Short-term Dorsal Genital Nerve Stimulation Increases Subjective Arousal in Women With and Without Spinal Cord Injury: A Preliminary Investigation.

OBJECTIVES: Female sexual dysfunction (FSD) affects an estimated 40% of women. Unfortunately, FSD is understudied, leading to limited treatment options for FSD. Neuromodulation has shown some success in alleviating FSD symptoms. We developed a pilot study to investigate the short-term effect of electrical stimulation of the dorsal genital nerve and tibial nerve on sexual arousal in healthy women, women with FSD, and women with spinal cord injury (SCI) and FSD. MATERIALS AND METHODS: This study comprises a randomized crossover design in three groups: women with SCI, women with non-neurogenic FSD, and women without FSD or SCI. The primary outcome measure was change in vaginal pulse amplitude (VPA) from baseline. Secondary outcome measures were changes in subjective arousal, heart rate, and mean arterial pressure from baseline. Participants attended one or two study sessions where they received either transcutaneous dorsal genital nerve stimulation (DGNS) or tibial nerve stimulation (TNS). At each session, a vaginal photoplethysmography sensor was used to measure VPA. Participants also rated their level of subjective arousal and were asked to report any pelvic sensations. RESULTS: We found that subjective arousal increased significantly from before to after stimulation in DGNS study sessions across all women. TNS had no effect on subjective arousal. There were significant differences in VPA between baseline and stimulation, baseline and recovery, and stimulation and recovery periods among participants, but there were no trends across groups or stimulation type. Two participants with complete SCIs experienced genital sensations. CONCLUSIONS: To our knowledge, this is the first study to measure sexual arousal in response to short-term neuromodulation in women. This study indicates that short-term DGNS but not TNS can increase subjective arousal, but the effect of stimulation on genital arousal is inconclusive. This study provides further support for DGNS as a treatment for FSD.

Demi-decadal land use land cover change analysis of Mizoram, India, with topographic correction using machine learning algorithm.

Mizoram (India) is part of UNESCO's biodiversity hotspots in India that is primarily populated by tribes who engage in shifting agriculture. Hence, the land use land cover (LULC) pattern of the state is frequently changing. We have used Landsat 5 and 8 satellite images to prepare LULC maps from 2000 to 2020 in every 5 years. The atmospherically corrected images were pre-processed for removal of cloud cover and then classified into six classes: waterbodies, farmland, settlement, open forest, dense forest, and bare land. We applied four machine learning (ML) algorithms for classification, namely, random forest (RF), classification and regression tree (CART), minimum distance (MD), and support vector machine (SVM) for the images from 2000 to 2020. With 80% training and 20% testing data, we found that the RF classifier works best with the most accuracy than other classifiers. The average overall accuracy (OA) and Kappa coefficient (KC) from 2000 to 2020 were 84.00% and 0.79 when the RF classifier was used. When using SVM, CART, and MD, the average OA and KC were 78.06%, 0.73; 78.60%, 0.72; and 73.32%, 0.65, respectively. We utilised three methods of topographic correction, namely, C-correction, SCS (sun canopy sensor) correction, and SCS + C correction to reduce the misclassification due to shadow effects. SCS + C correction worked best for this region; hence, we prepared LULC maps on SCS + C corrected satellite image. Hence, we have used RF classifier for LULC preparation demi-decadal from 2000 to 2020. The OA for 2000, 2005, 2010, 2015, and 2020 was found to be 84%, 81%, 81%, 85%, and 89%, respectively, using RF. The dense forest decreased from 2000 to 2020 with an increase in open forest, settlement, and agriculture; nevertheless, when Farmland was low, there was an increase in the barren land. The results were significantly improved with the topographic correction, and misclassification was quite less.

Comparison between perfusion index, pleth variability index, and pulse pressure variability for prediction of hypotension during major abdominal surgery under general anaesthesia: A prospective observational study.

Background and Aims: Short-term hypotension after general anaesthesia can negatively impact surgical outcomes. This study compared the predictive potential of the pleth variability index (PVI), pulse pressure variability (PPV), and perfusion index (PI) for anaesthesia-induced hypotension. This study's primary objective was to evaluate the predictive potential of PI, PVI, and PPV for hypotension. Methods: This observational study included 140 adult patients undergoing major abdominal surgery under general anaesthesia. Mean arterial pressure, heart rate, PVI, PPV, and PI were collected at 1-min intervals up to 20 min post anaesthesia induction. Hypotension was assessed at 5-min and 15-min intervals. Receiver operating characteristic (ROC) curves were plotted to determine the diagnostic performance and best cut-off for continuous variables in predicting a dichotomous outcome. Statistical significance was kept at P < 0.05. Results: Hypotension prevalence within 5 and 15 min of anaesthesia induction was 36.4% and 45%, respectively. A PI cut-off of <3.5 had an area under the ROC curve (AUROC) of 0.647 (P = 0.004) for a 5-min hypotension prediction. The PVI's AUROC was 0.717 (P = 0.001) at cut-off >11.5, while PPV's AUROC was 0.742 (P = 0.001) at cut-off >12.5. At 15 min, PVI's AUROC was 0.615 (95% confidence interval 0.521-0.708, P = 0.020), with 54.9% positive predictive value and 65.2% negative predictive value. Conclusion: PVI, PPV, and PI predicted hypotension within 5 min after general anaesthesia induction. PVI had comparatively higher accuracy, sensitivity, specificity, and positive predictive value than PI and PPV when predicting hypotension at 15 min.

Re-188 lipiodol in hepatocellular carcinoma with portal vein thrombosis: a pilot study using novel chelating agent N-DEDC and its comparison with (A)HDD.

OBJECTIVE: Hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT) have limited therapeutic options, Re-188 lipiodol transarterial therapy being one of them. We aimed to assess the safety and efficacy of Re-188 lipiodol exclusively in HCC with PVT as well as to compare two chelating agents for the synthesis of Re-188 lipiodol: novel bis-(diethyldithiocarbamato) nitrido (N-DEDC) with existing acetylated 4-hexadecyl 1-2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol [(A)HDD]. METHODS: Patients with radiological diagnosis of HCC with PVT having Eastern Cooperative Oncology Group (ECOG) performance status ≤2 and Child Pugh score (PS) A or B were recruited. Patients received an empirical dose of transarterial Re-188 lipiodol, labelled with (A)HDD or N-DEDC. Radiological response on MRI (modified response evaluation criteria in solid tumors), biochemical response with serum alpha fetoprotein and clinical response with ECOG PS was assessed at three months and survival was estimated at the end of the study. RESULTS: Fifteen therapies were performed in 14 patients with a median age of 62 years (range: 41-70 years). Eight therapies were with Re-188 (A)HDD lipiodol and seven with Re-188 N-DEDC lipiodol. Overall mean injected dose was 2.6 ±â€…0.37 GBq. Radiological objective response rate was 31% and disease control rate was 85%. Mean overall survival was 14.21 months and mean progression free survival was 10.23 months. Percentage survival assessed at 3, 6 and 9 months was 93%, 64% and 57%, respectively. Safety parameters, response and survival outcome were comparable for (A)HDD and N-DEDC groups. CONCLUSION: Transarterial Re-188 lipiodol in HCC with PVT is safe and effective in disease control as well as improving survival outcome. Additionally, cost-effective and high-yielding novel agent N-DEDC appears to be a comparable alternative to (A)HDD for the same.

Comparison of perioperative adverse events following suburethral sling placement using synthetic mesh, autologous rectus fascia, and autologous fascia lata in a national surgical registry.

AIMS: To assess and compare 30-day perioperative adverse events following suburethral sling surgery using synthetic mesh, autologous rectus fascia, and autologous fascia lata in women. METHODS: This was a retrospective cohort study of patients who underwent fascial or synthetic sling placement for stress urinary incontinence between 2008 and 2021 using the American College of Surgeons' National Surgical Quality Improvement Program database. Current Procedural Terminology codes were used to identify patients undergoing each type of sling procedure. Multivariable regression analysis with stepwise regression was used to assess the odds of composite adverse events (e.g., urinary tract infection, surgical site infection, pulmonary embolism, and other reportable events) between cohorts. RESULTS: Of the 41 533 female patients who underwent isolated suburethral sling placement without concurrent procedures, 41 292 (99.4%) received a synthetic mesh sling, and 241 (0.6%) received an autologous facial sling. In the fascial sling cohort, 160 (66.4%) underwent rectus fascia harvest and 81 (33.6%) underwent fascia lata harvest. Sling surgeries involving autologous fascia were associated with increased odds of adverse events compared to those involving synthetic mesh, even after adjusting for confounders (adjusted odds ratio [aOR]: 3.63, 95% confidence interval [CI]: 2.56-5.15). Compared to fascial slings from rectus fascia, slings from fascia lata were associated with increased odds of composite adverse events (aOR: 2.11, 95% CI: 1.03-4.04). However, with the exclusion of urinary tract infections, the adverse event rate was similar between slings using the two fascial harvest techniques (aOR: 1.93, 95% CI: 0.81-4.63). CONCLUSIONS: In this retrospective database study, suburethral sling surgeries using autologous fascia were independently associated with a 3.6-fold increase in odds of 30-day perioperative adverse events compared to sling surgeries using synthetic mesh.

Implications of Russia-Ukraine war on land surface temperature and air quality: long-term and short-term analysis.

The world is currently witnessing the military operations of Russia invading Ukraine, leading to missile bombing and shelling on various parts. Although the economic ill effects are more conspicuous and much talked about, the environmental impacts are grimmer and more devastating but ironically are less in the news. Hence, in this work, we focused on the environmental impact of the Russia-Ukraine war by quantifying the long-term (2001 to 2023) and short-term temperature changes using land surface temperature (LST) and air temperature (AT) as proxies and monitoring changes in air quality, mainly methane (CH4), carbon monoxide (CO) and carbon dioxide (CO2), between 2021 and 2022. We used NASA MODIS FIRMS fire points from 24th February 2022 to 08th September 2023 to prepare the heat map for identifying the regions heavily devastated by bombing. Thus, parts of Kiev, Lviv, Luhansk, Odesa, Donetsk, Kherson, etc., in Ukraine were chosen for assessing the LST, AT variations during the peak season of war along with analysis of long-term and short-term changes. We used MODIS Terra LST and Emissivity, ERA 5 AT, CH4, CO2 from AIRS and CO from Sentinel 5P. The results of the LST showed an average increase of around 2.32 °C (2022-2023), 3.44 °C (2021 and 2022) in parts of Ukraine and an increase of about 2 °C from COVID time, whilst a decrease of about 1 °C during COVID. This increase in LST will cause enhanced warming, thus changing the regional climate in a shorter time frame. A consistent upward trend in CH4, CO and CO2 is seen from 2019 to 2023. These heat waves and pollution will grip Ukraine and cause menace due to the cumulative effect of heat waves, changing climate and the aftermaths of war. This would be catastrophic as it might lead to a widespread impact on human health, agricultural yield and infrastructure, to name a few.

Prevalence and predictors of female sexual dysfunction among sexually active women in the diabetes prevention program outcomes study.

OBJECTIVE: To determine the burden and identify correlates of female sexual dysfunction (FSD) among women with prediabetes (PreD) and type 2 diabetes (T2D) enrolled in the Diabetes Prevention Program (DPP) Outcomes Study (DPPOS). METHODS: The DPPOS visit included the Female Sexual Function Index (FSFI) to determine sexual function. Of 1464 participants, 1320 (90%) completed the (FSFI) and 426 were sexually active. A backward selection multivariable logistic regression model estimated the odds of FSD for sociodemographic, clinical, and diabetes-related covariates. RESULTS: One hundred and eighty-five (43%) had a score of ≤26.55 and met the criteria for FSD. After adjustment for DPP treatment and age, urinary incontinence (UI) (odds ratio [OR] = 1.91, 95% confidence interval [CI] = 1.15-3.17) and hysterectomy (OR = 1.89, 95% CI = 1.01-3.53) were associated with increased odds of FSD. Increased body mass index was protective for FSD (OR = 0.93 per kg/m2, 95% CI = 0.89-0.96). Michigan Neuropathy Screening Instrument-based peripheral neuropathy (mean±SD scores 1.1±1.3 vs. 0.9±1.1, p < 0.0001) and Electrocardiogram (ECG)-based autonomic dysfunction measures (mean ± SD heart rate levels 64.3 ± 6.8 vs. 65.6 ± 10.2, p = 0.008) were associated with FSD. There were no differences in diabetes rates between women who did (66.5%) and did not (66%) have (p = 0.7). CONCLUSIONS: FSD is prevalent in women with PreD and T2D. Our findings suggest that FSD is associated with neuropathic complications commonly observed in PreD and T2D.

Bronchioalveolar organoids: A preclinical tool to screen toxicity associated with antibody-drug conjugates.

Despite extensive preclinical testing, cancer therapeutics can result in unanticipated toxicity to non-tumor tissue in patients. These toxicities may pass undetected in preclinical experiments due to modeling limitations involving poor biomimicry of 2-dimensional in vitro cell cultures and due to lack of interspecies translatability in in vivo studies. Instead, primary cells can be grown into miniature 3-dimensional structures that recapitulate morphological and functional aspects of native tissue, termed "organoids." Here, human bronchioalveolar organoids grown from primary alveolar epithelial cells were employed to model lung epithelium and investigate off-target toxicities associated with antibody-drug conjugates (ADCs). ADCs with three different linker-payload combinations (mafodotin, vedotin, and deruxtecan) were tested in bronchioalveolar organoids generated from human, rat, and nonhuman primate lung cells. Organoids demonstrated antibody uptake and changes in viability in response to ADC exposure that model in vivo drug sensitivity. RNA sequencing identified inflammatory activation in bronchioalveolar cells in response to deruxtecan. Future studies will explore specific cell populations involved in interstitial lung disease and incorporate immune cells to the culture.

miR-107 and miR-126 and Risk of Breast Cancer: A Case-Control Study.

Background: Micro RNAs are new diagnostic markers and therapeutic targets in breast cancer research. miR-107 and miR-126 have been reported to be linked with the pathogenesis of breast cancer. The present study investigates the levels of expression of miR-107 and miR-126 in patients with breast cancer to find their correlation with the risk of breast cancer in Amritsar, Punjab, Northwest India. Material and Methods: In total, 200 subjects, 100 patients with breast cancer and 100 controls, were enrolled to screen the expression of miR-107 and miR-126 using quantitative reverse transcription polymerase chain reaction (RT-PCR) technique. The Livak method (2-ΔΔCt) was used to calculate the fold change of the expression of micro RNAs. Student t-test was used to calculate the significant change in the expression of miRNAs in patients as compared with controls. Spearman rank correlation coefficient and ROC were conducted. The value of p < 0.05 was considered to indicate a statistically significant difference. Results: miR-107 was downregulated in patients with breast cancer as compared with controls (fold change = 0.467; p = 0.114) but not statistically significant. The expression of miR-126 was found to be 5.37 times elevated in patients with breast cancer, specifically in stage I and stage III patients (p = 0.009), compared with controls, which may indicate its oncogenic activity. The ROC analyses revealed that miR-126 could be a potential diagnostic marker. In conclusion oncogenic behavior of miR-126 is suggestive of its role in pathogenesis in patients with breast cancer.

Chemotherapy Assessment in Advanced Multicellular 3D Models of Pancreatic Cancer: Unravelling the Importance of Spatiotemporal Mimicry of the Tumor Microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) is a challenge for global health with very low survival rate and high therapeutic resistance. Hence, advanced preclinical models for treatment screening are of paramount importance. Herein, chemotherapeutic (gemcitabine) assessment on novel (polyurethane) scaffold-based spatially advanced 3D multicellular PDAC models is carried out. Through comprehensive image-based analysis at the protein level, and expression analysis at the mRNA level, the importance of stromal cells is confirmed, primarily activated stellate cells in the chemoresistance of PDAC cells within the models. Furthermore, it is demonstrated that, in addition to the presence of activated stellate cells, the spatial architecture of the scaffolds, i.e., segregation/compartmentalization of the cancer and stromal zones, affect the cellular evolution and is necessary for the development of chemoresistance. These results highlight that, further to multicellularity, mapping the tumor structure/architecture and zonal complexity in 3D cancer models is important for better mimicry of the in vivo therapeutic response.

Tinospora cordifolia (Giloy): An insight on the multifarious pharmacological paradigms of a most promising medicinal ayurvedic herb.

Medicinal herbs are being widely accepted as alternative remedies for preventing various diseases especially in India and other Asian countries. However, most plant-based herbal medicines are not yet being scientifically accepted worldwide. "Tinospora cordifolia (Willd.) Miers ex Hook.F. & Thomson", one of the most promising plant species of Tinospora known as "Giloy" or Guduchi that is used in several traditional medicines in treating diseases e.g., metabolic and immune disorders, diabetes, heart diseases, cancer, and infectious diseases, has been widely investigated. Varieties of bioactive phytochemical constituents isolated from the stem, root and whole plant of T. cordifolia have been identified. In the last two decades, the diverse pharmacological activities of T. cordifolia have been continuously studied. Due to its therapeutic efficacy in immune modulation, it could be effective in viral and other diseases treatment as well. A medicinal plant could be well-suited not only for the treatment of target site but also for boosting the body's immune system. As an alternate source of medication, medicinal herbs are continuously showing better compatibility with the human body with minimal side effects than other therapies. Keeping this in mind, the present review highlights the pharmacological potential of T. cordifolia against various diseases.

Dissociable components of attention exhibit distinct neuronal signatures in primate visual cortex.

Attention can be deployed in multiple forms and facilitates behavior by influencing perceptual sensitivity and choice bias. Attention is also associated with a myriad of changes in sensory neural activity. Yet, the relationship between the behavioral components of attention and the accompanying changes in neural activity remains largely unresolved. We examined this relationship by quantifying sensitivity and bias in monkeys performing a task that dissociated eye movement responses from the focus of covert attention. Unexpectedly, bias, not sensitivity, increased at the focus of covert attention, whereas sensitivity increased at the location of planned eye movements. Furthermore, neuronal activity within visual area V4 varied robustly with bias, but not sensitivity, at the focus of covert attention. In contrast, correlated variability between neuronal pairs was lowest at the location of planned eye movements, and varied with sensitivity, but not bias. Thus, dissociable behavioral components of attention exhibit distinct neuronal signatures within the visual cortex.

Analysis of root volatiles and functional characterization of a root-specific germacrene A synthase in Artemisia pallens.

MAIN CONCLUSION: The study demonstrated that Artemisia pallens roots can be a source of terpene-rich essential oil and root-specific ApTPS1 forms germacrene A contributing to major root volatiles. Davana (Artemisia pallens Bess) is a valuable aromatic herb within the Asteraceae family, highly prized for its essential oil (EO) produced in the aerial parts. However, the root volatile composition, and the genes responsible for root volatiles have remained unexplored until now. Here, we show that A. pallens roots possess distinct oil bodies and yields ~ 0.05% of EO, which is primarily composed of sesquiterpenes ß-elemene, neryl isovalerate, ß-selinene, and α-selinene, and trace amounts of monoterpenes ß-myrcene, D-limonene. This shows that, besides aerial parts, roots of davana can also be a source of unique EO. Moreover, we functionally characterized a terpene synthase (ApTPS1) that exhibited high in silico expression in the root transcriptome. The recombinant ApTPS1 showed the formation of ß-elemene and germacrene A with E,E-farnesyl diphosphate (FPP) as a substrate. Detailed analysis of assay products revealed that ß-elemene was the thermal rearrangement product of germacrene A. The functional expression of ApTPS1 in Saccharomyces cerevisiae confirmed the in vivo germacrene A synthase activity of ApTPS1. At the transcript level, ApTPS1 displayed predominant expression in roots, with significantly lower level of expression in other tissues. This expression pattern of ApTPS1 positively correlated with the tissue-specific accumulation level of germacrene A. Overall, these findings provide fundamental insights into the EO profile of davana roots, and the contribution of ApTPS1 in the formation of a major root volatile.

Ecological momentary assessment of pelvic pain and urinary urgency variability in urologic chronic pelvic pain syndrome and their association with illness impact and quality of life: Findings from the multidisciplinary approach to the study of chronic pelvic pain symptom patterns study.

PURPOSE: This study tested the hypothesis that ecological momentary assessment (EMA) of pelvic pain (PP) and urinary urgency (UU) would reveal unique Urologic Chronic Pelvic Pain Syndrome (UCPPS) phenotypes that would be associated with disease specific quality of life (QOL) and illness impact metrics (IIM). MATERIALS AND METHODS: A previously validated smart phone app (M-app) was provided to willing Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) participants. M-app notifications were sent 4-times daily for 14 days inquiring about PP and UU severity. A clustering algorithm that accounted for variance placed participants into PP and UU variability? clusters. Associations between clusters and QOL and IIM were then determined. RESULTS: A total of 204 participants enrolled in the M-app study (64% female). M-app compliance was high (median 63% of surveys). Cluster analysis revealed k = 3 (high, low, none) PP clusters and k = 2 (high, low) UU clusters. When adjusting for baseline pain severity, high PP variability, but not UU variability, was strongly associated with QOL and IIM; specifically worse mood, worse sleep and higher anxiety. UU and PP clusters were associated with each other (p < 0.0001), but a large percentage (33%) of patients with high PP variability had low UU variability. CONCLUSIONS: PP variability is an independent predictor of worse QOL and more severe IIM in UCPPS participants after controlling for baseline pain severity and UU. These findings suggest alternative pain indices, such as pain variability and unpredictability, may be useful adjuncts to traditional measures of worst and average pain when assessing UCPPS treatment responses.

Presaccadic attention does not facilitate the detection of changes in the visual field.

Planning a rapid eye movement (saccade) changes how we perceive our visual world. Even before we move the eyes visual discrimination sensitivity improves at the impending target of eye movements, a phenomenon termed "presaccadic attention." Yet, it is unknown if such presaccadic selection merely affects perceptual sensitivity, or also affects downstream decisional processes, such as choice bias. We report a surprising lack of presaccadic perceptual benefits in a common, everyday setting-detection of changes in the visual field. Despite the lack of sensitivity benefits, choice bias for reporting changes increased reliably for the saccade target. With independent follow-up experiments, we show that presaccadic change detection is rendered more challenging because percepts at the saccade target location are biased toward, and more precise for, only the most recent of two successive stimuli. With a Bayesian model, we show how such perceptual and choice biases are crucial to explain the effects of saccade plans on change detection performance. In sum, visual change detection sensitivity does not improve presaccadically, a result that is readily explained by teasing apart distinct components of presaccadic selection. The findings may have critical implications for real-world scenarios, like driving, that require rapid gaze shifts in dynamically changing environments.

Association of ATG10 rs1864183, ATG16L1 rs2241880 and miR-126 with esophageal cancer.

BACKGROUND: In India, esophageal cancer (EC) is among the major cause of cancer-related deaths in both sexes. In recent past, autophagy has emerged as one of the crucial process associated with cancer. In the development of EC, the role of autophagy and the precise molecular mechanism involved has yet to be fully understood. Recently, a small number of studies have proposed how variations in autophagy genes affect the growth and development of EC. Micro-RNA's are also known to play a critical role in the development of EC. Here, we examined the relationship between the risk of EC and two single-nucleotide polymorphisms (SNPs) in the key autophagy genes, ATG10 rs1864183 and ATG16L1 rs2241880. We also analyzed the association of miR-107 and miR-126 with EC as these miRNA's are associated with autophagy. METHODS AND RESULTS: A total of 230 EC patients and 230 healthy controls from North-west Indian population were enrolled. ATG10 rs1864183 and ATG16L1 rs2241880 polymorphism were analyzed using TaqMan genotyping assay. Expression levels of miR-107 and miR-126 were analyzed through quantitative PCR using SYBR green chemistry. We found significant association of CT + CC genotype (OR 0.64, p = 0.022) in recessive model for ATG10 rs1864183 polymorphism with decreased EC risk. For ATG16L1 rs2241880 polymorphism significant association for AG genotype (OR 1.48, p = 0.05) and G allele (OR 1.43, p = 0.025) was observed for increased EC risk. Expression levels of miR-126 were also found to be significantly up regulated (p = 0.008). CONCLUSION: Our results suggest that ATG10 rs1864183, ATG16L1 rs2241880 and miR-126 may be associated with esophageal carcinogenesis and warrant further investigation.

Estrogen receptor-related receptor (Esrra) induces ribosomal protein Rplp1-mediated adaptive hepatic translation during prolonged starvation.

Protein translation is an energy-intensive ribosome-driven process that is reduced during nutrient scarcity to conserve cellular resources. During prolonged starvation, cells selectively translate specific proteins to enhance their survival (adaptive translation); however, this process is poorly understood. Accordingly, we analyzed protein translation and mRNA transcription by multiple methods in vitro and in vivo to investigate adaptive hepatic translation during starvation. While acute starvation suppressed protein translation in general, proteomic analysis showed that prolonged starvation selectively induced translation of lysosome and autolysosome proteins. Significantly, the expression of the orphan nuclear receptor, estrogen-related receptor alpha (Esrra) increased during prolonged starvation and served as a master regulator of this adaptive translation by transcriptionally stimulating 60S acidic ribosomal protein P1 (Rplp1) gene expression. Overexpression or siRNA knockdown of Esrra expression in vitro or in vivo led to parallel changes in Rplp1 gene expression, lysosome/autophagy protein translation, and autophagy. Remarkably, we have found that Esrra had dual functions by not only regulating transcription but also controling adaptive translation via the Esrra/Rplp1/lysosome/autophagy pathway during prolonged starvation.

Believing women: a qualitative exploration of provider disbelief and pain dismissal among women with interstitial cystitis/bladder pain syndrome from the MAPP research network.

INTRODUCTION AND HYPOTHESIS: Although allusions to the importance of a good physician-patient relationship are present throughout the interstitial cystitis/bladder pain syndrome (IC/BPS) literature, qualitative analysis of patients' perspectives on the clinical encounter is lacking, particularly among women who are most commonly affected by IC/BPS. Therefore, we adopted a patient-centered experiential approach to understanding female patients' perception of clinical encounters. METHODS: We re-analyzed previously collected data from a qualitative study on patient flare experiences including eight focus groups of female IC/BPS patients (n = 57, mean = 7/group). Qualitative analysis applied grounded theory to index all physician-patient interactions, then thematically coded these interactions to elucidate common experiences of clinical encounters. RESULTS: Women with IC/BPS shared common experiences of provider disbelief and pain dismissal. Discussions with participants demonstrated the extent to which these negative encounters shape patients' health care-seeking behavior, outlook, and psychosocial well-being. Appearing in more than one guise, provider disbelief and dismissal occurred as tacit insinuations, explicit statements, silence, oversimplification, and an unwillingness to listen and discuss alternative treatment. As a result, women adopted several strategies including: rotating specialists; "testing" physicians; self-advocacy; self-management; avoiding the stigma of chronic pain; crying; and opting for alternative medicine over biomedicine. CONCLUSIONS: The prevalence of provider disbelief and pain dismissal among women with IC/BPS indicates a need to improve physician-patient communication, informed by the struggles, anxieties, and gendered inequities that female patients with chronic pain experience in their diagnostic journey. Results suggest that further investigation into the power dynamics of clinical encounters might be required.

Human Dose and Pharmacokinetic Predictions for Biologics at Boehringer Ingelheim: A Retrospective Analysis.

INTRODUCTION: Accurate predictions of pharmacokinetics and efficacious doses for biologics in humans are critical for selecting appropriate first-in-human starting doses and dose ranges and for estimating clinical material needs and cost of goods. This also impacts clinical feasibility, particularly for subcutaneously administered biologics. METHODS: We performed a comprehensive comparison between predicted and observed clearances and doses in humans for a set of 22 biologic drugs developed at Boehringer Ingelheim (BI) over the last 2 decades. The analysis included biologics across three therapeutic areas comprising a wide variety of modalities: mono- and bispecific monoclonal antibodies (mAbs) and nanobodies and a Fab fragment. RESULTS: Our analysis showed that observed clearances in humans were within twofold of predicted clearances for 17 out of 20 biologics (85%). Six biologics had uncharacteristically high observed human clearances (range 32-280 mL/h) for their respective molecular classes, impacting their clinical developability. For three molecules, molecular characteristics contributed to the high clearance. Clinically selected doses were within twofold of predicted for 58% of projects. With 42% and 25% of projects selecting clinical doses higher than two- or threefold the predicted value, respectively, the importance of better understanding not only the pharmacokinetic (PK) but also the predictivity of pharmacodynamic models is highlighted. CONCLUSIONS: We provide a clinical pharmacology perspective on the commonly accepted twofold range of human clearance predictions as well as the implications of higher than predicted targeted efficacious plasma concentration on clinical development. Finally, an analysis of key success factors for biologics at BI was conducted, which may be relevant for the entire pharmaceutical industry. This is one of the largest retrospective analyses for biologics and provides further evidence that successful predictions of human PK and efficacious dose will be further facilitated by gathering key translational data early in research.