Impact of neoadjuvant pembrolizumab adherence on pathologic complete response in triple-negative breast cancer: a real-world analysis.

BACKGROUND: The addition of pembrolizumab (pembro) to neoadjuvant chemotherapy (NAC) is standard of care for the treatment of early triple-negative breast cancer (TNBC) after KEYNOTE-522 trial demonstrated improved pathologic complete response (pCR) rates with the combination. However, the optimal treatment strategy for TNBC remains uncertain as questions persist about which patients benefit from pembro and the best treatment schedule and regimen. We identified real-world clinical characteristics and treatment variables associated with response to NAC plus pembro. METHODS: Patients with early TNBC treated with NAC plus pembro between February 2020 and September 2023 were identified. Univariate and multivariate analysis was performed using logistic regression to identify factors associated with pCR. Cox proportional hazard prediction models were used to identify predictors of invasive disease-free survival and overall survival in this cohort. RESULTS: A pCR was achieved in 75 (63.6%) of 118 patients. Age at diagnosis (P = .04), Ki-67 (P = .004), duration from start of pembro to surgery (P = .006) and NAC to surgery (P = .01), number of cycles of pembro (P = .04) and NAC (P = .02), and completion of at least 8 cycles of pembro (P = .015) and NAC (P = .015) were each significantly associated with pCR in univariate analysis. In multivariate analysis, patients younger than 55 years at time of diagnosis (vs age > 55 years) and those completing at least 8 cycles of pembro remained predictive of pCR (OR's 2.50, 2.49, P = .035 and .037, respectively). CONCLUSIONS: In this real-world analysis of patients with TNBC treated with NAC plus pembro, younger age and the completion of at least 8 cycles of pembrolizumab were associated with pCR.

Cost-Conscious Colposcopy: A Single-Institution Review of Biopsy Submission Practices and Outcomes.

OBJECTIVE: Distribution of cervical dysplasia may influence approach for excisional procedures. Separating colposcopy biopsies into multiple specimen cups for pathologic evaluation incurs additional costs. The authors aimed to determine whether the practice of separating biopsy specimens impacts patient outcomes. METHODS: A retrospective review of all colposcopy cases from a single institution was performed. A total of 1,331 cases were reviewed from January 1, 2017, to December 31, 2019. Multibiopsy cohorts were separated by number of specimen cups received by pathology (single or multiple). Cohorts were compared for histology, need for excisional procedure, and final excisional pathology results. Specimen processing fees were acquired from the Department of Pathology ($70/specimen). Statistical analysis performed on MINITAB using Pearson chi-square and Fisher exact tests. RESULTS: Excisional procedures were required by 30.4% (86/283) of multiple specimen submissions compared with 28.2% (154/547) of single specimen cup submissions ( p = .50). There was a higher, although not statistically significant, rate of additional procedures in the multiple specimen cup cohort (8.8 vs 2.9% [ p = .08]). Malignancy diagnosis was equivalent in each cohort. Cost analysis revealed adopting a single specimen cup model would reduce costs up to approximately $30,000/year. CONCLUSIONS: Patient outcomes were not improved by the practice of submitting multiple specimen cups. Given the additional cost associated with separating specimens, the authors recommend during routine colposcopy that all cervical biopsies be sent for evaluation as a single pathology specimen unless a lesion of concern is identified in an area not normally excised during traditional excisional procedures.

Outcomes of a community-led online-based HIV self-testing demonstration among cisgender men who have sex with men and transgender women in the Philippines during the COVID-19 pandemic: a retrospective cohort study.

INTRODUCTION: The Philippines, which has the fastest rising HIV epidemic globally, has limited options for HIV testing and its uptake remains low among cisgender men who have sex with men (cis-MSM) and transgender women (TGW), especially amid the COVID-19 pandemic. As HIV self-testing (HIVST) and technology-based approaches could synergize to expand uptake of HIV testing, we aimed to evaluate the outcomes of a community-led online-based HIVST demonstration and to explore factors associated with HIVST-related behaviours and outcomes. METHODS: We did a secondary data analysis among cis-MSM and TGW who participated in the HIVST demonstration, who were recruited online and tested out-of-facility, in Western Visayas, Philippines, from March to November 2020. We reviewed data on demographics, sexuality-, and context-related variables. Using multivariable logistic regression, we tested for associations between the aforementioned covariates and two primary outcomes, opting for directly-assisted HIVST (DAH) and willingness to secondarily distribute kits. RESULTS: HIVST kits were distributed to 647 individuals (590 cis-MSM, 57 TGW), 54.6% were first-time testers, 10.4% opted DAH, and 46.1% were willing to distribute to peers. Reporting rate was high (99.3%) with 7.6% reactivity rate. While linkage to prevention (100%) and care (85.7%) were high, pre-exposure prophylaxis (PrEP) (0.3%) and antiretroviral therapy (ART) (51.0%) initiation were limited. There were no reports of adverse events. Those who were employed, had recent anal intercourse, opted for DAH, not willing to secondarily distribute, and accessed HIVST during minimal to no quarantine restriction had significantly higher reactivity rates. Likelihood of opting for DAH was higher among those who had three or more partners in the past year (aOR = 2.01 [CI = 1.01-4.35]) and those who accessed during maximal quarantine restrictions (aOR = 4.25 [CI = 2.46-7.43]). Odds of willingness to share were higher among those in urban areas (aOR = 1.64 [CI = 1.15-2.36]) but lower among first-time testers (aOR = 0.45 [CI = 0.32-0.62]). CONCLUSIONS: HIVST could effectively reach hard-to-reach populations. While there was demand in accessing online-based unassisted approaches, DAH should still be offered. Uptake of PrEP and same-day ART should be upscaled by decentralizing these services to community-based organizations. Differentiated service delivery is key to respond to preferences and values of key populations amid the dynamic geographical and sociocultural contexts they are in.

Serial Assessment of Urinary Incontinence in Breast Cancer Survivors Undergoing (Neo)Adjuvant Therapy.

BACKGROUND: Among breast cancer survivors, urinary incontinence (UI) is often attributed to cancer therapy. We prospectively assessed urinary symptoms before and after (neo)adjuvant treatment of early-stage breast cancer. METHODS: With consent, women with stage I-III breast cancer completed the Urogenital Distress Inventory and the Incontinence Impact Questionnaire before and 3 months after initiating (neo)adjuvant therapy. Patients with UI were at least slightly bothered by urinary symptoms. If UI was present pretreatment, it was considered prevalent; if UI was new or worse at 3 months posttreatment, it was considered incident; if prevalent UI was no worse at 3 months posttreatment, it was considered stable. Ordinal logistic regression models identified characteristics associated with the level of prevalent UI and with the degree of UI impact on quality of life (QoL). RESULTS: On pretreatment surveys, participants (N=203; age 54.5 ± 11.4 years) reported 79.8% prevalence of UI, including overactive bladder (29.1%), stress incontinence (10.8%), or both (39.9%). The level of prevalent UI increased with body mass index (BMI; P<.05). Of 163 participants assessed at both time points, incident UI developed in 12 of 32 patients without prevalent UI and 27 of 131 patients with prevalent UI. Regardless of whether UI was prevalent (n=162), incident (n=39), or stable (n=94) at QoL assessment, the impact of UI increased (P<.01) with the number and severity of UI symptoms, subjective urinary retention, and BMI. Adjusted for those characteristics, incident UI had less impact on QoL (P<.05) than did prevalent or stable UI. CONCLUSIONS: We found that UI is highly prevalent at breast cancer diagnosis and that new or worsened UI is common after (neo)adjuvant therapy. Because UI often impairs QoL, appropriate treatment strategies are needed.

Quantitative, Qualitative, Mixed Methods, and Triangulation Research Simplified.

For the novice nurse researcher, identifying a clinical researchable problem may be simple, but discerning an appropriate research approach may be daunting. What are the differences among quantitative, qualitative, mixed methods, and triangulation research? Which method is applicable for the study one wants to conduct? This article discusses the two main research traditions (quantitative and qualitative) and the differences and similarities in methods for frontline nurses. It simplifies and clarifies how the reader might enhance the rigor of the research study by using mixed methods or triangulation. The four types of research are described, and examples are provided to support readers to plan projects, use the most appropriate method, and effectively communicate findings. [J Contin Educ Nurs. 2024;55(7):338-344.].

Research, Evidence-Based Practice, and Quality Improvement Simplified.

Is the research process different than evidence-based practice and quality improvement, or is it the same? Scattered evidence and misperceptions regarding research, evidence-based practice, and quality improvement make the answer unclear among nurses. This article clarifies and simplifies the three processes for frontline clinical nurses and nurse leaders. The three processes are described and discussed to give the reader standards for differentiating one from the other. The similarities and differences are highlighted, and examples are provided for contextualization of the methods. [J Contin Educ Nurs. 2023;54(1):40-48.].

CD103 and periplakin are potential biomarkers for response of metastatic melanoma to pembrolizumab.

This study was designed to screen for preliminary evidence of predictive markers of melanoma response to PD-1 blockade. We hypothesized that the following immune markers would be positive predictors of response: increased densities of CD103 + CD8 + T cells or Th1 lineage T-bet + T cells, high expression of CXCL9-11 and presence of tertiary lymphoid structures. Conversely, we hypothesized that the high expression of barrier molecules would be a negative predictor of response. Patients with advanced melanoma treated with pembrolizumab were identified, and clinical response as well as overall survival data were collected. Tumor samples were evaluated by multiplex immunofluorescence histology. All statistical analyses were performed in R Studio and Microsoft Excel using the Mann-Whitney U test, chi-square test, Spearman's rank correlation and Kaplan-Meier survival curves. Sixty-five advanced melanoma patients were identified, of whom 46 met inclusion criteria and were included in this study. Increased densities ( P = 0.04) and proportions ( P = 0.02) of CD8 + T cells expressing CD103 + were associated with complete response (CR) to pembrolizumab. Improved survival was associated with increased proportions of CD8 + cells expressing CD103 ( P = 0.0085) as well as decreased density of periplakin + cells ( P = 0.012) and periplakin + SOX10 + cells ( P = 0.0012). The density and proportion of CD8 + T cells expressing CD103 + positively correlated with PD-L1 expression, though PD-L1 expression was not significantly correlated with outcomes. This screening study found that increased density and proportion of CD8 + T cells expressing CD103 and decreased density of periplakin were associated with positive outcomes in patients with melanoma metastases treated with pembrolizumab and may warrant further study.

Methyl groups of trimethylamine N-oxide orient away from hydrophobic interfaces.

The molecular orientation of trimethylamine N-oxide (TMAO), a powerful protein stabilizer, was explored at aqueous/hydrophobic interfaces using vibrational sum frequency spectroscopy (VSFS). The systems studied included the octadecyltrichlorosilane (OTS)/water interface, which represents an aqueous solution in direct contact with a hydrophobic medium. Surprisingly, the measurements revealed that the methyl groups of TMAO pointed into the aqueous phase and away from the OTS. This orientation may arise from the more hydrophilic nature of methyl groups attached to a strongly electron-withdrawing atom such as a quaternary nitrogen. Additional studies were performed at the air/water interface. This interface showed a high degree of TMAO alignment, but the dangling OH from water was present even at 5 M TAMO. Moreover, the addition of this osmolyte modestly increased the surface tension of the interface. This meant that this species was somewhat depleted at the interface compared to the bulk solution. These findings may have implications for the stabilizing effect of TMAO on proteins. Specifically, the strong hydration required for the methyl groups as well as the oxide moiety should be responsible for the osmolyte's depletion from hydrophobic/aqueous interfaces. Such depletion effects should help stabilize proteins in their folded and native conformations on entropic grounds, although orientational effects may play an additional role.

Specific anion effects on water structure adjacent to protein monolayers.

Vibrational sum frequency spectroscopy (VSFS) was used to explore specific ion effects on interfacial water structure adjacent to a bovine serum albumin (BSA) monolayer adsorbed at the air/water interface. The subphase conditions were varied by the use of six different sodium salts and four different pH values. At pH 2 and 3, the protein layer was positively charged and it was found that the most chaotropic anions caused the greatest attenuation of water structure. The order of the salts followed an inverse Hofmeister series. On the other hand, when the protein layer was near its isoelectric point (pH 5), the most chaotropic anions caused the greatest increase in water structure, although the effect was weak. In this case, a direct Hofmeister series was obeyed. Finally, virtually no effect was observed when the protein layer was negatively charged with a subphase pH of 9. For comparison, similar experiments were run with positively charged, negatively charged, and zwitterionic surfactant monolayers. These experiments gave rise to nearly the identical results as the protein monolayer which suggested that specific anion effects are dominated by the charge state of the interfacial layer rather than its detailed chemical structure. In a final set of experiments, salt effects were examined with a monolayer made from an elastin-like polypeptide (ELP). The peptide consisted of 120 pentameric repeats of the sequence Val-Pro-Gly-Val-Gly. Data from this net neutral biopolymer followed a very weak, but direct Hofmeister series. This suggested that direct anion binding to the amide groups in the backbone of a polypeptide is quite weak in agreement with the BSA data. The results from the variously charged protein, surfactant, and polymer monolayers were compared with a modified Gouy-Chapman-Stern model. The agreement with this simple model was quite good.

Optimizing the use of anti-tumor necrosis factor in the management of patients with Crohn's disease.

Since the approval of the first anti-tumor necrosis factor (anti-TNF) therapy in late 1998, the treatment for Crohn's disease (CD) has been revolutionized. Anti-TNF therapy has been consistently shown in numerous clinical trials to be effective for patients with more aggressive perianal, internal penetrating, and fistulizing CD. However, the loss of clinical remission is frequent and only one-third of patients remain in clinical remission at 1 year. The pharmacokinetics of anti-TNF is highly variable among patients and could be influenced by many factors including serum albumin, gender, body weight, systemic inflammation and route of administration. The main factor impacting anti-TNF pharmacokinetics and efficacy is the development of immunogenicity where antidrug antibodies accelerate anti-TNF drug clearance. In this review paper, we evaluate the role of combination therapy with anti-TNF drugs and immunomodulators, the role of therapeutic drug monitoring, and strategies to recapture loss of clinical response in order to improve both short- and long-term outcomes in CD patients.

A Multi-Center Prospective Derivation and Validation of a Clinical Prediction Tool for Severe Clostridium difficile Infection.

BACKGROUND AND AIMS: Prediction of severe clinical outcomes in Clostridium difficile infection (CDI) is important to inform management decisions for optimum patient care. Currently, treatment recommendations for CDI vary based on disease severity but validated methods to predict severe disease are lacking. The aim of the study was to derive and validate a clinical prediction tool for severe outcomes in CDI. METHODS: A cohort totaling 638 patients with CDI was prospectively studied at three tertiary care clinical sites (Boston, Dublin and Houston). The clinical prediction rule (CPR) was developed by multivariate logistic regression analysis using the Boston cohort and the performance of this model was then evaluated in the combined Houston and Dublin cohorts. RESULTS: The CPR included the following three binary variables: age ≥ 65 years, peak serum creatinine ≥ 2 mg/dL and peak peripheral blood leukocyte count of ≥ 20,000 cells/µL. The Clostridium difficile severity score (CDSS) correctly classified 76.5% (95% CI: 70.87-81.31) and 72.5% (95% CI: 67.52-76.91) of patients in the derivation and validation cohorts, respectively. In the validation cohort, CDSS scores of 0, 1, 2 or 3 were associated with severe clinical outcomes of CDI in 4.7%, 13.8%, 33.3% and 40.0% of cases respectively. CONCLUSIONS: We prospectively derived and validated a clinical prediction rule for severe CDI that is simple, reliable and accurate and can be used to identify high-risk patients most likely to benefit from measures to prevent complications of CDI.

Mechanisms underlying capsaicin effects in canine coronary artery: implications for coronary spasm.

AIMS: The TRPV1, transient receptor potential vanilloid type 1, agonist capsaicin is considered to be beneficial for cardiovascular health because it dilates coronary arteries through an endothelial-dependent mechanism and may slow atheroma progression. However, recent reports indicate that high doses of capsaicin may constrict coronary arterioles and even provoke myocardial infarction. Thus far, the mechanisms by which TRPV1 activation modulates coronary vascular tone remain poorly understood. This investigation examined whether there is a synergistic interplay between locally acting vasoconstrictive pro-inflammatory hormones (autacoids) and capsaicin effects in the coronary circulation. METHODS AND RESULTS: Experiments were performed in canine conduit coronary artery rings and isolated smooth muscle cells (CASMCs). Isometric tension measurements revealed that 1-10 µM capsaicin alone did not affect resting tension of coronary artery rings. In contrast, in endothelium-intact rings pre-contracted with a Gq/11-coupled FP/TP (prostaglandin F/thromboxane) receptor agonist, prostaglandin F2α (PGF2α; 10 µM), capsaicin first induced transient dilation that was followed by sustained contraction. In endothelium-denuded rings pre-contracted with PGF2α or thromboxane analogue U46619 (1 µM, a TP receptor agonist), capsaicin induced only sustained contraction. Blockers of the TP receptor or TRPV1 significantly inhibited capsaicin effects, but these were still observed in the presence of 50 µM nifedipine and 70 mM KCl. Capsaicin also potentiated 20 mM KCl-induced contractions. Fluorescence imaging experiments in CASMCs revealed that the Gq/11-phospholipase C (PLC)-protein kinase C (PKC) and Ca(2+)-PLC-PKC pathways are likely involved in sensitizing CASMC TRPV1 channels. CONCLUSION: Capsaicin alone does not cause contractions in conduit canine coronary artery; however, pre-treatment with pro-inflammatory prostaglandin-thromboxane agonists may unmask capsaicin's vasoconstrictive potential.

Searching for evidence, not a war: reply to Lindquist, Siegel, Quigley, and Barrett (2013).

Lindquist, Siegel, Quigley, and Barrett (2013) critiqued our recent meta-analysis that reported the effects of discrete emotions on outcomes, including cognition, judgment, physiology, behavior, and experience (Lench, Flores, & Bench, 2011). Lindquist et al. offered 2 major criticisms-we address both and consider the nature of emotion and scientific debate. Their 1st criticism, that the meta-analysis did not demonstrate emotion-consistent and emotion-specific changes in outcomes, appears to have been based on a misunderstanding of the method that we employed. Changes in outcomes were coded according to predictions derived from a functional discrete emotion account. Their 2nd criticism, that the findings are consistent with a psychological constructionist approach to emotion, is partially supported by the data and our statements in Lench et al. (2011). However, only 1 meta-analytic finding is relevant to this hypothesis, and it does not offer unequivocal evidence. Further, we contend that no modern discrete emotion theories would make the claims described by Lindquist et al. as representing a "natural kind" perspective and that viewing a scientific debate as a war has negative implications for the ability to evaluate evidence.

The fast and the dangerous: the speed of events influences risk judgements.

A risk-as-feelings approach suggests that factors irrelevant to the potential risk can influence risk perception. This investigation focused on the speed of events as one such factor. Negative events that occur relatively quickly were judged as more likely to occur than events that occur more slowly. Speed influenced risk perception when it was salient and differences in risk perception were reduced when it was not salient. Further, the likelihood of a negative outcome was judged to be more likely when the same event was described as occurring relatively quickly compared to slowly. Even when only the speed at which information was presented changed, faster events were judged to be riskier than slower events. Theoretically, these findings suggest that speed of an event contributes to risk judgements and suggest speed may be the reason people fear fast but low incidence events and fail to fear slower but higher incidence events.

Role of carboxylate side chains in the cation Hofmeister series.

Thermodynamic and surface-specific spectroscopic investigations were carried with an elastin-like polypeptide (ELP) containing 16 aspartic acid residues. The goal was to explore the role of the carboxylate moieties in hydrophobic collapse and related Hofmeister effects. Experiments were conducted with a series of monovalent and divalent metal chloride salts. Both phase transition temperature and spectroscopic data demonstrated that the divalent cations showed relatively strong association to the carboxylate sites on the biopolymer with K(d) values in the range of 1 to 10 mM. The ordering of the divalent series was: Zn(2+) > Ca(2+) > Ba(2+) > Sr(2+) > Mg(2+). Monovalent cations displayed weaker binding which ranged from 78 mM for NH(4)(+) to 345 mM for Cs(+). The order for this series was: NH(4)(+) > Li(+) > Na(+) > NMe(4)(+) > K(+) > Rb(+) ≥ Cs(+). These results are in general agreement with the notion that strongly hydrated cations bind more tightly to carboxylate groups than do weakly hydrated cations. Moreover, the data for the monovalent series was partially consistent with the law of matching water affinity, although Li(+) and NH(4)(+) did not follow the model. The series for the divalent cations did not appear to obey the law of matching water affinity at all.

Discrete emotions predict changes in cognition, judgment, experience, behavior, and physiology: a meta-analysis of experimental emotion elicitations.

Our purpose in the present meta-analysis was to examine the extent to which discrete emotions elicit changes in cognition, judgment, experience, behavior, and physiology; whether these changes are correlated as would be expected if emotions organize responses across these systems; and which factors moderate the magnitude of these effects. Studies (687; 4,946 effects, 49,473 participants) were included that elicited the discrete emotions of happiness, sadness, anger, and anxiety as independent variables with adults. Consistent with discrete emotion theory, there were (a) moderate differences among discrete emotions; (b) differences among discrete negative emotions; and (c) correlated changes in behavior, experience, and physiology (cognition and judgment were mostly not correlated with other changes). Valence, valence-arousal, and approach-avoidance models of emotion were not as clearly supported. There was evidence that these factors are likely important components of emotion but that they could not fully account for the pattern of results. Most emotion elicitations were effective, although the efficacy varied with the emotions being compared. Picture presentations were overall the most effective elicitor of discrete emotions. Stronger effects of emotion elicitations were associated with happiness versus negative emotions, self-reported experience, a greater proportion of women (for elicitations of happiness and sadness), omission of a cover story, and participants alone versus in groups. Conclusions are limited by the inclusion of only some discrete emotions, exclusion of studies that did not elicit discrete emotions, few available effect sizes for some contrasts and moderators, and the methodological rigor of included studies.

Alternate site testing for hemoglobin A1C in children with diabetes.

PURPOSE: Alternate site testing is appropriate for blood glucose monitoring in euglycemic states, but use of alternate sites for collection of hemoglobin A1C has not been studied. The purpose of this study was to determine whether A1C results obtained from palm or forearm samples are equivalent to A1C results obtained from fingertip samples in a pediatric population. The secondary purposes were to determine whether there were differences in the perceived level of site pain and if there was a site preference. METHODS: Eighty-four children aged 5 to 20 years with type 1 or type 2 diabetes were randomly assigned to either fingertip and palm (N = 41) or fingertip and forearm (N = 40) groups. A1C samples were obtained in random order with 1 sample immediately following the other. RESULTS: Intraclass correlation coefficients were 0.99 for fingertip and palm, and 0.98 for fingertip and forearm. Paired t tests showed no differences between either set of values. Bland-Altman bias was minimal: -0.01% (95% confidence interval [CI], -0.07% to 0.05%) for the fingertip/palm comparison and 0.0% (95% CI, -0.001 to 0.001) for the fingertip/forearm comparison. The fingertip was preferred by 54.8%, the forearm by 25%, and the palm by 20.2% of the children. Pain ratings were lowest for the forearm followed by the fingertip and palm. CONCLUSIONS: Blood samples for measurement of A1C are clinically equivalent from the fingertip and palm or fingertip and forearm. Perceived pain was lowest when samples were obtained from the forearm. Just over half (54.8%) of the children preferred the fingertip.