Coming back together: a qualitative survey study of coping and support strategies used by people to cope with extended difficulties after the use of psychedelic drugs.

Introduction: A growing body of literature is investigating the difficulties that some individuals encounter after psychedelic experiences. Existing research has explored the nature and predictors of these difficulties; however, a research gap exists in understanding how individuals endeavour to cope with such difficulties. Methods: The current study collected data from an international cohort of 608 participants who reported experiencing difficulties that persisted for at least one day after a psychedelic experience. They provided written data on how they used coping strategies to alleviate these difficulties. The qualitative analysis of the written data on coping was conducted using Structured Tabular Thematic Analysis. Results: A wide range of individual and social coping strategies were employed that were found helpful. The most common individual strategies were meditation and prayer, followed by self-educational activities such as reading and journaling. The most prevalent forms of social coping involved seeking support from friends or family members, followed by obtaining assistance from a therapist or coach. Features of social coping that were reported to be helpful included feeling heard/accepted, a non-judgemental attitude and sharing similar experiences. Discussion: Our findings hold potential for informing the design of therapeutic interventions and educational resources aimed at enhancing positive outcomes for those experiencing extended difficulties after psychedelic use.

Experiences of moving an older parent into a care home or nursing home in the UK: a qualitative study.

The study explored the personal experiences of individuals making the decision to move an older parent into a residential care facility via retrospective narrative. It aimed to gain an understanding of how individuals experienced this transition, the emotions they felt at specific moments throughout the transition, and the perceived effect it had on their psychological wellbeing. 13 semi-structured video interviews were conducted online with individuals who had been active in the decision of moving an older parent into a care home or nursing home. The data was analysed using thematic analysis, along with relational analysis to explore relations between themes. Findings informed 8 different themes, which were subsumed under three meta-themes of The Decision Process, Conflicting Emotions and Reflective Evaluation. It was found that the decision was recalled as a complex and often stressful negotiation between multiple stakeholders, that emotions ranged from grief to guilt and relief, and that reflections emphasised the positive that had come out of the transition. The results from this study provide valuable insights into the uniqueness of this transition from the perspective of relatives and the range of emotions experienced at different stages of the transition.

Arcuate Fasciculus Microstructure Predicts Alcohol Dependence Risk through Higher IQ.

IQ has been found to correlate with alcohol consumption, with a higher IQ being a risk for alcohol misuse. Furthermore, recent research has shown that the microstructure of the arcuate fasciculus is associated with IQ. This study therefore aimed to examine the association between the arcuate fasciculus microstructure, IQ, and alcohol dependence risk. In this study, we performed probabilistic tractography between Wernicke's and Broca's areas in the left and right hemispheres to examine the association of the arcuate fasciculus's integrity with IQ and alcohol dependence risk, using DTI data from 344 individuals. Data regarding IQ were obtained from the Wechsler Abbreviated Scale of Intelligence (WASI-II). Alcohol substance involvement (SI) score was derived using the National Institute on Drug Abuse (NIDA) Quick Screen and was used as an index for alcohol dependence risk. Both the left arcuate fasciculus and IQ were found to have a significant association with alcohol dependence risk. A mediation analysis revealed that this association between the left arcuate fasciculus microstructure and an alcohol dependence risk was mediated by IQ. It is suggested that the left arcuate fasciculus microstructure is associated with IQ which is associated with alcohol dependence risk. While alcohol consumption is known to be robustly toxic to the brain, the left arcuate fasciculus shows exceptional characteristics in which its microstructure integrity is positively associated with an alcohol dependence risk through higher IQ. Clinical implications are discussed.

Mitigation of MAFLD in High Fat-High Sucrose-Fructose Fed Mice by a Combination of Genistein Consumption and Exercise Training.

Purpose: Metabolic dysfunction-associated fatty liver disease (MAFLD) is fueled by escalations in both sedentary behavior and caloric intake and is noted in obese type 2 diabetic (T2DM) patients. This study aimed to examine the effects of exercise and the phytoestrogen genistein in mice fed a high fat (60% fat) high sugar (55% fructose with 45% sucrose), HFHS diet. Methods: Male C57BL/6J mice were assigned to five groups: HFHS, HFHS with genistein (600 mg/kg diet, HFHS+Gen), HFHS with moderate exercise (HFHS+Ex), and HFHS with combined genistein and moderate exercise (HFHS-Gen+Ex). Control lean mice were fed standard chow and water. Exercise consisted of 30-minute sessions of treadmill running five days/week for the 12-week study duration. Body weight was assessed weekly. Liver, kidney, fecal pellets and serum were extracted at the end of the study and maintained at -80°C. Results: After 12 weeks of treatment, mice in the HFHS group had the highest hepatic lipid content. Plasma levels of glucose, insulin, leptin, cholesterol, amylin, and total fat content were significantly elevated in HFHS mice compared to control mice. HFHS feeding increased protein expression of carnitine palmitoyltransferase 1b (CPT-1b isoform) in gastrocnemius, CPT1a, glucose transporter protein 2 (GLUT2), glucocorticoid receptor (GR), and fructose 1,6-bisphosphate 1 (FBP1) expression in liver. Exercise alone had minor effects on these metabolic abnormalities. Genistein alone resulted in improvements in body weight, fat content, amylin, insulin sensitivity, and liver histopathology, GR, FBP1, and acetyl-CoA carboxylase 1 (ACC1). Combination treatment resulted in additional metabolic improvements, including reductions in hepatic lipid content and lipid area, alanine transferase activity, CPT1b, and CPT1a. Conclusion: Our results indicate that a HFHS diet is obesogenic, inducing metabolic perturbations consistent with T2DM and MAFLD. Genistein alone and genistein combined with moderate intensity exercise were effective in reducing MAFLD and the aberrations induced by chronic HFHS feeding.

Evaluation of Recombinant Botulinum Neurotoxin Type A1 Efficacy in Peripheral Inflammatory Pain in Mice.

Well-established efficacy of botulinum neurotoxin type A (BoNT/A) in aesthetic dermatology and neuromuscular hyperactivity disorders relies on canonical interruption of acetylcholine neurotransmission at the neuromuscular junction at the site of the injection. The mechanisms and the site of activity of BoNT/A in pain, on the other hand, remain elusive. Here, we explored analgesic activity of recombinant BoNT/A1 (rBoNT/A1; IPN10260) in a mouse model of inflammatory pain to investigate the potential role of peripheral sensory afferents in this activity. After confirming analgesic efficacy of rBoNT/A1 on CFA-induced mechanical hypersensitivity in C57Bl6J mice, we used GCaMP6s to perform in vivo calcium imaging in the ipsilateral dorsal root ganglion (DRG) neurons in rBoNT/A1 vs. vehicle-treated mice at baseline and following administration of a range of mechanical and thermal stimuli. Additionally, immunohisochemical studies were performed to detect cleaved SNAP25 in the skin, DRGs and the spinal cord. Injection of CFA resulted in reduced mechanical sensitivity threshold and increased calcium fluctuations in the DRG neurons. While rBoNT/A1 reduced mechanical hypersensitivity, calcium fluctuations in the DRG of rBoNT/A1- and vehicle-treated animals were similar. Cleaved SNAP25 was largely absent in the skin and the DRG but present in the lumbar spinal cord of rBoNT/A1-treated animals. Taken together, rBoNT/A1 ameliorates mechanical hypersensitivity related to inflammation, while the signal transmission from the peripheral sensory afferents to the DRG remained unchanged. This strengthens the possibility that spinal, rather than peripheral, mechanisms play a role in the mediation of analgesic efficacy of BoNT/A in inflammatory pain.

Pixelwise H-score: A novel digital image analysis-based metric to quantify membrane biomarker expression from immunohistochemistry images.

Immunohistochemistry (IHC) assays play a central role in evaluating biomarker expression in tissue sections for diagnostic and research applications. Manual scoring of IHC images, which is the current standard of practice, is known to have several shortcomings in terms of reproducibility and scalability to large scale studies. Here, by using a digital image analysis-based approach, we introduce a new metric called the pixelwise H-score (pix H-score) that quantifies biomarker expression from whole-slide scanned IHC images. The pix H-score is an unsupervised algorithm that only requires the specification of intensity thresholds for the biomarker and the nuclear-counterstain channels. We present the detailed implementation of the pix H-score in two different whole-slide image analysis software packages Visiopharm and HALO. We consider three biomarkers P-cadherin, PD-L1, and 5T4, and show how the pix H-score exhibits tight concordance to multiple orthogonal measurements of biomarker abundance such as the biomarker mRNA transcript and the pathologist H-score. We also compare the pix H-score to existing automated image analysis algorithms and demonstrate that the pix H-score provides either comparable or significantly better performance over these methodologies. We also present results of an empirical resampling approach to assess the performance of the pix H-score in estimating biomarker abundance from select regions within the tumor tissue relative to the whole tumor resection. We anticipate that the new metric will be broadly applicable to quantify biomarker expression from a wide variety of IHC images. Moreover, these results underscore the benefit of digital image analysis-based approaches which offer an objective, reproducible, and highly scalable strategy to quantitatively analyze IHC images.

First-in-Human Study of PF-06647020 (Cofetuzumab Pelidotin), an Antibody-Drug Conjugate Targeting Protein Tyrosine Kinase 7, in Advanced Solid Tumors.

PURPOSE: We investigated safety, tolerability, pharmacokinetics, and antitumor activity of the protein tyrosine kinase 7 (PTK7)-targeted, auristatin-based antibody-drug conjugate (ADC) PF-06647020/cofetuzumab pelidotin (NCT02222922). PATIENTS AND METHODS: Patients received PF-06647020 intravenously every 3 weeks at 0.2-3.7 mg/kg or every 2 weeks at 2.1-3.2 mg/kg, in sequential dose escalation, following a modified toxicity probability interval method. In dose expansion, pretreated patients with advanced, platinum-resistant ovarian cancer, non-small cell lung cancer (NSCLC), or triple-negative breast cancer (TNBC) received PF-06647020 2.8 mg/kg every 3 weeks. RESULTS: The most common, treatment-related adverse events for PF-06647020 administered every 3 weeks were nausea, alopecia, fatigue, headache, neutropenia, and vomiting (45%-25%); 25% of patients had grade ≥ 3 neutropenia. Two patients experienced dose-limiting toxicities (grade 3 headache and fatigue) at the highest every 3 weeks dose evaluated. The recommended phase II dose was 2.8 mg/kg every 3 weeks. The overall safety profile observed with PF-06647020 administered every 2 weeks was similar to that of the every 3 weeks regimen. Systemic exposure for the ADC and total antibody generally increased in a dose-proportional manner. Antitumor activity was observed in treated patients with overall objective response rates of 27% in ovarian cancer (n = 63), 19% in NSCLC (n = 31), and 21% in TNBC (n = 29). Responders tended to have moderate or high PTK7 tumor expression by IHC. CONCLUSIONS: This PTK7-targeted ADC demonstrated therapeutic activity in previously treated patients with ovarian cancer, NSCLC, and TNBC at a dose range of 2.1-3.2 mg/kg, supporting further clinical evaluation to refine dose, schedule, and predictive tissue biomarker testing in patients with advanced malignancies.

Ecological contexts of youth antisocial behaviors: A longitudinal perspective.

The current study examined and compared the relative influence of ecological factors on youth antisocial behaviors (i.e., aggression and rule-breaking) using longitudinal data while assessing the moderating effect of youth attention-deficit/hyperactivity disorder (ADHD) diagnosis. The study used the fifth and sixth wave of data from the Fragile Families and Child Wellbeing Study (n = 2595; mean age = 9.26 at wave five) for the analysis. Multivariate models show that youth ADHD, physically and psychologically abusive parenting, peer victimization, and community cohesion were important predictors of youth antisocial behaviors. Furthermore, youth ADHD diagnosis moderated some associations between the ecological factors and antisocial behaviors, suggesting that youth with and without ADHD may respond to some ecological contexts differently regarding the concerning behaviors. The findings imply that interventions targeting youth antisocial behaviors should involve collaboration across systems and coordination across programs to tackle a multilayered ecological context, especially when youth with ADHD are involved.

Ovarian cancer: new strategies and emerging targets for the treatment of patients with advanced disease.

Recently approved therapies have contributed to a significant progress in the management of ovarian cancer; yet, more options are needed to further improve outcomes in patients with advanced disease. Here we review the rationale and ongoing clinical trials of novel combination strategies involving chemotherapy, poly ADP ribose polymerase, programmed death 1 (PD-1)/PD-ligand 1 immune checkpoint and/or vascular endothelial growth factor receptor inhibitors. Further, we discuss novel agents aimed at targets associated with ovarian cancer growth or progression that are emerging as potential new treatment approaches. Among them, agents targeted to folate receptor α, tissue factor, and protein kinase-mediated pathways (WEE1 kinase, phosphatidylinositol-3 kinase α, cell cycle checkpoint kinase 1/2, ATR kinase) are currently in clinical development as mono- or combination therapies. If successful, findings from these extensive development efforts may further transform treatment of patients with advanced ovarian cancer.

Tobacco-Free Ambassador Partnership: Empowering Youth Advocates in Appalachian Communities.

Kentucky youth (14.3%) smoke more cigarettes as compared to the U.S. average (8.8%), and Appalachian communities suffer disproportionately from tobacco-related diseases such as lung cancer. Training youth to become advocates is an effective strategy to improve health equity. This article describes the development and impact of a youth advocacy program to promote tobacco control policies in Appalachian Kentucky. Phase I (2017-2018): two ½-day trainings followed by monthly meetings with one high school (n = 20 youth). Trainings provided information on tobacco use, consequences, industry tactics, evidence-based tobacco control, and advocacy skills. Results provided support for expansion to Phase II (2018-20119): A 1-day training followed by monthly information sharing implemented in three counties (N = 80). Youth were surveyed before and 6-months posttraining during both phases. Phase I: At posttraining, 85% of youth believed they could reduce the amount of tobacco use in their community versus 66% at baseline. More students tried at least once to convince school or government officials to be more concerned about tobacco use (77% vs. 47%). Phase II: More students supported tobacco policies at posttraining survey and realized policies are an effective strategy to reduce tobacco use. At posttraining survey, students reported greater interpersonal confidence talking with others about tobacco-related issues, with a 24% increase in confidence talking with adults in their communities, as well as greater advocacy self-efficacy. Youth in Appalachia demonstrate desire to influence tobacco use and policy to improve health equity. Findings reinforce the need for collaborative public health interventions to promote ongoing training and support for youth living in high-risk communities.

Preclinical Neuropathic Pain Assessment; the Importance of Translatability and Bidirectional Research.

For patients suffering with chronic neuropathic pain the need for suitable novel therapies is imperative. Over recent years a contributing factor for the lack of development of new analgesics for neuropathic pain has been the mismatch of primary neuropathic pain assessment endpoints in preclinical vs. clinical trials. Despite continuous forward translation failures across diverse mechanisms, reflexive quantitative sensory testing remains the primary assessment endpoint for neuropathic pain and analgesia in animals. Restricting preclinical evaluation of pain and analgesia to exclusively reflexive outcomes is over simplified and can be argued not clinically relevant due to the continued lack of forward translation and failures in the clinic. The key to developing new analgesic treatments for neuropathic pain therefore lies in the development of clinically relevant endpoints that can translate preclinical animal results to human clinical trials. In this review we discuss this mismatch of primary neuropathic pain assessment endpoints, together with clinical and preclinical evidence that supports how bidirectional research is helping to validate new clinically relevant neuropathic pain assessment endpoints. Ethological behavioral endpoints such as burrowing and facial grimacing and objective measures such as electroencephalography provide improved translatability potential together with currently used quantitative sensory testing endpoints. By tailoring objective and subjective measures of neuropathic pain the translatability of new medicines for patients suffering with neuropathic pain will hopefully be improved.

Bone Strength Is Improved with Genistein Treatment in Mice with Diet-Induced Obesity.

BACKGROUND: High caloric intake of saturated fat and refined sugars accelerates the development of obesity and diabetes and increases bone fracture risk. Some evidence suggests that consumption of a diet rich in phytoestrogens like genistein has the potential to strengthen bone biomechanical properties. Its bone-strengthening properties may mitigate fracture risk associated with metabolic conditions like obesity and diabetes, especially when combined with exercise. OBJECTIVE: In this study, we test the effects of genistein, exercise training, and combination treatment on biomechanical properties of cortical bone in mice fed a high-fat, high-sugar (HFHS) diet. METHODS: Eighty C67BL6 mice (40 females, 40 males) aged 6 wk were treated for 12 wk with an HFHS diet containing 60% fat and drinking water with 4.2 g/L sugar (55% sucrose, 45% fructose). Subgroups of the mice were also treated with genistein and/or moderate exercise (treadmill running). Genistein was incorporated into the HFHS diet (600 mg genistein/kg HFHS) and exercise was performed daily for 30 min, 5 d/wk (n = 10 females, 10 males per group). Three-point bending mechanical testing and quantitative fluorescence microscopy were conducted on femurs to measure bone strength and matrix quality. RESULTS: Mechanical testing revealed HFHS-fed mice treated with genistein, either alone or combined with exercise, had femurs that exhibited increased postyield displacement and reduced stiffness during 3-point bending in comparison with mice only treated with the HFHS diet. Femurs of genistein-treated mice also exhibited greater ultimate force required to achieve fracture. Quantitative fluorescence showed genistein reduced advanced glycation end product accumulation in bone matrix. Exercise treatment alone had no effect. CONCLUSIONS: Treatment with genistein, either alone or in combination with exercise, improves fracture resistance in mice fed an HFHS diet by improving bone matrix quality and increasing bone strength.

Correlation of bio-optical properties with photosynthetic pigment and microorganism distribution in microbial mats from Hamelin Pool, Australia.

Microbial mats and stromatolites are widespread in Hamelin Pool, Shark Bay, however the phototrophic capacity of these systems is unknown. This study has determined the optical properties and light-harvesting potential of these mats with light microsensors. These characteristics were linked via a combination of 16S rDNA sequencing, pigment analyses and hyperspectral imaging. Local scalar irradiance was elevated over the incident downwelling irradiance by 1.5-fold, suggesting light trapping and strong scattering by the mats. Visible light (400-700 nm) penetrated to a depth of 2 mm, whereas near-infrared light (700-800 nm) penetrated to at least 6 mm. Chlorophyll a and bacteriochlorophyll a (Bchl a) were found to be the dominant photosynthetic pigments present, with BChl a peaking at the subsurface (2-4 mm). Detailed 16S rDNA analyses revealed the presence of putative Chl f-containing Halomicronema sp. and photosynthetic members primarily decreased from the mat surface down to a depth of 6 mm. Data indicated high abundances of some pigments and phototrophic organisms in deeper layers of the mats (6-16 mm). It is proposed that the photosynthetic bacteria present in this system undergo unique adaptations to lower light conditions below the mat surface, and that phototrophic metabolisms are major contributors to ecosystem function.

High-fat, high-sugar diet induces splenomegaly that is ameliorated with exercise and genistein treatment.

OBJECTIVE: We tested the effect of exercise training and genistein treatment on splenomegaly in mice fed a high-fat, high-sugar diet (HFSD). RESULTS: Male and female C57BL6 mice fed HFSD containing 60% fat along with drinking water containing 42 g/L sugar (55% sucrose/45% fructose) for 12 weeks exhibited significant obesity, hyperglycemia, and elevated plasma IL-6 levels. This was accompanied by splenomegaly characterized by spleen weights 50% larger than mice fed standard chow (P < 0.05) with enlarged rad and white pulps. Mice fed HFSD and treated with a combination of exercise (30 min/day, 5 days/week) and genistein (600 mg genistein/kg diet) had reduced spleen weight (P < 0.05). The decrease in spleen weight was associated with a significant improvement in red-to-white pulp area ratio and plasma glucose and IL-6 (P < 0.05). Our findings indicate that reversal of splenomegaly by regular exercise and genistein treatment may be important in the clinical management of HFSD-induced obesity.

Inductive reasoning in the context of discovery: Analogy as an experimental stratagem in the history and philosophy of science.

Building on Norton's "material theory of induction," this paper shows through careful historical analysis that analogy can act as a methodological principle or stratagem, providing experimentalists with a useful framework to assess data and devise novel experiments. Although this particular case study focuses on late eighteenth and early nineteenth-century experiments on the properties and composition of acids, the results of this investigation may be extended and applied to other research programs. A stage in-between what Steinle calls "exploratory experimentation" and robust theory, I argue that analogy encouraged research to substantiate why the likenesses should outweigh the differences (or vice versa) when evaluating results and designing experiments.

Robert Hare's Theory of Galvanism: A Study of Heat and Electricity in Early Nineteenth-Century American Chemistry.

As a professor of chemistry at the University of Pennsylvania, Robert Hare actively shaped early American science. He participated in a large network of scholars, including Joseph Henry, François Arago, and Jacob Berzelius, and experimented with and wrote extensively about electricity and its associated chemical and thermal phenomena. In the early nineteenth century, prominent chemists such as Berzelius and Humphry Davy proclaimed that a revolution had occurred in chemistry through electrical research. Examining Robert Hare's contributions to this discourse, this paper analyzes how Hare's study of electricity and the caloric theory of heat led him to propose a new theory of galvanism. It also examines the reception of Hare's work in America and Great Britain, highlighting the contributions of early American chemists to the development of electrochemistry.

The Potential for Screening for Intimate Partner Violence in Community Pharmacies: An Exploratory Study of Female Consumers' Perspectives.

Intimate partner violence (IPV) is a substantial public health problem. The U.S. Preventive Services Task Force recently updated guidelines to recommend IPV screening for all women of childbearing age. Expansion of screening efforts to the community pharmacy setting could provide an opportunity to substantially impact the health of consumers. To date, no research has explored consumers' perspective on IPV screening in the community pharmacy environment. To address this gap, a descriptive survey research study was conducted to examine female consumers' attitudes and preferences for IPV screening in community pharmacies. Female pharmacy customers ( N = 60) completed an online survey assessing knowledge of and attitudes about community pharmacies as sources of health care advice, beliefs about IPV and IPV screening, and perspectives on IPV screening in the community pharmacy environment. Consumers who utilized pharmacies with more patient care services were more likely to report interest in IPV screening in the pharmacy environment. The majority of respondents thought IPV screening is an important thing to do (85.0%), and 33.3% agreed that it should happen in a pharmacy. A statistically significant relationship between the belief that the pharmacy is a good place for health education and preference for IPV screening in the community pharmacy environment was found, r(58) = .43, p < .001. Concern regarding the time required to conduct screenings and about the availability of appropriate space were identified as potential barriers to screening in the pharmacy environment.

Gemtuzumab Ozogamicin (GO) Inclusion to Induction Chemotherapy Eliminates Leukemic Initiating Cells and Significantly Improves Survival in Mouse Models of Acute Myeloid Leukemia.

Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody-drug conjugate for the treatment of acute myeloid leukemia (AML). Although GO shows a narrow therapeutic window in early clinical studies, recent reports detailing a modified dosing regimen of GO can be safely combined with induction chemotherapy, and the combination provides significant survival benefits in AML patients. Here we tested whether the survival benefits seen with the combination arise from the enhanced reduction of chemoresidual disease and leukemic initiating cells (LICs). Herein, we use cell line and patient-derived xenograft (PDX) AML models to evaluate the combination of GO with daunorubicin and cytarabine (DA) induction chemotherapy on AML blast growth and animal survival. DA chemotherapy and GO as separate treatments reduced AML burden but left significant chemoresidual disease in multiple AML models. The combination of GO and DA chemotherapy eliminated nearly all AML burden and extended overall survival. In two small subsets of AML models, chemoresidual disease following DA chemotherapy displayed hallmark markers of leukemic LICs (CLL1 and CD34). In vivo, the two chemoresistant subpopulations (CLL1+/CD117- and CD34+/CD38+) showed higher ability to self-renewal than their counterpart subpopulations, respectively. CD33 was coexpressed in these functional LIC subpopulations. We demonstrate that the GO and DA induction chemotherapy combination more effectively eliminates LICs in AML PDX models than either single agent alone. These data suggest that the survival benefit seen by the combination of GO and induction chemotherapy, nonclinically and clinically, may be attributed to the enhanced reduction of LICs.