Universal pictures: A lithophane codex helps teenagers with blindness visualize nanoscopic systems.

People with blindness have limited access to the high-resolution graphical data and imagery of science. Here, a lithophane codex is reported. Its pages display tactile and optical readouts for universal visualization of data by persons with or without eyesight. Prototype codices illustrated microscopy of butterfly chitin-from N-acetylglucosamine monomer to fibril, scale, and whole insect-and were given to high schoolers from the Texas School for the Blind and Visually Impaired. Lithophane graphics of Fischer-Spier esterification reactions and electron micrographs of biological cells were also 3D-printed, along with x-ray structures of proteins (as millimeter-scale 3D models). Students with blindness could visualize (describe, recall, distinguish) these systems-for the first time-at the same resolution as sighted peers (average accuracy = 88%). Tactile visualization occurred alongside laboratory training, synthesis, and mentoring by chemists with blindness, resulting in increased student interest and sense of belonging in science.

Synchrotron speciation of umbilical cord mercury and selenium after environmental exposure in Niigata.

The insidious and deadly nature of mercury's organometallic compounds is informed by two large scale poisonings due to industrial mercury pollution that occurred decades ago in Minamata and Niigata, Japan. The present study examined chemical speciation for both mercury and selenium in a historic umbilical cord sample from a child born to a mother who lived near the Agano River in Niigata. The mother had experienced mercury exposure leading to more than 50 ppm mercury measured in her hair and was symptomatic 9 years prior to the birth. We sought to determine the mercury and selenium speciation in the child's cord using Hg Lα1 and Se Kα1 high-energy resolution fluorescence detected X-ray absorption spectroscopy, the chemical speciation of mercury was found to be predominantly organometallic and coordinated to a thiolate. The selenium was found to be primarily in an organic form and at levels higher than those of mercury, with no evidence of mercury-selenium chemical species. Our results are consistent with mercury exposure at Niigata being due to exposure to organometallic mercury species.

Critical test of the assumption that the hypothalamic entopeduncular nucleus of rodents is homologous with the primate internal pallidum.

The globus pallidus (GP) of primates is divided conventionally into distinct internal and external parts. The literature repeats since 1930 the opinion that the homolog of the primate internal pallidum in rodents is the hypothalamic entopeduncular nucleus (embedded within fiber tracts of the cerebral peduncle). To test this idea, we explored its historic fundaments, checked the development and genoarchitecture of mouse entopeduncular and pallidal neurons, and examined relevant comparative connectivity data. We found that the extratelencephalic mouse entopeduncular structure consists of four different components arrayed along a dorsoventral sequence in the alar hypothalamus. The ventral entopeduncular nucleus (EPV), with GABAergic neurons expressing Dlx5&6 and Nkx2-1, lies within the hypothalamic peduncular subparaventricular area. Three other formations-the dorsal entopeduncular nucleus (EPD), the prereticular entopeduncular nucleus (EPPRt ), and the preeminential entopeduncular nucleus (EPPEm )-lie within the overlying paraventricular area, under the subpallium. EPD contains glutamatergic neurons expressing Tbr1, Otp, and Pax6. The EPPRt has GABAergic cells expressing Isl1 and Meis2, whereas the EPPEm population expresses Foxg1 and may be glutamatergic. Genoarchitectonic observations on relevant areas of the mouse pallidal/diagonal subpallium suggest that the GP of rodents is constituted as in primates by two adjacent but molecularly and hodologically differentiable telencephalic portions (both expressing Foxg1). These and other reported data oppose the notion that the rodent extratelencephalic entopeduncular nucleus is homologous to the primate internal pallidum. We suggest instead that all mammals, including rodents, have dual subpallial GP components, whereas primates probably also have a comparable set of hypothalamic entopeduncular nuclei. Remarkably, there is close similarity in some gene expression properties of the telencephalic internal GP and the hypothalamic EPV. This apparently underlies their notable functional analogy, sharing GABAergic neurons and thalamopetal connectivity.

Marijuana and Cannabidiol Use Prevalence and Symptom Management Among Patients with Cancer.

Symptoms such as pain, nausea, and anxiety are common in individuals with cancer. Treatment of these issues is often challenging. Cannabis products may be helpful in reducing the severity of these symptoms. While some studies include data on the prevalence of cannabis use among patients with cancer, detailed data remain limited, and none have reported the prevalence of cannabidiol (CBD) use in this population. Adult patients with cancer attending eight clinics at a large, NCI-designated Comprehensive Cancer Center completed a detailed, cannabis-focused questionnaire between 2021 and 2022. Eligible participants were diagnosed with invasive cancer and treated in the past 12 months. Summary statistics were calculated to describe the sample regarding cannabis use. Approximately 15% (n = 142) of consented patients (n = 934) reported current cannabis use (defined as use within the past 12 months). Among which, 75% reported cannabis use in the past week. Among current cannabis users, 39% (n = 56; 6% overall) used CBD products. Current users reported using cannabis a median of 4.5 (interquartile range: 0.6­7.0) days/week, 2.0 (1.0­3.0) times per use/day, and for 3 years (0.8­30.0). Use patterns varied by route of administration. Patients reported moderate to high relief of symptoms with cannabis use. This study is the most detailed to date in terms of cannabis measurement and provides information about the current state of cannabis use in active cancer. Future studies should include complete assessments of cannabis product use, multiple recruitment sites, and diverse patient populations. SIGNIFICANCE: Clinicians should be aware that patients are using cannabis products and perceive symptom relief with its use.

Streambank erosion and phosphorus loading to surface waters: Knowns, unknowns, and implications for nutrient loss reduction research and policy.

To monitor and meet water quality objectives, it is necessary to understand and quantify the contribution of nonpoint sources to total phosphorus (P) loading to surface waters. However, the contribution of streambank erosion to surface water P loads remains unclear and is typically unaccounted for in many nutrient loading assessments and policies. As a result, agricultural contributions of P are overestimated, and a potentially manageable nonpoint source of P is missed in strategies to reduce loads. In this perspective, we review and synthesize the results of a special symposium at the 2022 ASA-CSSA-SSSA annual meeting in Baltimore, MD, that focused on streambank erosion and its contributions to P loading of surface waters. Based on discussions among researchers and policy experts, we overview the knowns and unknowns, propose next steps to understand streambank erosion contribution to P export budgets, and discuss implications of the science of streambank erosion for policy and nutrient loss reduction strategies.

Models of integrated care for multi-morbidity assessed in systematic reviews: a scoping review.

BACKGROUND: The prevalence of multi-morbidity is increasing globally. Integrated models of care present a potential intervention to improve patient and health system outcomes. However, the intervention components and concepts within different models of care vary widely and their effectiveness remains unclear. We aimed to describe and map the definitions, characteristics, components, and reported effects of integrated models of care in systematic reviews (SRs). METHODS: We conducted a scoping review of SRs according to pre-specified methods (PROSPERO 2019 CRD42019119265). Eligible SRs assessed integrated models of care at primary health care level for adults and children with multi-morbidity. We searched in PubMed (MEDLINE), Embase, Cochrane Database of Systematic Reviews, Epistemonikos, and Health Systems Evidence up to 3 May 2022. Two authors independently assessed eligibility of SRs and extracted data. We identified and described common components of integrated care across SRs. We extracted findings of the SRs as presented in the conclusions and reported on these verbatim. RESULTS: We included 22 SRs, examining data from randomised controlled trials and observational studies conducted across the world. Definitions and descriptions of models of integrated care varied considerably. However, across SRs, we identified and described six common components of integrated care: (1) chronic conditions addressed, (2) where services were provided, (3) the type of services provided, (4) healthcare professionals involved in care, (5) coordination and organisation of care and (6) patient involvement in care. We observed differences in the components of integrated care according to the income setting of the included studies. Some SRs reported that integrated care was beneficial for health and process outcomes, while others found no difference in effect when comparing integrated care to other models of care. CONCLUSIONS: Integrated models of care were heterogeneous within and across SRs. Information that allows the identification of effective components of integrated care was lacking. Detailed, standardised and transparent reporting of the intervention components and their effectiveness on health and process outcomes is needed.

Equal but Separate: The Slow Assimilation of Osteopathic Surgery Residents Two Years After the Unified Match.

OBJECTIVES: The purpose of this study was to monitor the integration of general surgery residency programs before and after the 2020 unified match. We hypothesized that integration of osteopathic (DO) surgery residents would increase. DESIGN: We performed a retrospective cohort study of surgery residency programs between 2019 and 2021 utilizing data provided by the Association of American Medical Colleges. Program composition (2021) and changes in composition (2019-2021) were compared by program type. Multivariable logistic regression models assessed variables associated with DO presence (2021) and integration (2019-2021). SETTING: General surgery residency programs across the United States. PARTICIPANTS: Civilian surgery residencies that completed the 2019-2021 program survey. RESULTS: Out of 320 programs, DO residents were integrated at 69% (221/320), including 52% (63/122) university programs, 78% (101/129) university-affiliated programs and 83% (57/69) community programs (p < 0.01). Overall, 23 (8%) programs integrated DO residents from 2019 to 2021, and 9 (21%) ex-American Osteopathic Association programs integrated MD residents (both p < 0.01). The median number of DO residents was 1 (interquartile range, IQR 0-2) at university programs, 2 (IQR 1-7) at university-affiliated programs, and 5 (IQR 2-12) at community programs (p < 0.01). The median number of DO residents at all programs increased from 1 (IQR 0-5) to 2 (IQR 0-6) since 2019 (p < 0.01). Community (OR 2.6, p = 0.04), university-affiliated (OR 2.3, p = 0.02), and programs with DOs in 2019 (OR 19.0, p < 0.01) were associated with increased odds of DOs present in 2021, while DO faculty (OR 2.6, p = 0.02) was the only factor independently associated with integrating DOs after 2019. CONCLUSIONS: While some programs have integrated DO residents, progress is slow, median numbers of DO residents remain low, and familiarity with DOs is most associated with integration. We explore barriers to integration, and advance recommendations to eliminate potential disparities.

Attraction of the Air Potato Leaf Beetle, Lilioceris Cheni, (Coleoptera: Chrysomelidae) to leaf Volatiles of the Air Potato, Dioscorea bulbifera.

Air potato, Dioscorea bulbifera L., is an invasive vine found in the southeastern United States and is native to Asia and Africa. The air potato leaf beetle Lilioceris cheni (Coleoptera: Chrysomelidae), is a host specific biological control agent introduced for D. bulbifera control. In this study, odor cues that control the attraction of L. cheni to D. bulbifera were investigated. The first experiment investigated the response of L. cheni to D. bulbifera leaves versus no leaves in the presence or absence of air flow. The experiment showed a significant response of L. cheni to D. bulbifera leaves in the presence of air flow with leaves placed upwind. When air flow and/or leaves were absent, L. cheni dispersed randomly between the upwind and downwind targets, indicating L. cheni uses volatiles from D. bulbifera in host selection. The second experiment investigated L. cheni response to undamaged, larval-damaged, and adult-damaged plants. Lilioceris cheni showed preference to move towards conspecific damaged plants compared to undamaged plants but did not discriminate between larvae-damaged or adult-damaged plants. The third experiment investigated volatile profiles of damaged D. bulbifera plants using gas chromatography coupled with mass spectroscopy. We found significant differences in volatile profiles between adult and larval damaged plants compared to mechanically damaged and undamaged plants, with increases in 11 volatile compounds. However, larval and adult-damaged volatile profiles did not differ. The information acquired during this study could be used to develop strategies to monitor for L. cheni and improve its biological control program.

Physical pain among Indigenous Peoples in Canada: a scoping review.

PURPOSE: Pain is a multifaceted experience shaped by various factors including context of pain, previous life events, and ongoing ethnocultural circumstances. Moreover, the definition of pain is inconsistent across cultures. Western medicine views physical pain (e.g., associated with a bone fracture) and nonphysical mental pain (e.g., depression) as two distinct conditions. Indigenous perspectives are often more wholistic, encompassing mental, spiritual, emotional, and physical hurt. The subjective nature of pain invites ample opportunity for discrimination in both its assessment and management. As such, it is important to consider Indigenous perspectives of pain in research and clinical practice. To investigate which aspects of Indigenous pain knowledge are currently considered by Western research, we conducted a scoping review of the literature on pain in Indigenous Peoples of Canada. SOURCE: In June 2021, we searched nine databases and downloaded 8,220 papers after removal of duplicates. Two independent reviewers screened abstracts and full-text articles. PRINCIPLE FINDINGS: Seventy-seven papers were included in the analysis. Using grounded theory, five themes emerged: pain measures/scales (n = 7), interventions (n = 13), pharmaceuticals (n = 17), pain expression/experiences (n = 45), and pain conditions (n = 70). CONCLUSION: This scoping review shows that there is a paucity of research on pain measurement in Indigenous Peoples of Canada. This finding is concerning in light of numerous studies reporting that Indigenous Peoples experience their pain as ignored, minimized, or disbelieved. Furthermore, a clear disconnect emerged between pain expression in Indigenous Peoples and assessment in medical professionals. We hope that this scoping review will serve to translate current knowledge to other non-Indigenous academics and to initiate meaningful collaboration with Indigenous partners. Future research led by Indigenous academics and community partners is critically needed to better address pain needs in Canada.

RéSUMé: OBJECTIF: La douleur est une expérience multidimensionnelle façonnée par divers facteurs, notamment le contexte de la douleur, les événements antérieurs de la vie et les circonstances ethnoculturelles courantes. De plus, la définition de la douleur change d'une culture à l'autre. La médecine occidentale considère la douleur physique (par exemple, celle associée à une fracture osseuse) et la douleur mentale non physique (par exemple, la dépression) comme deux conditions distinctes. Les perspectives autochtones sont souvent plus holistiques, englobant les blessures mentales, spirituelles, émotionnelles et physiques. La nature subjective de la douleur ouvre la voie à de nombreuses possibilités de discrimination tant dans son évaluation que dans sa prise en charge. C'est pourquoi il est important de tenir compte des perspectives autochtones en matière de douleur dans la recherche et la pratique clinique. Afin d'étudier quels aspects des connaissances autochtones concernant la douleur sont actuellement pris en compte par la recherche occidentale, nous avons réalisé une étude de portée de la littérature sur la douleur chez les peuples autochtones du Canada. SOURCES: En juin 2021, nous avons consulté neuf bases de données et téléchargé 8220 articles après suppression des doublons. Deux personnes ont passé en revue et évalué de manière indépendante les résumés et textes intégraux. CONSTATATIONS PRINCIPALES: Soixante-dix-sept articles ont été inclus dans l'analyse. À l'aide de la théorie ancrée, cinq thèmes sont ressortis : les mesures/échelles de la douleur (n = 7), les interventions (n = 13), les produits pharmaceutiques (n = 17), l'expression/les expériences de la douleur (n = 45), et les conditions de douleur (n = 70). CONCLUSION: Cette étude de portée démontre le peu de recherches sur la mesure de la douleur chez les peuples autochtones du Canada. Cette conclusion est préoccupante à la lumière de nombreuses études indiquant que les peuples autochtones voient leur douleur ignorée, minimisée ou discréditée. De plus, un décalage évident est apparu entre l'expression de la douleur chez les peuples autochtones et l'évaluation par les professionnels de la santé. Nous espérons que cette étude de portée servira à transférer les connaissances actuelles à d'autres chercheurs et chercheuses non autochtones et à établir une collaboration significative avec des partenaires autochtones. Les recherches futures menées par des universitaires autochtones et des partenaires de la collectivité sont essentielles pour mieux répondre aux besoins en matière de douleur au Canada.

Uncertainty in phosphorus fluxes and budgets across the US long-term agroecosystem research network.

Phosphorus (P) budgets can be useful tools for understanding nutrient cycling and quantifying the effectiveness of nutrient management planning and policies; however, uncertainties in agricultural nutrient budgets are not often quantitatively assessed. The objective of this study was to evaluate uncertainty in P fluxes (fertilizer/manure application, atmospheric deposition, irrigation, crop removal, surface runoff, and leachate) and the propagation of these uncertainties to annual P budgets. Data from 56 cropping systems in the P-FLUX database, which spans diverse rotations and landscapes across the United States and Canada, were evaluated. Results showed that across cropping systems, average annual P budget was 22.4 kg P ha-1 (range = -32.7 to 340.6 kg P ha-1 ), with an average uncertainty of 13.1 kg P ha-1 (range = 1.0-87.1 kg P ha-1 ). Fertilizer/manure application and crop removal were the largest P fluxes across cropping systems and, as a result, accounted for the largest fraction of uncertainty in annual budgets (61% and 37%, respectively). Remaining fluxes individually accounted for <2% of the budget uncertainty. Uncertainties were large enough that determining whether P was increasing, decreasing, or not changing was inconclusive in 39% of the budgets evaluated. Findings indicate that more careful and/or direct measurements of inputs, outputs, and stocks are needed. Recommendations for minimizing uncertainty in P budgets based on the results of the study were developed. Quantifying, communicating, and constraining uncertainty in budgets among production systems and multiple geographies is critical for engaging stakeholders, developing local and national strategies for P reduction, and informing policy.

Similar performance after intake of carbohydrate plus whey protein and carbohydrate only in the early phase after non-exhaustive cycling.

AIM: The aim of the present study was to compare performance 5 h after a 90-min endurance training session when either carbohydrate only or carbohydrate with added whey hydrolysate or whey isolate was ingested during the first 2 h of the recovery period. METHODS: Thirteen highly trained competitive male cyclists completed three exercise and diet interventions (double-blinded, randomized, crossover design) separated by 1 week. The 90-min morning session (EX1) included a 60 min time-trial (TT60 ). Immediately and 1 h after exercise, participants ingested either (1) 1.2 g carbohydrate∙kg-1 ∙h-1 (CHO), (2) 0.8 g carbohydrate∙kg-1 ∙h-1 + 0.4 g isolate whey protein∙kg-1 ∙h-1 (ISO) or (3) 0.8 g carbohydrate∙kg-1 ∙h-1 + 0.4 g hydrolysate whey protein∙kg-1 ∙h-1 (HYD). Additional intakes were identical between interventions. After 5 h of recovery, participants completed a time-trial performance (TTP ) during which a specific amount of work was performed. Blood and urine were collected throughout the day. RESULTS: TTP did not differ significantly between dietary interventions (CHO: 43:54 ± 1:36, ISO: 46:55 ± 2:32, HYD: 44:31 ± 2:01 min). Nitrogen balance during CHO was lower than ISO (p < 0.0001) and HYD (p < 0.0001), with no difference between ISO and HYD (p = 0.317). In recovery, the area under the curve for blood glucose was higher in CHO compared to ISO and HYD. HR, VO2 , RER, glucose, and lactate during EX2 were similar between interventions. CONCLUSION: Performance did not differ after 5 h of recovery whether carbohydrate only or isocaloric carbohydrate plus protein was ingested during the first 2 h. Correspondingly, participants were not in negative nitrogen balance in any dietary intervention.

Metabolic Control Analysis of triacylglycerol accumulation in oilseed rape.

The increasing global demand for vegetable oils will only be met if there are significant improvements in the productivity of the major oil crops, such as oilseed rape. Metabolic engineering offers the prospect of further gains in yield beyond that already achieved by breeding and selection but requires guidance as to the changes that need to be made. Metabolic Control Analysis, through measurement and estimation of flux control coefficients, can indicate which enzymes have the most influence on a desired flux. Some experiments have previously reported flux control coefficients for oil accumulation in the seeds of oilseed rape, and others have measured control coefficient distributions for multi-enzyme segments of oil synthesis in seed embryo metabolism measured in vitro. In addition, other reported manipulations of oil accumulation contain results that are exploited further here to calculate previously unknown flux control coefficients. These results are then assembled within a framework that allows an integrated interpretation of the controls on oil accumulation from the assimilation of CO2 to deposition of oil in the seed. The analysis shows that the control is distributed to an extent that the gains from amplifying any single target are necessarily limited, but there are candidates for joint amplification that are likely to act synergistically to produce much more significant gains.

Feasibility of low-carbon electrolytic manganese residue-based supplementary cementitious materials.

In this work, the electrolytic manganese residues (EMR) were used as sulfate activators for fly ash and granulated blast-furnace slag to fabricate highly reactive supplementary cementitious materials (SCMs). The findings promote the implementation of a win-win strategy for carbon reduction and waste resource utilisation. The effects of EMR dosing on the mechanical properties, microstructure and CO2 emission of the EMR-doped cementitious materials are investigated. The results show that low dosing EMR (5 %) produced more ettringite, fostering early strength development. The fly ash-doped mortar strength increases and then decreases with the addition of EMR from 0 to 5 % to 5-20 %. It was found that blast furnace slag contributes less to strength than fly ash. Moreover, the sulfate activation and the micro-aggregate effect compensate for the EMR-induced dilution effect. The significant increase in strength contribution factor and direct strength ratio at each age verifies the sulfate activation of EMR. The lowest EIF90 value of 5.4 kg∙MPa-1∙m3 was achieved for the fly ash-doped mortar with 5 % EMR, suggesting the synergistic effect between fly ash and EMR optimised the mechanical properties while maintaining lower CO2 emissions.

Metastasis-Directed Therapy for Oligometastatic Castration-Sensitive Prostate Cancer: An Alternative to ADT?

PURPOSE OF REVIEW: The standard treatment of patients with metastatic prostate cancer is systemic treatment with androgen-deprivation therapy (ADT). The spectrum-based model of metastatic disease includes the presence of an oligometastatic state, an intermediary between localized and widespread metastatic disease, in which radical local treatment might improve systemic control. Our purpose is to review the literature on metastasis-directed therapy in the treatment of oligometastatic prostate cancer. RECENT FINDINGS: Several prospective clinical trials have reported improvements in ADT-free survival and progression-free survival with metastasis-directed therapy of oligometastatic prostate cancer. Retrospective studies have found improvements in oncologic outcomes for patients with oligometastatic prostate cancer undergoing metastasis-directed therapy, and several recent prospective clinical trials have confirmed these results. Advancements in imaging as well as an understanding of the genomics of oligometastatic prostate cancer may allow for better patient selection for metastasis-directed therapy and the potential for cure in selected patients.

Analysis of immune-related microRNAs in cows and newborn calves.

Bovine colostrum contains a high concentration of immune-related microRNAs (miRNAs) that are packaged in exosomes and are very stable. In this study, 5 immune-related miRNAs (miR-142-5p, miR-150, miR-155, miR-181a, and miR-223) were quantified in dam blood, colostrum, and calf blood using reverse transcription quantitative PCR. Their levels in calf blood after colostrum ingestion were investigated to assess whether miRNAs are transferred from the dam to newborn calves. Three groups of Holstein-Friesian bull calves were bottle-fed 2 L of colostrum or milk from different sources twice per day. The group A calves received colostrum from their own dam and the group B calves were fed foster dam colostrum. Each pair of group A and group B calves were fed identical colostrum from the same milking of the corresponding group A dam for 3 d and then bulk tank milk for 7 d after birth. Group C calves were fed only 2L of "pooled colostrum" from multiple dams d 0 to 4 postpartum, and then fed bulk tank milk thereafter for 7 d after birth. The groups were fed colostrum from different sources and different amounts to assess possible miRNA absorption from the colostrum. All miRNAs were at the highest level in colostrum at d 0 and then decreased rapidly after d 1. The level of miR-150 had the largest decrease from 489 × 106 copies/µL (d 0) to 78 × 106 copies/µL (d 1). MicroRNA-223 and miR-155 were the most abundant in both colostrum and milk. Dam colostrum had significantly higher levels of miR-142-5p, miR-155, and miR-181a than the bulk tank milk. However, only the miR-155 concentration was significantly higher in the dam colostrum than in the pooled colostrum. The concentrations of miRNAs in the colostrum were less than in the cow blood (100- to 1,000-fold less). There was no significant correlation between the level of miRNAs in the dam blood and their colostrum, suggesting that miRNA is synthesized locally by the mammary gland rather than being transferred from the blood. MicroRNA-223 had the highest level in both calf and cow blood compared with the other 4 immune-related miRNAs. Calves were born with high levels of immune-related miRNAs in their blood, and there were no significant differences in miRNA levels between the 3 calf groups at birth or after they were fed different colostrum. This suggests that these miRNAs were not transferred from the colostrum to the newborn calves.

A Phase 1/2 Study of Rapamycin and Cisplatin/Gemcitabine for Treatment of Patients With Muscle-Invasive Bladder Cancer.

INTRODUCTION: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by cystectomy is the standard for muscle-invasive bladder cancer (MIBC), however, NAC confers only a small survival benefit and new strategies are needed to increase its efficacy. Pre-clinical data suggest that in response to DNA damage the tumor microenvironment (TME) adopts a paracrine secretory phenotype dependent on mTOR signaling which may provide an escape mechanism for tumor resistance, thus offering an opportunity to increase NAC effectiveness with mTOR blockade. PATIENTS & METHODS: We conducted a phase I/II clinical trial to assess the safety and efficacy of gemcitabine-cisplatin-rapamycin combination. Grapefruit juice was administered to enhance rapamycin pharmacokinetics by inhibiting intestinal enzymatic degradation. Phase I was a dose determination/safety study followed by a single arm Phase II study of NAC prior to radical cystectomy evaluating pathologic response with a 26% pCR rate target. RESULTS: In phase I, 6 patients enrolled, and the phase 2 dose of 35 mg rapamycin established. Fifteen patients enrolled in phase II; 13 were evaluable. Rapamycin was tolerated without serious adverse events. At the preplanned analysis, the complete response rate (23%) did not meet the prespecified level for continuing and the study was stopped due to futility. With immunohistochemistry, successful suppression of the mTOR signaling pathway in the tumor was achieved while limited mTOR activity was seen in the TME. CONCLUSION: Adding rapamycin to gemcitabine-cisplatin therapy for patients with MIBC was well tolerated but failed to improve therapeutic efficacy despite evidence of mTOR blockade in tumor cells. Further efforts to understand the role of the tumor microenvironment in chemotherapy resistance is needed.

Tailoring Adjuvant Chemotherapy to Biologic Response Following Neoadjuvant Chemotherapy Impacts Overall Survival in Pancreatic Cancer.

BACKGROUND: The role of postoperative chemotherapy in patients with resected pancreatic cancer who receive neoadjuvant treatment is unknown. Clinicians use changes in CA19-9 and histopathologic scores to assess treatment response. We sought to investigate if CA19-9 normalization in response to NAT can help guide the need for postoperative treatment. METHODS: Patients with elevated baseline CA19-9 (CA19-9 > 37U/mL) who received NAT followed by surgery between 2011 and 2019 were retrospectively reviewed. Treatment response was determined by CA19-9 normalization following NAT and histopathologic scoring. The role of postoperative chemotherapy was analyzed in light of CA19-9 normalization and histopathologic response. RESULTS: We identified and included 345 patients. Following NAT, CA19-9 normalization was observed in 125 patients (36.2%). CA19-9 normalization was associated with a favorable histopathologic response (41.6% vs 23.2%, p < 0.001) and a lower ypT (p < 0.001) and ypN stage (p = 0.003). Receipt of adjuvant chemotherapy was associated with improved overall survival in patients in whom CA19-9 did not normalize following NAT (26.8 vs 16.4 months, p = 0.008). In patients who received 5FU-based NAT and in whom CA19-9 did not normalize, receipt of 5FU-based adjuvant chemotherapy was associated with improved OS (p = 0.014). CONCLUSION: CA19-9 normalization in response to NAT was associated with favorable outcomes and can serve as a biomarker for treatment response. In patients where CA19-9 did not normalize, receipt of postoperative chemotherapy was associated with improved OS. These patients also benefited from additional 5FU-based postoperative chemotherapy following 5FU-based NAT.

Dorsoventral Arrangement of Lateral Hypothalamus Populations in the Mouse Hypothalamus: a Prosomeric Genoarchitectonic Analysis.

The lateral hypothalamus (LH) has a heterogeneous cytoarchitectonic organization that has not been elucidated in detail. In this work, we analyzed within the framework of the prosomeric model the differential expression pattern of 59 molecular markers along the ventrodorsal dimension of the medial forebrain bundle in the mouse, considering basal and alar plate subregions of the LH. We found five basal (LH1-LH5) and four alar (LH6-LH9) molecularly distinct sectors of the LH with neuronal cell groups that correlate in topography with previously postulated alar and basal hypothalamic progenitor domains. Most peptidergic populations were restricted to one of these LH sectors though some may have dispersed into a neighboring sector. For instance, histaminergic Hdc-positive neurons were mostly contained within the basal LH3, Nts (neurotensin)- and Tac2 (tachykinin 2)-expressing cells lie strictly within LH4, Hcrt (hypocretin/orexin)-positive and Pmch (pro-melanin-concentrating hormone)-positive neurons appeared within separate LH5 subdivisions, Pnoc (prepronociceptin)-expressing cells were mainly restricted to LH6, and Sst (somatostatin)-positive cells were identified within the LH7 sector. The alar LH9 sector, a component of the Foxg1-positive telencephalo-opto-hypothalamic border region, selectively contained Satb2-expressing cells. Published studies of rodent LH subdivisions have not described the observed pattern. Our genoarchitectonic map should aid in systematic approaches to elucidate LH connectivity and function.

Effect of Tuberculosis (TB) and Diabetes mellitus (DM) integrated healthcare on bidirectional screening and treatment outcomes among TB patients and people living with DM in developing countries: a systematic review.

A systematic review (Prospero CRD42017075562) including articles published between 1 January 1990 and 31 October 2021 was performed to synthesize evidence on the effect of integrating tuberculosis (TB) and diabetes mellitus (DM) healthcare on screening coverage and treatment loss to follow-up as compared to non-integrated care services for TB and DM in low- to middle-income countries (LMICs). Searches were performed in PubMed, Web of Science, WHO Global Index Medicus, and Cochrane Central Library. This review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and we adopted Cochrane data collection form for Randomized Controlled Trials (RCTs) and non-RCTs. Due to heterogeneity and limited data of studies included, meta-analysis was not performed. Of 6902 abstracts, 10 studies from South America, Asia, and Africa were included. One study from Zimbabwe showed 57% increase in DM screening among TB patients in integrated care as compared to non-integrated care; 95% CI: 54.1, 59.8. Seven studies with before-after comparison groups reported increased screening coverage during implementation of integrated healthcare that ranged from 10.1% in Mexico to 99.1% in China. Three studies reported reduction in loss to follow-up among TB patients in integrated care; two in China showed 9.2%, 95% CI: -16.7, -1.7, and -9.5%, 95% CI: -18.4, -0.7 differences, while a study from Mexico showed -5.3% reduction, 95% CI: -9.8, -0.9.With few and heterogenous included studies, the synthesized evidence is weak to establish effect of TB/DM integrated care. Therefore, further robust studies such as randomized clinical trials and well-designed observational studies are needed.

Is Electroacupuncture Contraindicated for Preventing and Treating Chemotherapy-Induced Peripheral Neuropathy?

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side-effect of several drugs used to combat cancer. Thus, researchers have sought better treatments for and prevention of CIPN, such as electroacupuncture (EA). Some trials show EA worsens or prolongs CIPN pain and recommend against further studies on this. This narrative review explores EA for preventing or treating CIPN, comparing positive and negative outcomes. Methods: PubMed, ScienceDirect, and Google Scholar were searched for electroacupuncture, CIPN, and peripheral neuropathy. A snowballing method was used to find systematic reviews and studies in systematic reviews. Results: Seven English-language trials were found on using EA for preventing or treating CIPN. In 3 prevention studies, 1 had significant benefits, 1 had modest benefits, and 1 had worse pain in an EA group at follow-up, compared to sham controls. In 4 treatment studies, 2 had significant benefits, 1 had no difference from 3 controls, and 1 had sham control was superior to verum EA. Conclusions: Most of the studies were limited by small sample sizes, and some studies used EA protocols and treatment doses (frequency and total number of sessions) that were potentially suboptimal. The quantity and quality of the studies are insufficient to draw firm conclusions on effectiveness and safety. More studies must test optimal EA protocols and treatment dosages. It is inappropriate to say that EA is not recommended for CIPN prevention or treatment, because there is no robust evidence to justify this. Generally, research has found benefits and no harms.