Demonstration of Inappropriate Validation Method for a Cracker Baking Process Using Predictive Modeling.

Validation of baking processes for the inactivation of Salmonella is complicated by the combined effects of product heating and drying. The goal of this study was to quantitatively evaluate a previously disseminated approach to validating baking processes utilizing a predictive model developed using only isothermal and single-moisture inactivation data for the initially formulated dough. A simple cracker dough was formulated using flour inoculated with a five-strain cocktail of Salmonella. Side-by-side isothermal and baking experiments were performed to estimate Salmonella inactivation kinetics and to quantify survivors in a dynamic environment, respectively. Isothermal, single-moisture inactivation experiments were performed with cracker dough (water activity, aw = 0.956 ± 0.002; moisture content = 0.50 ± 0.01 dry basis) at three temperatures (56, 60, or 63°C) with ≥6 time intervals. Baking experiments were performed in a convection oven at 177°C with samples pulled every 30 s up to 360 s, with an endpoint product aw (25°C) of 0.45. The Salmonella isothermal, single-moisture inactivation kinetics in cracker dough resulted in D60°C and z-values of 4.6 min and 4.9°C, respectively; this model was then integrated over the dynamic product temperature profiles from the baking experiments. In the baking experiments, an average of 5-log reductions of Salmonella was achieved by 150 s of treatment; however, >100-log reductions were predicted by the dough-based models at that time point. This fail-dangerous overestimation of Salmonella lethality in crackers explicitly demonstrated that single-level moisture-based prediction models are inappropriate for describing inactivation in a process with both dynamic temperature and moisture, and that model-based validations must incorporate moisture/aw. Furthermore, end-users should exercise caution when utilizing unvalidated models to validate preventive control processes.

Clinical use of progesterone in human sperm preparation media for increasing IVF success.

RESEARCH QUESTION: Can the addition of progesterone and neurotensin, molecular agents found in the female reproductive tract, after sperm washing increase the fertilization potential of human spermatozoa? DESIGN: (i) Cohort study of 24 men. Spermatozoa selected by swim-up were incubated in either progesterone or neurotensin (0.1-100 µM) for 1-4 h, and hyperactive motility and binding to hyaluronan (0.1-100 µM) were assessed. The effect of progesterone 10 µM on sperm function was assessed in a blinded manner, including: hyperactive motility, binding to hyaluronan, tyrosine phosphorylation, acrosome reaction and oxidative DNA damage. (i) Embryo safety testing [one-cell mouse embryo assay (MEA), endotoxin and sterility counts (n = 3)] in preclinical embryo models of IVF (murine and porcine, n = 7 each model) and a small preliminary human study (n = 4) of couples undergoing standard IVF with oocytes inseminated with spermatozoa ± 10 µM progesterone. RESULTS: Progesterone 10 µM increased sperm binding to hyaluronan, hyperactive motility and tyrosine phosphorylation (all P < 0.05). Neurotensin had no effect (P > 0.05). Progesterone 10 µM in human embryo culture media passed embryo safety testing (MEA, endotoxin concentration and sterility plate count). In preclinical models of IVF, the exposure of spermatozoa to progesterone 10 µM and oocytes to progesterone 1 µM was not detrimental, and increased the fertilization rate in mice and the blastocyst cell number in mice and pigs (all P ≤ 0.03). In humans, every transferred blastocyst that had been produced from spermatozoa exposed to progesterone resulted in a live birth. CONCLUSION: The addition of progesterone to sperm preparation media shows promise as an adjunct to current methods for increasing fertilization potential. Randomized controlled trials are required to determine the clinical utility of progesterone for improving IVF outcomes.

Impact of bariatric surgery, lifestyle change, and pharmacotherapy on fertility in men with obesity: a systematic review protocol.

OBJECTIVE: This review will determine whether various health interventions designed to reduce weight (lifestyle change, bariatric surgery, pharmacotherapy) in men with obesity are associated with improved fertility markers. The review will also establish whether the degree of weight loss achieved through these methods is associated with improvement. BACKGROUND: Current preconception guidelines provide limited information for men with obesity. Small studies implementing lifestyle changes in men are associated with improvement in sperm quality, whereas bariatric surgery has not been associated with improvements in sperm quality. Determining the benefit of different interventions and the relationship to weight lost is necessary to optimize male fertility. INCLUSION CRITERIA: The population will be men < 50 years who are either overweight (BMI > 25 kg/m2) or obese (BMI > 30 kg/m2). The exposure of interest will be an intervention undertaken to improve health or reduce weight, categorized as lifestyle change, bariatric surgery, or pharmacotherapy. Outcomes will include time to conception, fecundity rate, assisted reproduction outcomes, and semen quality measures. Secondary analysis will determine whether degree of weight loss achieved is associated with degree of improvement. METHODS: This review will follow the JBI methodology for systematic reviews of etiology and risk. Databases to be searched will include PubMed, Embase (Ovid), Cochrane Central Register of Controlled Trials, Web of Science, and Scopus. Articles not translated into English will be excluded. Methodological quality will be assessed using the JBI critical appraisal tools. Data will be extracted using a standardized tool developed by the reviewers. Statistical meta-analysis will be performed where possible to synthesize outcomes of similar methods. REVIEW REGISTRATION NUMBER: PROSPERO CRD 42022349665.

The influence of lifestyle and biological factors on semen variability.

PURPOSE: Semen parameters are subjected to within-individual variability over time. The driving factors for this variability are likely multi-factorial, with healthier lifestyle associated with better semen quality. The extent in which variations in individual's lifestyle contributes to within-individual semen variability is unknown. METHODS: A total of 116 repeat semen samples from 29 men aged 19-37 over 6 months were collected. Basic semen analysis as per 5th WHO manual and extended semen parameters (sperm DNA fragmentation, redox potential and lipid peroxidation, sperm binding to hyaluronan and hyperactive motility) were assessed. An additional 39 lifestyle/biological factors (weight, blood pressure, etc.) were collected at each sample including validated health questionnaires SF36 Health Status, Australian Recommend Food Score, and International Physical Activity Questionnaire. RESULTS: Only 10 out of the 39 lifestyle factors varied within men across samples including age (P = 0.0024), systolic blood pressure (P = 0.0080), social functioning (P = 0.0340), energy (P = 0.0069), non-alcoholic caffeinated beverages (P = 0.0010), and nutrition (P < 0.0001). The only semen parameter that varied between collections was sperm morphology (coefficient of variation 23.8 (6.1-72.0), P < 0.05). We only observed weak (r < 0.3) to moderate (r > 0.3- < 0.6) correlations between lifestyle factors, including body mass index, waist circumference, nutrition, exercise, blood pressure and semen parameters including sperm count, progressive motility, and sperm DNA fragmentation (P < 0.05). CONCLUSION: In healthy men from the general population, semen quality and associated lifestyle factors do not significantly vary over 6 months, indicating that one semen sample is likely sufficient for determining male fertility in this population.

Assessing the influence of preconception diet on male fertility: a systematic scoping review.

BACKGROUND: The last decade has seen increased research on the relationship between diet and male fertility, but there are no clearly defined nutritional recommendations for men in the preconception period to support clinical fertility outcomes. OBJECTIVE AND RATIONALE: The purpose of this scoping review is to examine the extent and range of research undertaken to evaluate the effect(s) of diet in the preconception period on male clinical fertility and reproductive outcomes. SEARCH METHODS: Four electronic databases (MEDLINE and EMBASE via Ovid, CAB Direct, and CINAHL via EBSCO) were searched from inception to July 2023 for randomized controlled trials (RCTs) and observational studies (prospective/retrospective, case-control, and cross-sectional). Intervention studies in male participants or couples aiming to achieve dietary or nutritional change, or non-intervention studies examining dietary or nutritional components (whole diets, dietary patterns, food groups or individual foods) in the preconception period were included. Controls were defined as any comparison group for RCTs, and any/no comparison for observational studies. Primary outcomes of interest included the effect(s) of male preconception diet on clinical outcomes such as conception (natural or via ART), pregnancy rates and live birth rates. Secondary outcomes included time to conception and sperm parameters. OUTCOMES: A total of 37 studies were eligible, including one RCT and 36 observational studies (prospective, cross-sectional, and case-control studies; four studies in non-ART populations) published between 2008 and 2023. Eight reported clinical outcomes, 26 reported on secondary outcomes, and three reported on both. The RCT did not assess clinical outcomes but found that tomato juice may benefit sperm motility. In observational studies, some evidence suggested that increasing fish or reducing sugar-sweetened beverages, processed meat or total fat may improve fecundability. Evidence for other clinical outcomes, such as pregnancy rates or live birth rates, showed no relationship with cereals, soy and dairy, and inconsistent relationships with consuming red meat or a 'healthy diet' pattern. For improved sperm parameters, limited evidence supported increasing fish, fats/fatty acids, carbohydrates and dairy, and reducing processed meat, while the evidence for fruits, vegetables, cereals, legumes, eggs, red meat and protein was inconsistent. Healthy diet patterns in general were shown to improve sperm health. WIDER IMPLICATIONS: Specific dietary recommendations for improving male fertility are precluded by the lack of reporting on clinical pregnancy outcomes, heterogeneity of the available literature and the paucity of RCTs to determine causation or to rule out reverse causation. There may be some benefit from increasing fish, adopting a healthy dietary pattern, and reducing consumption of sugar-sweetened beverages and processed meat, but it is unclear whether these benefits extend beyond sperm parameters to improve clinical fertility. More studies exploring whole diets rather than singular foods or nutritional components in the context of male fertility are encouraged, particularly by means of RCTs where feasible. Further assessment of core fertility outcomes is warranted and requires careful planning in high-quality prospective studies and RCTs. These studies can lay the groundwork for targeted dietary guidelines and enhance the prospects of successful fertility outcomes for men in the preconception period. Systematic search of preconception diet suggests that increasing fish and reducing sugary drinks, processed meats and total fat may improve male fertility, while consuming healthy diets, fish, fats/fatty acids, carbohydrates and dairy and reducing processed meat can improve sperm health.

Improved fertilization, degeneration, and embryo quality rates with PIEZO-intracytoplasmic sperm injection compared with conventional intracytoplasmic sperm injection: a sibling oocyte split multicenter trial.

OBJECTIVE: To investigate whether PIEZO-intracytoplasmic sperm injection (PIEZO-ICSI) increases the fertilization rate, decreases the degeneration rate, and increases the utilization rate per oocyte injected compared with conventional intracytoplasmic sperm injection (ICSI). DESIGN: Sibling oocyte split multicenter trial. SETTING: Fertility clinics. PATIENTS: Women with a diagnosis of infertility who used ICSI as their method of insemination and had ≥6 mature oocytes for injection. INTERVENTIONS: Participants had their mature oocyte cohort divided, where half were injected using conventional ICSI and the other half were injected using PIEZO-ICSI. For patients with an uneven oocyte number, the extra oocyte was injected using conventional ICSI. The injection technique used first was also randomized to ensure that there was no bias due to order of injection. MAIN OUTCOME MEASURE: The primary outcome measure was the fertilization rate after injection. RESULTS: A total of 108 patients underwent a sibling split use of conventional ICSI and PIEZO-ICSI. The fertilization rate was 71.6% in PIEZO-ICSI, which significantly increased compared with that in conventional ICSI 65.6%. In addition, the oocyte degeneration rate decreased in PIEZO-ICSI compared with that in conventional ICSI (6.3% vs. 12.1% respectively), and the blastocyst quality increased, as measured by the number of grade A and B quality blastocysts present on day 5 of development (33.3% vs. 27.5%). No significant differences in the aneuploidy or utilization rate, clinical pregnancy, or live birth outcome after single embryo transfer were noted between the two injection techniques. CONCLUSIONS: This trial supports the possibility that PIEZO-ICSI increases the fertilization rates, decreases the oocyte degeneration rates, and increases the blastocyst quality compared with conventional ICSI; however, it does not appear to influence the clinical pregnancy or live birth rate per transfer. CLINICIAN TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trial Registry ACTRN12620000407998.

Sexual Exposures Associated With Mpox Infection: California, November 2022 to June 2023.

BACKGROUND: Exposures associated with mpox infection remain imperfectly understood. METHODS: We conducted a case-control study enrolling participants who received molecular tests for mpox/orthopoxvirus in California from November 2022 through June 2023. We collected data on behaviors during a 21-day risk period before symptom onset or testing among mpox case patients and test-negative controls. RESULTS: Thirteen of 54 case patients (24.1%) and 5 of 117 controls (4.3%) reported sexual exposure to individuals they identified as potential mpox case patients ("index contacts"; odds ratio [OR], 7.7 [95% confidence interval (CI), 2.5-19.3] relative to individuals who did not report exposure to potential mpox case patients). Among these participants, 10 of 13 case patients (76.9%) and 2 of 5 controls (40.0%) reported that their index contacts were not experiencing symptoms visible to participants during sex (OR, 14.9 [95% CI, 3.6-101.8]). Only 3 of 54 case patients (5.6%) reported exposure to symptomatic index contacts. Case patients reported more anal/vaginal sex partners than did controls (adjusted OR, 2.2 [95% CI, 1.0-4.8] for 2-3 partners and 3.8 [1.7-8.8] for ≥4 partners). Male case patients with penile lesions more commonly reported insertive anal/vaginal sex than those without penile lesions (adjusted OR, 9.3 [95% CI, 1.6-54.8]). Case patients with anorectal lesions more commonly reported receptive anal sex than those without anorectal lesions (adjusted OR, 14.4 [95% CI, 1.0-207.3]). CONCLUSIONS: Sexual exposure to contacts known or suspected to have experienced mpox was associated with increased risk of infection, often when index contacts lacked apparent symptoms. Exposure to more sex partners, including those whom participants did not identify as index contacts, was associated with increased risk of infection in a site-specific manner. While participants' assessment of symptoms in partners may be imperfect, these findings suggest that individuals without visibly prominent mpox symptoms transmit infection.

"No One Asked Me If I'm Alright": A Mixed-Methods Study Exploring Information/Support Needs and Challenges Engaging Men Diagnosed With Male-Factor Infertility.

There is limited research exploring men's experiences of infertility, and fewer previous studies have examined what information and support men desire after being diagnosed specifically with male-factor infertility. We conducted a mixed-methods study utilizing a combined sequential, concurrent design (online survey/semi-structured interviews). Survey outcomes (N =12) were analyzed using quantitative data analysis, while qualitative survey data (N = 5) was analyzed by reflexive thematic analysis. Heterosexual men (>18 years), fluent in English, diagnosed solely with male-factor infertility/sub-fertility, who required assisted reproductive treatment within Australia in the past 5 years were recruited online and through fertility clinics Australia-wide. Most men reported that their information and support needs were only somewhat, slightly or not at all met. Preferred information sources on male infertility were a dedicated online resource, app, or fertility doctor/specialist, while support was preferred from fertility specialists and partners. Three themes were identified from the qualitative analysis about men's experiences and support needs when diagnosed with male infertility (a) Ultimate threat to masculinity; (b) Holistic care, and (c) the power of words. The information-rich data collected provided valuable insights into men's experiences of male-factor infertility and important considerations to improve recruitment for future research. A diagnosis of male-factor infertility has the potential to be deeply impactful and difficult to navigate for men. Adequate and holistic information, recognition of emotional impacts, proactive offers of support and sensitive language are needed to improve men's experiences when undergoing assisted reproductive technology.

Phase Ib study of HSP90 inhibitor, onalespib (AT13387), in combination with paclitaxel in patients with advanced triple-negative breast cancer.

Background: Heat shock protein 90 (HSP90) is a molecular chaperone required for stabilization of client proteins over-activated in triple-negative breast cancer (TNBC). Over-expression of HSP90 client proteins has been implicated in paclitaxel resistance. Onalespib (AT13387) is a potent inhibitor of HSP90 that could improve paclitaxel efficacy when administered in combination. Design: This phase Ib trial administered onalespib with paclitaxel in patients with advanced TNBC to assess safety and establish a recommended phase II dose (RP2D). Objectives: The primary objectives were determining the dose-limiting toxicities and maximum tolerated dose of combination therapy. Secondary objectives included pharmacokinetic (PK) analysis and determination of overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Methods: Patients with advanced TNBC were treated with standard dose intravenous paclitaxel in combination with intravenous onalespib at doses ranging from 120 to 260 mg/m2 administered on days 1, 8, and 15 of a 28-day cycle using a standard 3 + 3 design. A total of 15 patients were enrolled to dose expansion cohort at RP2D to confirm safety profile. Results: Thirty-one patients were enrolled in the study, of which over 90% had received prior taxane therapy. Paclitaxel was given for metastatic disease in 23% of patients. Adverse events (AEs) included anemia (grade 3: 20%), lymphopenia (grade 3: 17%), and neutropenia (grade 3: 33%, grade 4: 4%). The most frequent grade ⩾3 non-hematologic AE was diarrhea (7%). The established RP2D was 260 mg/m2 onalespib when given with paclitaxel at 80 mg/m2. PK analysis revealed a modest drug interaction profile for onalespib in the combination regimen. ORR was 20%. Three patients achieved complete responses, all of whom had received prior taxane therapy. Median DOR was 5.6 months; median PFS was 2.9 months. Conclusion: Combination treatment with onalespib and paclitaxel had an acceptable toxicity profile and RP2D was determined to be 260 mg/m2 of onalespib. Combination therapy showed antitumor activity in patients with advanced TNBC. Trial registration: Onalespib and paclitaxel in treating patients with advanced TNBC https://clinicaltrials.gov/ct2/show/NCT02474173.

Phase 1b study of HSP90 inhibitor called onalespib in combination with paclitaxel in patients with advanced triple-negative breast cancer This Phase 1b study demonstrated that treatment with a combination of onalespib and paclitaxel was reasonably well tolerated by most patients. Onalespib at 260 mg/m² given intravenously on days 1, 8 and 15 on 28-day cycles in combination with standard dose and schedule of paclitaxel was established as the recommended phase 2 dose for further clinical development. Despite minor drug-drug interactions between these 2 agents, onalespib did not alter paclitaxel exposure and paclitaxel did not affect exposure to onalespib. While onalespib with paclitaxel combination therapy did not yield durable objective responses or prolonged progression-free survival, there were several patients with long-lasting benefit from this combination including patients who previously experienced progression on taxane therapy.

Depression, Inflammation, and Intestinal Permeability: Associations with Subjective and Objective Cognitive Functioning throughout Breast Cancer Survivorship.

About one-in-three breast cancer survivors have lingering cognitive complaints and objective cognitive impairment. Chronic inflammation and intestinal permeability (i.e., leaky gut), two risk factors for cognitive decline, can also fuel depression-another vulnerability for cognitive decline. The current study tested whether depression accompanied by high levels of inflammation or intestinal permeability predicted lower subjective and objective cognitive function in breast cancer survivors. We combined data from four breast cancer survivor studies (n = 613); some had repeated measurements for a total of 1015 study visits. All participants had a blood draw to obtain baseline measures of lipopolysaccharide binding protein-a measure of intestinal permeability, as well as three inflammatory markers that were incorporated into an inflammatory index: C-reactive protein, interleukin-6, and tumor necrosis factor-α. They reported depressive symptoms on the Center for Epidemiological Studies depression scale (CES-D), and a binary variable indicated clinically significant depressive symptoms (CES-D ≥ 16). The Kohli (749 observations) and the Breast Cancer Prevention Trial (591 observations) scales assessed subjective cognitive function. Objective cognitive function tests included the trail-making test, Hopkins verbal learning test, Conners continuous performance test, n-back test, FAS test, and animal-naming test (239-246 observations). Adjusting for education, age, BMI, cancer treatment type, time since treatment, study visit, and fatigue, women who had clinically elevated depressive symptoms accompanied by heightened inflammation or intestinal permeability reported poorer focus and marginally poorer memory. However, poorer performance across objective cognitive measures was not specific to inflammation-associated depression. Rather, there was some evidence of lower verbal fluency; poorer attention, verbal learning and memory, and working memory; and difficulties with visuospatial search among depressed survivors, regardless of inflammation. By themselves, inflammation and intestinal permeability less consistently predicted subjective or objective cognitive function. Breast cancer survivors with clinically significant depressive symptoms accompanied by either elevated inflammation or intestinal permeability may perceive greater cognitive difficulty, even though depression-related objective cognitive deficits may not be specific to inflammation- or leaky-gut-associated depression.

IκBζ is an essential mediator of immunity to oropharyngeal candidiasis.

Fungal infections are a global threat; yet, there are no licensed vaccines to any fungal pathogens. Th17 cells mediate immunity to Candida albicans, particularly oropharyngeal candidiasis (OPC), but essential downstream mechanisms remain unclear. In the murine model of OPC, IκBζ (Nfkbiz, a non-canonical NF-κB transcription factor) was upregulated in an interleukin (IL)-17-dependent manner and was essential to prevent candidiasis. Deletion of Nfkbiz rendered mice highly susceptible to OPC. IκBζ was dispensable in hematopoietic cells and acted partially in the suprabasal oral epithelium to control OPC. One prominent IκBζ-dependent gene target was ß-defensin 3 (BD3) (Defb3), an essential antimicrobial peptide. Human oral epithelial cells required IκBζ for IL-17-mediated induction of BD2 (DEFB4A, human ortholog of mouse Defb3) through binding to the DEFB4A promoter. Unexpectedly, IκBζ regulated the transcription factor Egr3, which was essential for C. albicans induction of BD2/DEFB4A. Accordingly, IκBζ and Egr3 comprise an antifungal signaling hub mediating mucosal defense against oral candidiasis.

Inflamed but not impulsive: Acute inflammatory cytokine response does not impact prepotent response inhibition.

BACKGROUND: Prior evidence has linked inflammation with impulsivity, but most of this evidence is cross-sectional. In this study, we provoked an acute inflammatory cytokine response to see whether it lowered prepotent response inhibition on three cognitive tasks. METHOD: This study features secondary analyses from a randomized crossover trial in which 171 postmenopausal breast cancer survivors (Stage I-IIIA) each received a typhoid capsular polysaccharide vaccination and a saline placebo injection in a random sequence at two separate visits at least one month apart. Participants completed the Stroop Color-Discrepant Task, the 2-back, and the Conners Continuous Performance Test (CPT) on the computer between 5 and 7 h after the injections. They had their blood drawn once before and repeatedly after the injection to measure interleukin-1 receptor antagonist and interleukin-6 responses. RESULTS: Women committed marginally fewer errors on the Stroop color-discrepant trials after the typhoid vaccine (M = 0.36, SE = 0.08), compared to placebo (M = 0.54, SE = 0.09, p = .076). Injection type did not predict 2-back accuracy (p = .80) or CPT commission errors (p = .47). Inflammatory cytokine responses were also unrelated to the outcomes of interest (ps>.16). CONCLUSION: We found no evidence that an acute inflammatory cytokine response provokes response disinhibition - an important facet of impulsivity. In fact, our only marginally non-significant result suggested that women were better able to inhibit their prepotent responses on the Stroop after receiving the typhoid vaccine, compared to placebo. Further experimental tests of the acute inflammatory cytokine response's effect on other aspects of impulsivity are warranted. LIMITATIONS: The sample was female, primarily White, highly educated cancer survivors, and recruitment was not premised on impulsive traits or diagnosis with an impulsive-related disorder. Also, there are many facets of impulsivity, and this study only measured response inhibition.

SARS-CoV-2 ORF8 Mediates Signals in Macrophages and Monocytes through MyD88 Independently of the IL-17 Receptor.

SARS-CoV-2 has caused an estimated 7 million deaths worldwide to date. A secreted SARS-CoV-2 accessory protein, known as open reading frame 8 (ORF8), elicits inflammatory pulmonary cytokine responses and is associated with disease severity in COVID-19 patients. Recent reports proposed that ORF8 mediates downstream signals in macrophages and monocytes through the IL-17 receptor complex (IL-17RA, IL-17RC). However, generally IL-17 signals are found to be restricted to the nonhematopoietic compartment, thought to be due to rate-limiting expression of IL-17RC. Accordingly, we revisited the capacity of IL-17 and ORF8 to induce cytokine gene expression in mouse and human macrophages and monocytes. In SARS-CoV-2-infected human and mouse lungs, IL17RC mRNA was undetectable in monocyte/macrophage populations. In cultured mouse and human monocytes and macrophages, ORF8 but not IL-17 led to elevated expression of target cytokines. ORF8-induced signaling was fully preserved in the presence of anti-IL-17RA/RC neutralizing Abs and in Il17ra-/- cells. ORF8 signaling was also operative in Il1r1-/- bone marrow-derived macrophages. However, the TLR/IL-1R family adaptor MyD88, which is dispensable for IL-17R signaling, was required for ORF8 activity yet MyD88 is not required for IL-17 signaling. Thus, we conclude that ORF8 transduces inflammatory signaling in monocytes and macrophages via MyD88 independently of the IL-17R.

Worry and Mindfulness Differentially Impact Symptom Burden Following Treatment Among Breast Cancer Survivors: Findings From a Randomized Crossover Trial.

BACKGROUND: Breast cancer survivors often experience many somatic and cognitive side effects resulting from their cancer diagnosis and treatment, including higher rates of pain, fatigue, and memory/concentration problems. Emotion regulation offers opportunities to either enhance or dampen physical health. PURPOSE: In a secondary analysis of a double-blind randomized controlled trial (RCT) using a typhoid vaccine to assess factors associated with breast cancer survivors' inflammatory responses, we assessed how two specific aspects of emotion regulation, mindfulness, and worry, corresponded to acute changes in focus problems, memory problems, and fatigue along with performance on pain sensitivity and cognitive tasks across two visits among breast cancer survivors. METHODS: Breast cancer survivors (N = 149) completed two 8.5-hr visits at a clinical research center. Survivors were randomized to either the vaccine/saline placebo or a placebo/vaccine sequence. Worry and mindfulness questionnaires provided data on trait-level emotion regulation abilities. Fatigue, memory problems, and focus difficulties were assessed via Likert scales six times-once before the injections and then every 90 min for 7.5 hr thereafter. Women also completed a pain sensitivity task and several cognitive tasks at each visit. RESULTS: Findings from this study showed that breast cancer survivors who worried more and were less mindful experienced subjective memory problems, focus problems, and cold pain sensitivity across two visits and irrespective of injection type. Lower mindfulness also corresponded to higher subjective fatigue and hot pain sensitivity and objective ratings. Emotion regulation skills did not predict objective pain sensitivity or cognitive problems. CONCLUSION: Results from this study highlight the benefits of adaptive emotion regulation in helping mitigate symptoms associated with breast cancer survivorship.

Breast cancer survivors experience side effects resulting from their cancer diagnosis and treatment, including higher rates of pain, fatigue, and memory/concentration problems. Emotion regulation offers the possibility to either better or worse physical health. This study assessed how two emotion regulation strategies, mindfulness and worry, corresponded to changes in focus problems, memory problems, and fatigue along with performance on pain sensitivity and cognitive tasks across two visits among breast cancer survivors. A total of 149 survivors completed 2 day-long visits in the laboratory where they rated their fatigue and memory problems six times across the day, completed cognitive tests, and a pain sensitivity test. Findings from this study showed that breast cancer survivors who worried more and were less mindful experienced subjective memory problems, focus problems, and cold pain sensitivity across two visits. Emotion regulation skills did not predict objective pain sensitivity or cognitive problems. Results from this study highlight the benefits of adaptive emotion regulation skills like mindfulness in helping improve the cognitive and physical symptoms commonly experienced by breast cancer survivorship.

Comparing 7-Day Versus 6-8-Day Penicillin Treatment Intervals Among Pregnant People With Syphilis of Late or Unknown Duration: No Difference Found in Incidence of Congenital Syphilis.

Background: Guidelines recommend that pregnant patients with syphilis of late/unknown duration be treated with benzathine penicillin G, dosed as 3 weekly intramuscular injections (BPGx3) given ideally at strict 7-day intervals. Given limited pharmacokinetic data, it is unknown whether more flexible BPG treatment intervals might be effective in preventing congenital syphilis (CS). Methods: We used California surveillance data to identify birthing parent/infant dyads wherein the pregnant parent had syphilis of late/unknown duration between January 1, 2016 - June 30, 2019. We divided the dyads into 3 groups based on prenatal treatment: (1) BPGx3 at strict 7-day intervals, (2) BPGx3 at 6-8 day intervals, and (3) no/inadequate treatment. We then compared CS incidence among infants in each group. Results: We analyzed 1,092 parent/infant dyads: 607 (55.6%) in the 7-day treatment group, 70 (6.4%) in the 6-8 day treatment group, and 415 (38.0%) in the no/inadequate treatment group. The incidence proportion of infants meeting CS criteria in each group was, respectively, 5.6%, 5.7%, and 36.9%. Compared with BPGx3 at 7-day intervals, the odds of CS were 1.0 [95% CI 0.4-3.0] in the 6-8 day group and 9.8 [95% CI 6.6-14.7] in the no/inadequate treatment group. Conclusions: Prenatal BPGx3 at 6-8 days was no more likely to lead to CS in infants than 7-days. These findings hint that 6-8-day intervals might be adequate to prevent CS among pregnant people with syphilis of late/unknown duration. Consequently, it is possible that CS evaluation beyond an RPR at delivery may be unnecessary in asymptomatic infants whose parents received BPGx3 at 6-8 days.

64-year-old woman • hot flashes, facial flushing, excessive sweating, and palpitations • daily headaches • history of hypertension • Dx?

► hot flashes, facial flushing, excessive sweating, and palpitations ► daily headaches ► history of hypertension.

Culturally-tailored cookbook for promoting positive dietary change among hypertensive Filipino Americans: a pilot study.

Introduction: Among all Asian American subgroups, Filipino-Americans have consistently been shown to have the highest rates of hypertension, raising risks of heart attack and stroke. Despite this alarming fact, little has been done to investigate culturally-sensitive interventions to control hypertension rates in this vulnerable population. To address the lack of culturally-relevant lifestyle options for blood pressure management currently available to the Filipino community, this exploratory pilot study used a design thinking approach informed by culinary medicine to develop a culturally-tailored, heart-healthy, and low sodium recipe cookbook for Filipino Americans with hypertension and evaluate its feasibility as a hypertension intervention. Methods: Our team developed a cookbook using participatory methods and design thinking, utilizing input from five Filipino culinary experts and a Registered Dietitian. The cookbook incorporates traditional Filipino recipes, excerpts from community members' interviews, and nutrient analyses. Twenty Filipinx-identifying individuals* who self-reported physician-diagnosed hypertension were recruited from Filipino community-based organizations, enrolled into this study, provided with the cookbook, and asked to cook at least one recipe. Pre- and post-intervention surveys were conducted and centered around behavior change and features of the cookbook. Results: This study provided evidence for the cookbook's acceptability and feasibility, with participants' open-ended responses revealing that the recipes, nutrition labels, illustrations, and cultural aspects of the cookbook increased motivation to achieve dietary change, including reducing sodium in their diet to improve their blood pressure. Participant responses also indicated positive behavior change as a result of using the cookbook, with participants reporting increased likelihood of adopting recommended actions to lower their BP after utilizing the cookbook ( x ¯ = 80.83%), compared to before ( x ¯ = 63.75%, p < 0.008), according to Hypertension Self-Care Management scaled scores. Discussion: In conclusion, the results of this pilot study demonstrated acceptability of this unique cookbook and provide preliminary findings consistent with increased motivation in participants to make dietary changes and improve personal health, drawing attention to the importance of considering future culturally-tailored health interventions. Next steps should include a robust, randomized controlled trial design comparing measured blood pressure outcomes of an intervention vs. control group. *Filipinx is an inclusive term representing the gender identities of all participants in our study.

EGR1 regulates oral epithelial cell responses to Candida albicans via the EGFR- ERK1/2 pathway.

Candida albicans is a fungal pathobiont colonising mucosal surfaces of the human body, including the oral cavity. Under certain predisposing conditions, C. albicans invades mucosal tissues activating EGFR-MAPK signalling pathways in epithelial cells via the action of its peptide toxin candidalysin. However, our knowledge of the epithelial mechanisms involved during C. albicans colonisation is rudimentary. Here, we describe the role of the transcription factor early growth response protein 1 (EGR1) in human oral epithelial cells (OECs) in response to C. albicans. EGR1 expression increases in OECs when exposed to C. albicans independently of fungal viability, morphology, or candidalysin release, suggesting EGR1 is involved in the fundamental recognition of C. albicans, rather than in response to invasion or 'pathogenesis'. Upregulation of EGR1 is mediated by EGFR via Raf1, ERK1/2 and NF-κB signalling but not PI3K/mTOR signalling. Notably, EGR1 mRNA silencing impacts on anti-C. albicans immunity, reducing GM-CSF, IL-1α and IL-1ß release, and increasing IL-6 and IL-8 production. These findings identify an important role for EGR1 in priming epithelial cells to respond to subsequent invasive infection by C. albicans and elucidate the regulation circuit of this transcription factor after contact.

A troubled heart: Mood disorder history longitudinally predicts faster cardiopulmonary aging in breast cancer survivorship.

OBJECTIVE: Breast cancer survivors live longer due to more advanced cancer treatments; however, cardiovascular disease (CVD) is the leading non-cancer cause of death in breast cancer survivors. Previous studies have shown that depression is associated with an increased risk of CVD development. This study investigated whether depressive symptoms or mood disorder history, either independently or in combination with cardiotoxic treatments, predicted older cardiopulmonary age using a novel index-the Age Based on Exercise Stress Test (ABEST)-among breast cancer survivors. METHODS: Breast cancer survivors (N = 80, ages 26-72, stage I-IIIA) were assessed an average of 53 days (SD = 26) post-surgery, but before adjuvant treatment, and again an average of 32 (SD = 6) months thereafter. At both visits, they reported depressive symptoms on the Center for Epidemiologic Studies Depression Scale (CES-D), completed the Structured Clinical Interview for DSM-V, and engaged in an exercise stress test to obtain ABEST scores. RESULTS: Controlling for treatment type, age, education, trunk fat, antidepressant use, and time between visits, longitudinal analyses showed that breast cancer survivors with a mood disorder history had worsening ABEST scores over time, compared to their peers without this history (p = .046). Change in physical activity between Visits 1 and 2 did not mediate this relationship (95% CI: -0.16-0.51). Ancillary analyses provided some additional support for the primary finding, such that those with a mood disorder history trended toward greater decreases in Vo2max, although results were marginally non-significant (p = .095). There were no cross-sectional relationships between depressive symptoms or mood disorder history and ABEST scores (ps>.20). Treatment type did not modulate observed relationships (ps>.22). CONCLUSIONS: Breast cancer survivors with a mood disorder history may experience faster cardiopulmonary aging compared to their peers without such a history, raising risk for CVD.

Conflicts hurt: social stress predicts elevated pain and sadness after mild inflammatory increases.

ABSTRACT: Individuals respond differently to inflammation. Pain, sadness, and fatigue are common correlates of inflammation among breast cancer survivors. Stress may predict response intensity. This study tested whether breast cancer survivors with greater exposure to acute or chronic social or nonsocial stress had larger increases in pain, sadness, and fatigue during an acute inflammatory response. In total, 156 postmenopausal breast cancer survivors (ages 36-78 years, stage I-IIIA, 1-9 years posttreatment) were randomized to either a typhoid vaccine/saline placebo or the placebo/vaccine sequence, which they received at 2 separate visits at least 1 month apart. Survivors had their blood drawn every 90 minutes for the next 8 hours postinjection to assess levels of interleukin-6 and interleukin-1 receptor antagonist (IL-1Ra). Shortly after each blood draw, they rated their current levels of pain, sadness, and fatigue. Women also completed the Test of Negative Social Exchange to assess chronic social stress and the Trier Inventory of Chronic Stressors screen to index chronic general stress. At each visit, a trained experimenter administered the Daily Inventory of Stressful Events to assess social and nonsocial stress exposure within the past 24 hours. After statistical adjustment for relevant demographic and behavioral covariates, the most consistent results were that survivors who reported more chronic social stress reported more pain and sadness in response to IL-1Ra increases. Frequent and ongoing social stress may sensitize the nervous system to the effects of inflammation, with potential implications for chronic pain and depression risk among breast cancer survivors.