The evolution of precision oncology: The ongoing impact of the Drug Rediscovery Protocol (DRUP).

BACKGROUND AND PURPOSE: The Drug Rediscovery Protocol (DRUP) is a Dutch, pan-cancer, nonrandomized clinical trial that aims to investigate the efficacy and safety of targeted and immunotherapies outside their registered indication in patients with advanced or metastatic cancer. PATIENTS: Patients with advanced or metastatic cancer are eligible when there are no standard of care treatment options left and the tumor possesses a molecular genomic variant for which commercially available anticancer treatment is accessible off-label in DRUP. Clinical benefit is the study's primary endpoint, characterized by a confirmed objective response or stable disease after at least 16 weeks of treatment. RESULTS: More than 2,500 patients have undergone evaluation, of which over 1,500 have started treatment in DRUP. The overall clinical benefit rate (CBR) remains 33%. The nivolumab cohort for patients with microsatellite instable metastatic tumors proved highly successful with a CBR of 63%, while palbociclib or ribociclib in patients with tumors harboring CDK4/6 pathway alterations showed limited efficacy, with a CBR of 15%. The formation of two European initiatives (PCM4EU and PRIME-ROSE) strives to accelerate implementation and enhance data collection to broaden equitable access to anticancer treatments and gather more evidence. CONCLUSION: DRUP persists in improving patients access to off-label targeted or immunotherapy in the Netherlands and beyond. The expansion of DRUP-like clinical trials across Europe provides countless opportunities for broadening the horizon of precision oncology.

Trastuzumab plus pertuzumab for HER2-amplified advanced colorectal cancer: Results from the drug rediscovery protocol (DRUP).

BACKGROUND: In 2-5% of patients with colorectal cancer (CRC), human epidermal growth factor 2 (HER2) is amplified or overexpressed. Despite prior evidence that anti-HER2 therapy confers clinical benefit (CB) in one-third of these patients, it is not approved for this indication in Europe. In the Drug Rediscovery Protocol (DRUP), patients are treated with off-label drugs based on their molecular profile. Here, we present the results of the cohort 'trastuzumab/pertuzumab for treatment-refractory patients with RAS/BRAF-wild-type HER2amplified metastatic CRC (HER2+mCRC)'. METHODS: Patients with progressive treatment-refractory RAS/BRAF-wild-type HER2+mCRC with measurable disease were included for trastuzumab plus pertuzumab treatment. Primary endpoints of DRUP are CB (defined as confirmed objective response (OR) or stable disease (SD) ≥ 16 weeks) and safety. Patients were enrolled using a Simon-like 2-stage model, with 8 patients in stage 1 and 24 patients in stage 2 if at least 1/8 patients had CB. To identify biomarkers for response, whole genome sequencing (WGS) was performed on pre-treatment biopsies. RESULTS: CB was observed in 11/24 evaluable patients (46%) with HER2+mCRC, seven patients achieved an OR (29%). Median duration of response was 8.4 months. Patients had undergone a median of 3 prior treatment lines. Median progression-free survival and overall survival were 4.3 months (95% CI 1.9-10.3) and 8.2 months (95% CI 7.2-14.7), respectively. No unexpected toxicities were observed. WGS provided potential explanations for resistance in 3/10 patients without CB, for whom WGS was available. CONCLUSIONS: The results of this study confirm a clinically significant benefit of trastuzumab plus pertuzumab treatment in patients with HER2+mCRC.

Efficacy and Safety of Panitumumab in Patients With RAF/RAS-Wild-Type Glioblastoma: Results From the Drug Rediscovery Protocol.

BACKGROUND: The prognosis of malignant primary high-grade brain tumors, predominantly glioblastomas, is poor despite intensive multimodality treatment options. In more than 50% of patients with glioblastomas, potentially targetable mutations are present, including rearrangements, altered splicing, and/or focal amplifications of epidermal growth factor receptor (EGFR) by signaling through the RAF/RAS pathway. We studied whether treatment with the clinically available anti-EGFR monoclonal antibody panitumumab provides clinical benefit for patients with RAF/RAS-wild-type (wt) glioblastomas in the Drug Rediscovery Protocol (DRUP). METHODS: Patients with progression of treatment refractory RAF/RASwt glioblastoma were included for treatment with panitumumab in DRUP when measurable according to RANO criteria. The primary endpoints of this study are clinical benefit (CB: defined as confirmed objective response [OR] or stable disease [SD] ≥ 16 weeks) and safety. Patients were enrolled using a Simon-like 2-stage model, with 8 patients in stage 1 and up to 24 patients in stage 2 if at least 1 in 8 patients had CB in stage 1. RESULTS: Between 03-2018 and 02-2022, 24 evaluable patients were treated. CB was observed in 5 patients (21%), including 2 patients with partial response (8.3%) and 3 patients with SD ≥ 16 weeks (12.5%). After median follow-up of 15 months, median progression-free survival and overall survival were 1.7 months (95% CI 1.6-2.1 months) and 4.5 months (95% CI 2.9-8.6 months), respectively. No unexpected toxicities were observed. CONCLUSIONS: Panitumumab treatment provides limited CB in patients with recurrent RAF/RASwt glioblastoma precluding further development of this therapeutic strategy.

N-Glycosylation-dependent regulation of immune-specific tetraspanins CD37 and CD53.

Tetraspanin proteins play an important role in many cellular processes as they are key organizers of different receptors on the plasma membrane. Most tetraspanins are highly glycosylated at their large extracellular loop; however, little is known about the function of tetraspanin glycosylation in immune cells. In this study we investigated the effects of glycosylation of CD37 and CD53, two tetraspanins important for cellular and humoral immunity. Broad and cell-specific repertoires of N-glycosylated CD37 and CD53 were observed in human B cells. We generated different glycosylation mutants of CD37 and CD53 and analyzed their localization, nanoscale plasma membrane organization, and partner protein interaction capacity. Abrogation of glycosylation in CD37 revealed the importance of this modification for CD37 surface expression, whereas surface expression of CD53 was unaffected by its glycosylation. Single-molecule dSTORM microscopy revealed that the nanoscale organization of CD53 was not dependent on glycosylation. CD37 interaction with its partner proteins CD53 and CD20 was affected by glycosylation in a localization-dependent way, whereas its interaction with IL-6Rα was independent of glycosylation. Surprisingly, glycosylation was found to inhibit the interaction between CD53 and its partner proteins CD45, CD20, and, to a lesser extent CD37. Together, our data show that glycosylation affects the interaction capacity of immune-specific tetraspanins CD37 and CD53, which adds another layer of regulation to immune membrane organization.

An Exploratory Study Investigating Factors Influencing the Outpatient Delivery of Geriatric Rehabilitation.

BACKGROUND: Outpatient delivery of geriatric rehabilitation (GR) might contribute to preserving the accessibility and quality of GR, whilst dealing with an increasing demand for healthcare in an aging population. However, the application of outpatient GR differs between GR facilities. This study aimed to gain insight into factors influencing outpatient GR utilization. METHODS: In this case study, 24 semi-structured interviews were conducted with physicians, physiotherapists, nurse practitioners, occupational therapists, and managers in GR. Interviews were transcribed and analyzed using summative content analysis. RESULTS: Various patient-related barriers for using outpatient GR were mentioned including lacking social support and limited capacities and self-management skills. Additionally, professional-related barriers included a lack of awareness and consensus among care professionals regarding the possibilities and potential advantages of outpatient GR. Yet, most perceived barriers were related to efficiency and organization of outpatient GR (e.g., reimbursement system, lacking practical guidance). Still, most participants were in favor of increasing outpatient GR because of expected advantages for patients, GR organizations, and society. CONCLUSIONS: Despite experienced barriers, there seems to be agreement on the need to increase outpatient GR application. It is recommended to use the present findings to develop and evaluate new ways of organizing and reimbursing outpatient GR.

Low-Threshold-For-Surgery Versus Primarily-Conservative Treatment for Odontoid Fractures in the Elderly: Evaluating Practice Variation in The Netherlands.

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: Odontoid fractures are the most common cervical spine fractures in the elderly. The optimal treatment remains controversial. The aim of this study was to compare results of a low-threshold-for-surgery strategy (surgery for dislocated fractures in relatively healthy patients) to a primarily-conservative strategy (for all patients). METHODS: Patient records from 5 medical centers were reviewed for patients who met the selection criteria (e.g. age ≥55 years, type II/III odontoid fractures). Demographics, fracture types/characteristics, fracture union/stability, clinical outcome and mortality were compared. The influence of age on outcome was studied (≥55-80 vs ≥80 years). RESULTS: A total of 173 patients were included: 120 treated with low-threshold-for-surgery (of which 22 primarily operated, and 23 secondarily) vs 53 treated primarily-conservative. No differences in demographics and fracture characteristics between the groups were identified. Fracture union (53% vs 43%) and fracture stability (90% vs 85%) at last follow-up did not differ between groups. The majority of patients (56%) achieved clinical improvement compared to baseline. Analysis of differences in clinical outcome between groups was infeasible due to data limitations. In both strategies, patients ≥80 years achieved worse union (64% vs 30%), worse stability (97% vs 77%), and - as to be expected - increased mortality <104 weeks (2% vs 22%). CONCLUSIONS: Union and stability rates did not differ between the treatment strategies. Advanced age (≥80 years) negatively influenced both radiological outcome and mortality. No cases of secondary neurological deficits were identified, suggesting that concerns for the consequences of under-treatment may be unjustified.

Effects of musical mnemonics on working memory performance in cognitively unimpaired older adults and persons with amnestic mild cognitive impairment.

Episodic memory (EM) and working memory (WM) are negatively affected by healthy ageing, and additional memory impairment typically occurs in clinical ageing-related conditions such as amnestic mild cognitive impairment (aMCI). Recent studies on musical mnemonics in Alzheimer's dementia (AD) showed promising results on EM performance. However, the effects of musical mnemonics on WM performance have not yet been studied in (a)MCI or AD. Particularly in (a)MCI the use of musical mnemonics may benefit the optimisation of (working) memory performance. Therefore, in the present study, we examined the effects of musical presentation of digits consisting of pre-recorded rhythms, sung unfamiliar pitch sequences, and their combinations, as compared to spoken presentation. Furthermore, musical expertise was assessed with two perceptual tests and the Self-Report Inventory of the Goldsmiths Musical Sophistication Index. Thirty-two persons with aMCI and 32 cognitively unimpaired older adults (OA) participated in this study. Confirming and extending previous findings in research on ageing, our results show a facilitating effect of rhythm in both cognitively unimpaired OA and persons with aMCI (p = .001, ηp 2 = .158). Furthermore, pitch (p = .048, ηp 2 = .062) and melody (p = .012, ηp 2 = .098) negatively affected performance in both groups. Musical expertise increased this beneficial effect of musical mnemonics (p = .021, ηp 2 = .090). Implications for the future design of music-based memorisation strategies in (a)MCI are discussed.

Host-device interactions: exposure of lung epithelial cells and fibroblasts to nickel, titanium, or nitinol affect proliferation, reactive oxygen species production, and cellular signaling.

Endoscopic implantation of medical devices for the treatment of lung diseases, including airway stents, unidirectional valves and coils, is readily used to treat central airway disease and emphysema. However, granulation and fibrotic tissue formation impairs treatment effectiveness. To date little is known about the interaction between implanted devices, often made from metals, such as nickel, titanium or nitinol, and cells in the airways. Here, we study the response of lung epithelial cells and fibroblasts to implant device materials. The adhesion and proliferation of bronchial epithelial cells and lung fibroblasts upon exposure to 10 × 3 × 1 mm pieces of nickel, titanium or nitinol is examined using light and scanning electron microscopy. Pro-inflammatory cytokine mRNA expression and release, signaling kinase activity and intracellular free radical production are assessed. Nitinol, and to a lesser extent nickel and titanium, surfaces support the attachment and growth of lung epithelial cells. Nitinol induces a rapid and significant alteration of kinase activity. Cells directly exposed to nickel or titanium produce free radicals, but those exposed to nitinol do not. The response of lung epithelial cells and fibroblasts depends on the metal type to which they are exposed. Nitinol induces cellular surface growth and the induction of kinase activity, while exposure of lung epithelial cells to nickel and titanium induces free radical production, but nitinol does not.

Satiating Capacity of Plant-Based Meat in Realistic Meal Contexts at Home.

Plant-based meat substitutes replacing animal meat can potentially support the transition towards more sustainable diets. To enable the required transition, consumer acceptance of plant-based meat is essential. An important aspect of this is the feeling of satiety or being full after eating. This study determined the satiating capacity of both plant-based meat and animal meat in 60 adults under real-life in-home conditions. Participants consumed four fixed ready-to eat meals for lunch at home once per week. Two types of Indian curry with 'chicken' were investigated as well as two types of pasta Bolognese with 'minced meat'. The two 'chicken' dishes and the two 'minced meat' dishes had the same recipe except for a gram-for-gram swap (125 g each) of either animal meat (chicken breast and minced meat) or plant-based (soy) meat. Results showed no difference in the satiating power of an animal meat dish and a plant-based meat dish when these were eaten as part of a full lunch meal at home. In addition, the meals did not result in energy nor macronutrient compensation during the rest of the day after consuming the meals. This occurred despite the caloric differences of the meals as a result of the real-life conditions (i.e., a lower energy content of the pasta with plant-based meat compared to the other meals). We conclude that meals with plant-based meat can be as satiating as meals with animal meat.

Acid-base potentiometric titration using a stainless steel electrode without oxidative treatment.

An AISI 304 stainless steel laminar electrode without oxidative treatment was investigated for the potentiometric titration of hydrochloric acid with sodium hydroxide. The proposed electrode was obtained from metalworking cuttings. Scanning electron microscopy, energy dispersive X-ray spectroscopy, X-ray fluorescence spectroscopy and X-ray diffraction were used to study the surface morphology and chemical composition of the electrode. The electrode showed a sensitivity of 59.18 ± 0.37 mV/pH, which was reproducible under intermediate conditions. Potentiometric titration showed a curve with deviations from pH 9.5 with respect to the glass electrode. However, this did not affect the quantification as the jumps of the curves coincided. The endpoint was 9.25 mL for both electrodes and the hydrochloric acid concentration was 0.0845 mol/L, with a deviation of 0.0004 mol/L from the standard concentration of 0.0841 mol/L. The nonartificially oxidised electrode did not show any crystalline oxide phases, whereas after oxidation it showed semicrystalline phases of iron and chromium oxides and increased the crystallinity of the steel. Despite the low content of surface oxides, stainless steel electrodes can give a Nernstian response to pH, depending on the surface characteristics of the material. This leads to the need to calibrate any electrode prior to oxidative treatment to rule out a Nernstian response without surface modification.

Which factors promote and prohibit successful implementation and normalization of a healthy school lunch program at primary schools in the Netherlands?

BACKGROUND: A school provided healthy lunch might help to improve the nutritional quality of children's lunches. However, in the Netherlands, school lunch programs are not common. The aim of this study was to identify factors that promote or inhibit the implementation of a school lunch program at primary schools, from the viewpoint of school professionals. METHODS: A cross-sectional online survey was conducted among 204 primary school professionals. The normalization process theory and its four constructs (i.e. coherence, cognitive participation, collective action, reflective monitoring) were used to develop questions and interpret findings. Descriptive statistics were used for 14 multiple choice questions (yes, no, don't know) and thematic content analysis for qualitative responses. RESULTS: Participants had a shared understanding about how a lunch program differed from current practices. Most participants had the same view on the rationale for implementation (coherence), such as equality among children. Sixty percent expected that a healthy school lunch will contribute to healthier eating by the children. Participants showed different degrees of cognitive participation (46% indicated that healthy school lunch is good idea). Commitment depended on their belief whether providing a healthy lunch was part of their responsibility as school and 30% expected a large effect on their daily work (collective action). When appraising school lunch implementation (reflective monitoring), participants' concerns focused on feasibility and adaptability of a program in their own school. CONCLUSIONS: The introduction of a school lunch program will require substantial effort, although there is considerable support and understanding about potential benefits. The findings point to a number of preconditions for large-scale introduction, including the need for support-both financially and organizationally-bottom-up involvement of teachers, children and parents and freedom to adapt the program.

Unusual Presentation of Wünderlich Syndrome.

Background: Wünderlich syndrome is a rare but important condition because it involves a sudden blood collection in the renal fossa that can cause hemodynamic instability. Case Report: A 38-year-old female with a history of type 2 diabetes mellitus and hypertension with poor adherence to treatment presented to the emergency department with abdominal pain of 2 weeks' duration accompanied by irritative lower urinary symptoms. Abdominal computed tomography (CT) scan showed bilateral pyelonephritis and an abscess in the lower pole of the right kidney. A second CT scan, performed because of the patient's abrupt decrease in hemoglobin and hematocrit, showed active bleeding secondary to the infectious process in the right kidney. The patient was hemodynamically unstable, so a nephrectomy was performed. Conclusion: Wünderlich syndrome is a spontaneous renal hemorrhage, in most cases attributed to a tumorous etiology and rarely of infectious origin. The clinical picture is varied but can present with the Lenk triad of acute onset flank pain, flank mass, and hypovolemic shock. It is diagnosed principally via an imaging study such as abdominal CT scan. Treatment is conservative in principle, but urgent surgical intervention is sometimes necessary depending on the clinical situation of the patient.

The Intracellularly Acting Effector Foa3 Suppresses Defense Responses When Infiltrated Into the Apoplast.

Plant pathogens employ secreted proteins, among which are effectors, to manipulate and colonize their hosts. A large fraction of effectors is translocated into host cells, where they can suppress defense signaling. Bacterial pathogens directly inject effectors into host cells via the type three secretion system, but it is little understood how eukaryotic pathogens, such as fungi, accomplish this critical process and how their secreted effectors enter host cells. The root-infecting fungus Fusarium oxysporum (Fo) secrets numerous effectors into the extracellular space. Some of these, such as Foa3, function inside the plant cell to suppress host defenses. Here, we show that Foa3 suppresses pattern-triggered defense responses to the same extent when it is produced in planta irrespective of whether the protein carries the PR1 secretory signal peptide or not. When a GFP-tagged Foa3 was targeted for secretion it localized, among other locations, to mobile subcellular structures of unknown identity. Furthermore, like the well-known cell penetrating peptide Arginine 9, Foa3 was found to deliver an orthotospovirus avirulence protein-derived peptide into the cytosol, resulting in the activation of the matching resistance protein. Finally, we show that infiltrating Foa3 into the apoplast results in strong suppression of the pattern-triggered immune responses, potentially indicating its uptake by the host cells in absence of a pathogen.

Facial Emotion Expression and the Inducibility of Myocardial Ischemia During Cardiac Stress Testing: The Role of Psychological Background Factors.

OBJECTIVE: Negative emotional states, such as anger and anxiety, are associated with the onset of myocardial infarction and other acute clinical manifestations of ischemic heart disease. The likelihood of experiencing these short-term negative emotions has been associated with long-term psychological background factors such as depression, generalized anxiety, and personality factors. We examined the association of acute emotional states preceding cardiac stress testing (CST) with inducibility of myocardial ischemia and to what extent psychological background factors account for this association. METHODS: Emotional states were assessed in patients undergoing CST (n = 210; mean [standard deviation] age = 66.9 [8.2] years); 91 (43%) women) using self-report measures and video recordings of facial emotion expression. Video recordings were analyzed for expressed anxiety, anger, sadness, and happiness before CST. Psychological background factors were assessed with validated questionnaires. Single-photon emission computed tomography was used to evaluate inducibility of ischemia. RESULTS: Ischemia occurred in 72 patients (34%). Emotional states were not associated with subsequent inducibility of ischemia during CST (odds ratio between 0.93 and 1.04; p values > .50). Psychological background factors were also not associated with ischemia (odds ratio between 0.96 and 1.06 per scale unit; p values > .20) and did not account for the associations of emotional states with ischemia. CONCLUSIONS: Emotional states immediately before CST and psychological background factors were not associated with the inducibility of ischemia. These findings indicate that the well-documented association between negative emotions with acute clinical manifestations of ischemic heart disease requires a different explanation than a reduced threshold for inducible ischemia.

Adverse stem cell clones within a single patient's tumor predict clinical outcome in AML patients.

Acute myeloid leukemia (AML) patients suffer dismal prognosis upon treatment resistance. To study functional heterogeneity of resistance, we generated serially transplantable patient-derived xenograft (PDX) models from one patient with AML and twelve clones thereof, each derived from a single stem cell, as proven by genetic barcoding. Transcriptome and exome sequencing segregated clones according to their origin from relapse one or two. Undetectable for sequencing, multiplex fluorochrome-guided competitive in vivo treatment trials identified a subset of relapse two clones as uniquely resistant to cytarabine treatment. Transcriptional and proteomic profiles obtained from resistant PDX clones and refractory AML patients defined a 16-gene score that was predictive of clinical outcome in a large independent patient cohort. Thus, we identified novel genes related to cytarabine resistance and provide proof of concept that intra-tumor heterogeneity reflects inter-tumor heterogeneity in AML.

Academy of Breastfeeding Medicine Clinical Protocol #2: Guidelines for Birth Hospitalization Discharge of Breastfeeding Dyads, Revised 2022.

A central goal of the Academy of Breastfeeding Medicine is the development of clinical protocols for managing common medical problems that may impact breastfeeding success. These protocols serve only as guidelines for the care of breastfeeding mothers and infants and do not delineate an exclusive course of treatment or serve as standards of medical care. Variations in treatment may be appropriate according to the needs of an individual patient. The Academy of Breastfeeding Medicine recognizes that not all lactating individuals identify as women. Using gender-inclusive language, however, is not possible in all languages and all countries and for all readers. The position of the Academy of Breastfeeding Medicine (https://doi.org/10.1089/bfm.2021.29188.abm) is to interpret clinical protocols within the framework of inclusivity of all breastfeeding, chestfeeding, and human milk-feeding individuals.

Psychological factors of suspect coronary microvascular dysfunction in patients undergoing SPECT imaging.

BACKGROUND: Patients with myocardial ischemia in the absence of obstructive coronary artery disease (CAD) often experience anginal complaints and are at risk of cardiac events. Stress-related psychological factors and acute negative emotions might play a role in these patients with suspect coronary microvascular dysfunction (CMD). METHODS AND RESULTS: 295 Patients (66.9 ± 8.7 years, 46% women) undergoing myocardial perfusion single-photon-emission computed tomography (MPI-SPECT), were divided as follows: (1) a non-ischemic reference group (n = 136); (2) patients without inducible ischemia, but with a history of CAD (n = 62); (3) ischemia and documented CAD (n = 52); and (4) ischemia and suspect CMD (n = 45). These four groups were compared with regard to psychological factors and acute emotions. Results revealed no differences between the groups in psychological factors (all P > .646, all effect sizes d < .015). State sadness was higher for patients with suspect CMD (16%) versus the other groups (P = .029). The groups did not differ in the association of psychological factors or emotions with anginal complaints (all P values > .448). CONCLUSION: Suspect CMD was not associated with more negative psychological factors compared to other groups. State sadness was significantly higher for patients with suspect CMD, whereas no differences in state anxiety and other psychological factors were found.

Ghrelin as a prominent endocrine factor in stress-induced obesity.

Objectives: Ghrelin acts on a variety of central- and peripheral organs causing an orexigenic effect, conclusively followed by increased caloric intake. Recent studies have indicated that ghrelin's function as an orexigenic agent does not entirely reflect the full functional properties of the peptide. Specifically, ghrelin regulates stress-hormone synthesis and secretion therewith affecting the stress-axis. The role of stress in the development of obesity has been extensively studied. However, the orexigenic and underlying stress-regulatory effect of ghrelin has not yet been further considered in the development of stress-induced obesity.Methods: Therefore, this review aims to accentuate the potential of ghrelin as a factor in the pathological development of stress-induced obesity.Results: In this review we discuss (1) the ghrelin-mediated intracellular cascades and elucidate the overall bioactivation of the peptide, and (2) the mechanisms of ghrelin signalling and regulation within the central nervous system and the gastro-intestinal system.Discussion: These biological processes will be ultimately discussed in relation to the pathogenesis of stress-induced obesity.

Latino/a Farmworkers' Concerns about Safety and Health in the Pennsylvania Mushroom Industry.

The purposes of this study were to analyze Latino/a immigrant mushroom workers' perceptions of how the workplace environment shapes occupational safety and health, examine whether and how those perceptions differ by gender, and identify future areas for research on occupational safety and health in the mushroom industry. Researchers conducted structured interviews with 15 women and 45 men on 6 Pennsylvania mushroom farms to obtain their descriptions and perspectives of safety and health risk factors in their workplaces. Approximately one third of respondents had suffered an injury at work, and nearly half felt that there are workplace factors that affect their health and safety. The study found that Latino/a mushroom farmworkers perceive risks that are posed by the indoor infrastructure of mushroom production houses, including poorly maintained wooden walkways and cool indoor temperatures, and by the organization of mushroom production work, including the application of chemicals including pesticides, physical demands of the job, use of small knives, contact with compost, and the piece rate payment system. Workers commonly discussed back pain and believed it was associated with the organization of work. Women in the sample were more likely to be concerned about slips and falls than men and less likely to be concerned about aches and pains. Mushroom farm infrastructure and the specific demands of the jobs pose occupational safety and health risks to Latino/a farmworkers that merit further study to develop adequate public health interventions. Future research should obtain gender-disaggregated objective reports of injury, aches and pains, and discomfort and test for relationships between these reports and the indoor infrastructure and conditions of mushroom production work.

Milk fat globule membrane attenuates high fat diet-induced neuropathological changes in obese Ldlr-/-.Leiden mice.

BACKGROUND: Milk-fat globule membrane (MFGM) is a complex structure secreted by the mammary gland and present in mammalian milk. MFGM contains lipids and glycoproteins as well as gangliosides, which may be involved in myelination processes. Notably, myelination and thereby white matter integrity are often altered in obesity. Furthermore, MFGM interventions showed beneficial effects in obesity by affecting inflammatory processes and the microbiome. In this study, we investigated the impact of a dietary MFGM intervention on fat storage, neuroinflammatory processes and myelination in a rodent model of high fat diet (HFD)-induced obesity. METHODS: 12-week-old male low density lipoprotein receptor-deficient Leiden mice were exposed to a HFD, a HFD enriched with 3% whey protein lipid concentrate (WPC) high in MFGM components, or a low fat diet. The impact of MFGM supplementation during 24-weeks of HFD-feeding was examined over time by analyzing body weight and fat storage, assessing cognitive tasks and MRI scanning, analyzing myelinization with polarized light imaging and examining neuroinflammation using immunohistochemistry. RESULTS: We found in this study that 24 weeks of HFD-feeding induced excessive fat storage, increased systolic blood pressure, altered white matter integrity, decreased functional connectivity, induced neuroinflammation and impaired spatial memory. Notably, supplementation with 3% WPC high in MFGM components restored HFD-induced neuroinflammation and attenuated the reduction in hippocampal-dependent spatial memory and hippocampal functional connectivity. CONCLUSIONS: We showed that supplementation with WPC high in MFGM components beneficially contributed to hippocampal-dependent spatial memory, functional connectivity in the hippocampus and anti-inflammatory processes in HFD-induced obesity in rodents. Current knowledge regarding exact biological mechanisms underlying these effects should be addressed in future studies.