<.01). Laparotomy was associated with an increased rate of minor complications (adjusted odds ratio [aOR] 2.86 (95% CI 2.24-3.67) for smaller leiomyoma burden (11.91% vs 4.28%) and for larger leiomyoma burden (21.59% vs 6.75%, aOR 3.43, 95% CI 2.64-4.47) cases. Laparotomy demonstrated an increased cumulative major complication rate (3.31% vs 1.25%) (aOR 2.45, 95% CI 1.35-4.45) for larger myomectomies. CONCLUSION: A minimally invasive surgical approach for both smaller and larger myomectomies was associated with fewer minor complications compared with laparotomy. Minimally invasive surgery for larger myomectomies was associated with fewer cumulative major complications compared with laparotomy.

Massively Parallelized Molecular Force Manipulation with On-Demand Thermal and Optical Control.

In single-molecule force spectroscopy (SMFS), a tethered molecule is stretched using a specialized instrument to study how macromolecules extend under force. One problem in SMFS is the serial and slow nature of the measurements, performed one molecule at a time. To address this long-standing challenge, we report on the origami polymer force clamp (OPFC) which enables parallelized manipulation of the mechanical forces experienced by molecules without the need for dedicated SMFS instruments or surface tethering. The OPFC positions target molecules between a rigid nanoscale DNA origami beam and a responsive polymer particle that shrinks on demand. As a proof-of-concept, we record the steady state and time-resolved mechanical unfolding dynamics of DNA hairpins using the fluorescence signal from ensembles of molecules and confirm our conclusion using modeling.

Documentation of drug abuse in the family or household of children admitted to the hospital for non-accidental trauma.

BACKGROUND: Drug abuse in the family is known to increase the risk of child abuse, but its impact on outcomes of hospitalizations for non-accidental trauma (NAT) has not been characterized. OBJECTIVE: We aimed to identify how frequently drug abuse in the household was documented among children with known or suspected NAT, and to correlate drug abuse in the family with hospitalization outcomes. PARTICIPANTS AND SETTING: At our tertiary care hospital, we retrospectively queried hospital admissions of children ages 0-17 who had a Child Abuse and Neglect consultation ordered during an inpatient stay. METHODS: Case manager documentation and consult notes from the inpatient response team were used to determine suspected or confirmed presence of household substance abuse. RESULTS: We identified 185 children meeting inclusion criteria (59 % <1 year; 34 % 1-5 years; 7% 6-14 years of age). Drug abuse in the family was documented in 44 cases (24 %). Among 178 children surviving to discharge, drug abuse was associated with lower likelihood of discharge home (50 % vs. 70 % among children with no documented drug abuse, p = 0.018). After discharge, we found no statistically significant differences in rehospitalizations or emergency department visits according to documentation of drug abuse in the family. CONCLUSION: Our study addresses the role of family drug abuse in outcomes of hospitalizations for NAT. Significantly, half of cases with suspected or known drug abuse had no prior CPS involvement, and drug abuse was associated with discharge outcomes after controlling for prior CPS involvement.

Small molecule cores demonstrate non-competitive inhibition of lactate dehydrogenase.

Lactate dehydrogenase (LDH) has recently garnered attention as an attractive target for cancer therapies, owing to the enzyme's critical role in cellular metabolism. Current inhibition strategies, employing substrate or cofactor analogues, are insufficiently specific for use as pharmaceutical agents. The possibility of allosteric inhibition of LDH was postulated on the basis of theoretical docking studies of a small molecule inhibitor to LDH. The present study examined structural analogues of this proposed inhibitor to gauge its potency and attempt to elucidate the molecular mechanism of action. These analogues display encouraging in vitro inhibition of porcine heart LDH, including micromolar Ki values and a maximum inhibition of up to 50% in the steady state. Furthermore, Michaelis-Menten kinetics and fluorescence data both suggest the simple, acetaminophen derivatives are non-competitive in binding to the enzyme. Kinetic comparisons of a panel of increasingly decorated structural analogues imply that the binding is specific, and the small molecule core provides a privileged scaffold for further pharmaceutical development of a novel, allosteric drug.

Kinetic analysis of the Ku-DNA binding activity reveals a redox-dependent alteration in protein structure that stimulates dissociation of the Ku-DNA complex.

Ku is a heterodimeric protein comprising 70- and 80-kDa subunits that participate in the non-homologous end-joining (NHEJ) repair pathway for rejoining DNA double strand breaks. We have analyzed the pre-steady state binding of Ku with various DNA duplex substrates and identified a redox-sensitive Ku-DNA interaction. Pre-steady state analysis of Ku DNA binding was monitored via intrinsic Ku quenching upon binding DNA and revealed that, under fully reduced conditions, binding occurred in a single-step process. Reactions performed under limited reduction revealed a two-step binding process, whereas under fully oxidized conditions, we were unable to detect quenching of Ku fluorescence upon binding DNA. The differential quenching observed under the different redox conditions could not be attributed to two Ku molecules binding to a single substrate or Ku sliding inward on the substrate. Although only modest differences in Ku DNA binding activity were observed in the stoichiometric anisotropy and electrophoretic mobility shift assay studies, as a function of redox conditions, a dramatic difference in the rate of Ku dissociation from DNA was observed. This effect was also induced by diamide treatment of Ku and could be abrogated by dithiothreitol treatment, demonstrating a reversible redox effect on the stability of the Ku-DNA complex. The redox-dependent alteration in Ku-DNA interactions is manifested by a redox-dependent alteration in Ku structure, which was confirmed by limited proteolysis and mass spectrometry analyses. The results support a model for the interaction of Ku with DNA that is regulated by redox status and is achieved by altering the dissociation of the Ku-DNA complex.

Differential activation of DNA-PK based on DNA strand orientation and sequence bias.

DNA-PKcs and Ku are essential components of the complex that catalyzes non-homologous end joining (NHEJ) of DNA double-strand breaks (DSBs). Ku, a heterodimeric protein, binds to DNA ends and facilitates recruitment of the catalytic subunit, DNA-PKcs. We have investigated the effect of DNA strand orientation and sequence bias on the activation of DNA-PK. In addition, we assessed the effect of the position and strand orientation of cisplatin adducts on kinase activation. A series of duplex DNA substrates with site-specific cisplatin-DNA adducts placed in three different orientations on the duplex DNA were prepared. Terminal biotin modification and streptavidin (SA) blocking was employed to direct DNA-PK binding to the unblocked termini with a specific DNA strand orientation and cisplatin-DNA adduct position. DNA-PK kinase activity was measured and the results reveal that DNA strand orientation and sequence bias dramatically influence kinase activation, only a portion of which could be attributed to Ku-DNA binding activity. In addition, cisplatin-DNA adduct position resulted in differing degrees of inhibition depending on distance from the terminus as well as strand orientation. These results highlight the importance of how local variations in DNA structure, chemistry and sequence influence DNA-PK activation and potentially NHEJ.

Development of a high-throughput screen for inhibitors of replication protein A and its role in nucleotide excision repair.

The heterotrimeric protein, replication protein A (RPA), is essential for DNA repair and replication. RPA is a viable target in the treatment of cancer as many chemotherapeutic agents act by blocking DNA replication. Furthermore, inhibition of RPA could prove useful in treating cancers that have acquired resistance to DNA damaging agents through enhanced DNA repair mechanisms as has been observed with certain platinum-resistant carcinomas. In an effort to identify inhibitors of RPA, we employed a novel fluorescent reporter and established a homogeneous high-throughput screening assay to measure RPA's DNA binding activity. Using this assay, we have screened a collection of small molecules and determined the effect they have on the RPA-DNA interaction. Of the 2000 compounds screened, 79 scored positive for inhibition of RPA binding activity. Secondary screenings were performed using an electrophoretic mobility shift assay; of the 79 compounds, 9 scored positive and were further characterized in titration experiments to determine the most potent inhibitor, resulting in several compounds showing an IC50 in the low micromolar range. Fluorescence polarization analyses were also performed to determine the mechanism of inhibition for each compound. Validation of the inhibitory activity of selected compounds was verified using in vitro nucleotide excision repair (NER) catalyzed excision of a single cisplatin lesion in a duplex DNA. The identification and use of RPA inhibitors may aid in inhibiting NER activity that could potentially circumvent resistance to certain chemotherapeutic agents as well as be useful in the characterization of RPA and its interaction with DNA.