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Depression and related mood disorders constitute an enormous burden on health, quality of life, and the global economy, and women have roughly twice the lifetime risk of men for experiencing depression. Here, we review sex differences in human brain physiology that may be connected to the increased susceptibility of women to major depressive disorder (MDD). Moreover, we summarize decades of preclinical research using animal models for the study of mood dysfunction that uncover some of the potential molecular, cellular, and circuit-level mechanisms that may underlie sex differences and disease etiology. We place particular emphasis on a series of recent studies demonstrating the central contribution of the circuit projecting from ventral hippocampus to nucleus accumbens and how inherent sex differences in the excitability of this circuit may predict and drive depression-related behaviors. The findings covered in this review underscore the continued need for studies using preclinical models and circuit-specific strategies for uncovering molecular and physiological mechanisms that could lead to potential sex-specific diagnosis, prognosis, prevention, and/or treatments for MDD and other mood disorders.

• The placenta is the first organ to form in mammals and is required for establishment of a maternal–fetal vascular interface capable of supplying the bioenergetic needs of the developing conceptus. • Multiple placental cell types engage in highly varied functions, from attachment, invasion, and vascular remodeling to cell fusion, hormone production, and nutrient transport. • Multiple mechanisms allow transport of waste and nutrients across the placenta, including diffusion, transporter protein-mediated (facilitated diffusion and active transporters), and receptor-mediated mechanisms. • The placenta is not an inert transport interface. It consumes 40%–60% of the oxygen and glucose delivered to the uterus at term. Thus conditions that alter placental metabolism can indirectly affect nutrient transport to the fetus. • Maternal and fetal health alter placental function, which in turn influences fetal adaptations and contributes to in utero fetal programming. • Abnormal placentation and placental infections can lead to preeclampsia (PE), fetal growth retardation, or preterm birth, which can have lifelong bearing on health. • In the United States, iatrogenic delivery is responsible for almost half the births that occur between 28 and 37 weeks of gestation, primarily caused by placental pathologies such as PE or intrauterine growth restriction. • Efforts to standardize placental examination after delivery are in progress so that connections between specific placental problems and poor outcomes can be better defined. In parallel, new advanced imaging techniques and biomarkers for placental function are being developed.

• Owing to their cutaneous, immunologic, and renal immaturity, newborns (especially premature neonates) are at increased risk of infection. • As a group of potentially life-threatening but often treatable diseases, infections must always be considered in a newborn with skin lesions. • Prompt diagnosis and initiation of therapy are crucial to prevent devastating long-term sequelae, particularly in instances of disseminated disease. • Staphylococcus aureus, Streptococcus species, Candida albicans, and herpes simplex virus are the most common causes of skin infections in the neonate.

Cystic hydatid disease or cystic echinococcosis (CE) is a globally endemic zoonosis caused by the larval cyst stage of the tapeworm Echinococcus granulosus. Concomitant presence of CE and hepatocellular carcinoma (HCC) is a rare clinical scenario. A 70-year-old male patient presented with acute abdominal pain to the surgical outpatient department. On evaluation, a cystic lesion with solid components and free fluid in the abdomen was observed, which led to multiple differentials in the working diagnosis. A CT showed the mass to have a delayed enhancement. Surgical exploration revealed a partially ruptured hydatid cyst with daughter cysts in the abdominal cavity and a solid-component mass lesion. We proceeded with a right partial hepatectomy. Pathological evaluation revealed a pale mass lesion with a large collapsed cyst. HCC with unusual dense fibrillar fibrosis and cystic interface with normal parenchyma was observed. This case connects the multimodal assessment of radiology, surgery and pathology.

Bladder cancer is mostly present in the form of urothelium carcinoma, causing over 150.000 deaths each year. Its histopathological classification as muscle invasive (MIBC) and non-muscle invasive (NMIBC) is the most prominent aspect, affecting the prognosis and progression of this disease. In this study, we defined the active regulatory landscape of MIBC and NMIBC cell lines using H3K27ac-seq and used an integrative data approach to combine our findings with existing data. Our analysis revealed FRA1 and FLI1 as the two critical transcription factors differentially regulating MIBC regulatory landscape. Importantly, we show that FRA1 and FLI1 regulate the genes involved in epithelial cell migration and cell junction organization. Knock-down of FRA1 and FLI1 in MIBC revealed the downregulation of several EMT-related genes such as MAP4K4 and FLOT1. Further, ChIP-SICAP performed for FRA1 and FLI1 enabled us to infer chromatin binding partners of these two transcription factors and link this information with their target genes, providing a comprehensive regulatory circuit for the genes implicated in invasive ability of the bladder cancer cells. Finally, for the first time we show that knock-down of FRA1 and FRA1-FLI1 double knock-down results in significant reduction of invasion capacity of MIBC cells towards muscle microenvironment using IC-CHIP assays. Our results collectively highlight the role of these two transcription factors in invasive characteristics of bladder cancer in selection and design of targeted options for treatment of MIBC.

Occurrence of biogenic amines in fresh fish and fishery products constitute a significant safety concern. Ingestion of histamine is identified as the causative agent of several food poisoning incidences on an annual basis. In addition, cadaverine, putrescine and tyramine have been recognized as potentiators of histamine poisoning. Accumulation of biogenic amines in fresh fish and fishery products has been mainly attributed to growth of bacteria possessing amino acid decarboxylase activity, which is facilitated by lack of hygienic conditions and strict temperature control during their storage. To this end, the effectiveness of traditional and modern approaches to control biogenic amine accumulation has been in the epicenter of intensive study. The aim of the present review article is to update and integrate current knowledge regarding the biogenic amine content of fresh fish and fishery products as well as the capacity of traditional and emerging control strategies.

The average values of the seasonal flesh biochemical composition (%) of the pearl oyster Pinctada imbricata radiata originated form 2 sampling sites, the gulfs of Evoikos (E) and Saronikos (S) in the Western Aegean Sea, showed that is rich in proteins (64.00 ± 1.86 -(E), 64.67 ± 2.95-(S)) with low fat content (10.96 ± 1.04-(E), 11.86 ± 1.13-(S)) and carbohydrates (13.29 ± 2.48- (E), 9.94 ± 4.32 (S)). The condition index ranged from 26.16% ± 5.04 in the autumn in (E), to 44.73% ± 7.50 in the summer in (S). The meat yield varied from 20.49% ± 3.20% in the summer in (E) to 30.73% ± 3.47% in the summer in (S). Both results demonstrate the high nutritional profile of the pearl oyster, supporting its suitability as a potential new Mediterranean seafood source for human consumption.

Background Ibrutinib is an oral inhibitor of Bruton’s tyrosine kinase (BTK) that is FDA-approved for several lymphoproliferative disorders and chronic GVHD. Objective To characterize cutaneous eruptions arising from ibrutinib and highlight overlap with epidermal growth factor receptor inhibitor (EGFRi)-induced dermatologic adverse events (dAEs). Methods Single-center retrospective cohort of patients referred to the Skin Toxicities Program for management of cutaneous eruptions while taking ibrutinib. Results Among 19 patients, cutaneous eruptions manifested as facial-predominant papulopustular eruptions, petechiae or ecchymoses, photosensitivity, panniculitis, xerosis, and clinical staphylococcal overgrowth. The majority of patients were able to continue ibrutinib therapy with focused management of their cutaneous toxicities. Limitations This study represents cases at a single tertiary care center and is limited to patients referred for toxicity. Conclusions With the exception of petechiae, the cutaneous toxicities of ibrutinib overlap with those associated with selective EGFR inhibitors. We observed that these reactions can be successfully managed using approaches for EGFR inhibitor-induced cutaneous adverse events.

This is a case of a young woman who developed neurological and psychiatric symptoms 3 days after resection of an immature teratoma. She was diagnosed with anti-NMDA receptor encephalitis via positive serum antibody titres, which was later confirmed with cerebrospinal fluid antibody titres. Given her cancer diagnosis, she underwent treatment with bleomycin, etoposide and cisplatin chemotherapy in addition to 5 days of high-dose steroids (1 g of intravenous methylprednisolone) for the encephalitis. This treatment regimen led to significant clinical improvement 3 weeks after completion of one cycle of chemotherapy.

Current literature suggests an increased risk of venous thromboembolism (VTE) in people living with HIV (PLWH) with poorly controlled viraemia and immunodeficiency. VTE treatment guidelines do not specifically address anticoagulation management in PLWH. We report a case of a 33-year-old woman diagnosed with an unprovoked pulmonary embolism (PE) and deemed protein S deficient. Three years later, she was diagnosed with AIDS. Antiretroviral therapy (ART) was promptly initiated with viral suppression and immune reconstitution within 12 months. Eight years after her initial PE, the patient self-discontinued warfarin. Multiple repeat protein S values were normal. ART without anticoagulation has continued for 3 years with no thrombotic events. This case describes a patient with VTE presumably secondary to undiagnosed HIV with possible consequent acquired protein S deficiency. Additional research is needed to understand the characteristics of PLWH with VTE who may warrant long-term anticoagulation as opposed to shorter courses.

Disseminated histoplasmosis is a life-threatening condition in immunocompromised patients. The majority of healthy persons have benign disease not requiring treatment. However, in persons living with HIV, mortality is high and accurate diagnosis is paramount. We present a case of a 48-year-old HIV-positive woman who presented with haematuria and flank pain. She had a history of recurrent urinary tract infection and nephrolithiasis with obstructive hydronephrosis. During cystoscopy, a bladder lesion was found. Pathological evaluation demonstrated abundant intracellular organisms with apparent budding. Subsequent urine histoplasma antigen was negative. Given the high index of suspicion for histoplasmosis based on the surgical pathology findings and epidemiological history, the patient was started immediately on antifungal therapy. One week later, PCR results of the bladder lesion confirmed the presence of Histoplasma capsulatum. This case highlights a rare presentation of genitourinary histoplasmosis and the utility of surgical pathology evaluation and PCR for diagnosis.

We present a case of a 51-year-old immunosuppressed man with underlying chronic lymphoproliferative leukaemia (CLL), who presented to us in emergency with breathlessness, hydrophobia, anxiety and restlessness. He had a history of category 3 dog bite 2 months ago and had received a full course of rabies immunoglobulin and antirabies vaccine (ARV) as per the national schedule. As there were frank clinical reports of rabies, the patient was managed according to Milwaukee regimen. The patients died within a week of the appearance of symptoms. The brain autopsy revealed Negri bodies conforming the mortality due to rabies.Immunosuppressed patients, like our patient who had CLL have low antibody formation after rabies prophylaxis. Antibody titres in immunosuppressed patients need to be measured after the 2–4 weeks of the last injection of ARV to decide whether a booster of ARV needs to be administered or not.

Heart regeneration is a remarkable process whereby regrowth of damaged cardiac tissue rehabilitates organ anatomy and function. Unfortunately, the human heart is highly resistant to regeneration, which creates a shortage of cardiomyocytes in the wake of ischemic injury, and explains, in part, why coronary artery disease remains a leading cause of death worldwide. Luckily, a detailed blueprint for achieving therapeutic heart regeneration already exists in nature because several lower vertebrate species successfully regenerate amputated or damaged heart muscle through robust cardiomyocyte proliferation. A growing number of species are being interrogated for cardiac regenerative potential, and several commonalities have emerged between those animals showing high or low innate capabilities. In this review, we provide a historical perspective on the field, discuss how regenerative potential is influenced by cardiomyocyte properties, mitogenic signals, and chromatin accessibility, and highlight unanswered questions under active investigation. Ultimately, delineating why heart regeneration occurs preferentially in some organisms, but not in others, will uncover novel therapeutic inroads for achieving cardiac restoration in humans.

OBJECTIVE Somatic complaints are known to complicate recovery after mild traumatic brain injury (mTBI), but the construct is poorly understood due to evolving definitions of associated disorders and uncertainty related to its position within the broader construct network of psychopathology. Methods: To better understand measures of somatic symptom reporting widely used with mTBI patients, we examined relationships between the Brief Symptom Inventory-18 Somatization (SOM) scale, the Minnesota Multiple Personality Inventory-2-Restructured Form Somatic Complaints (RC1) scale, other measures of psychological and personality functioning, and mTBI in both athlete concussion (n = 100) and civilian trauma (n = 75 mTBI, n = 79 orthopedic injury) samples. Results: The association between post-injury SOM and RC1 was moderate (r=.37-.46) and similar to associations between these inventories and depression and anxiety symptoms. In civilians with mTBI, RC1 was more strongly associated with diverse personality dimensions than SOM. mTBI athletes reported increases in somatic symptoms from pre- to post-injury, with larger group effect sizes on SOM (ηp2 = 0.34, p < .001) than RC1 (ηp2 = 0.09, p = .003). Civilian mTBI patients showed a trend for somewhat higher post-injury RC1 scores than orthopedic trauma controls (ηp2 = 0.02, p = .068). Conclusions: Findings add to the current knowledge of the influence of somatic complaints in mTBI. BSI-18 SOM and MMPI-2-RF RC1 are not interchangeable, as they are only modestly correlated and demonstrate differing associations with other clinical outcomes and mTBI.

Modulation of proteasome function by pharmacological interventions and molecular biology tools is an active area of research in cancer biology and neurodegenerative diseases. Curcumin (diferuloylmethane) is a naturally occurring polyphenol that affects multiple signaling pathways and known to modulate PKC activities. The therapeutic significance of curcumin is often considered to reside in its anti-inflammatory, antioxidant, anti-angiogenic, or anti-apoptotic properties. However, recent research suggests that the therapeutic efficacy of curcumin may be due to its activity as a potent inhibitor of the proteasome. In this study, we show that both curcumin and its synthetic polyphenolic derivative (didemethylcurcumin), CUIII modulated proteasome activity in a biphasic manner. Curcumin and CUIII increased proteasome activity at nanomolar concentrations but inhibited proteasome activity at micromolar concentrations. Curcumin was more effective than CUIII in relative proteasome activity increase at nanomolar concentrations. Also, curcumin was more effective than CUIII in relative proteasome activity inhibition at micromolar concentration. The docking study was conducted on the 20S proteasome catalytic subunit. Estimated Kd values for curcumin and didemethylcurcumin are 0.0054μM and 1.3167μM, respectively. These values correlate well with the results of the effectiveness of modulation by curcumin compare to CUIII. The small size of CUIII makes its dock to the narrow cavity of the active site, but the binding interaction is not strong compare to curcumin. This study suggests that curcumin and its didemethyl derivative can be used to modulate proteasome activity. This communication implicates the reason why curcumin and its didemethyl derivative can be used to two different disease mechanisms, neurodegeneration, and cancer.

The advent of immunotherapy has revolutionised the treatment of metastatic lung cancer and it has recently been established as the standard of care in the radical treatment of lung cancer. However, immune-related adverse events (IrAEs) frequently occur in patients treated with immunotherapy, and rare IrAEs continue to be identified. We report a case of immunotherapy-induced coeliac disease due to adjuvant durvalumab post-chemoradiotherapy in a patient receiving curative treatment for lung cancer. The patient had raised anti-tissue transglutaminase IgA and histological findings consistent with coeliac disease. This is the first published case report of probable immunotherapy-induced coeliac disease both with the immunotherapy drug durvalumab and in the curative lung cancer setting.

Essential thrombocythaemia (ET) is a myeloproliferative neoplasm where there is a clonal proliferation of thrombocytes. Whilst most often diagnosed incidentally, it can uncommonly present with arterial thrombosis. This is a case presentation of a 36-year-old male who was diagnosed with ET following myocardial infarction caused by multiple thrombotic emboli. The patient was initially misdiagnosed with viral myopericarditis based on an atypical history of chest pain with a viral prodrome. Reattendance a month later with further chest pain, dynamically raised troponin and ECG changes raised suspicions of ACS. Analysis of blood markers from both admissions showed consistently elevated platelet counts. A CMR scan revealed focal ischaemic scars in multiple cardiac segments consistent with an acute coronary event or coronary embolisation. A subsequent coronary angiography demonstrated minimal coronary artery disease. JAK2 gene V617F mutation was detected, confirming ET. The patient was commenced on pegylated interferon-alpha and dual antiplatelet therapy, and discharged with follow-up.

Eight-and-a-half syndrome is a rare entity characterised by conjugate horizontal gaze palsy, ipsilateral internuclear ophthalmoplegia and ipsilateral lower motor neuron type facial palsy. It is due to a lesion affecting median longitudinal fasciculus, paramedian pontine reticular formation and facial nerve fascicle on the same side at the level of pons. The diagnosis is easily missed as it needs detailed ocular movement examination. It is mainly caused due to infarction or demyelinating conditions. We are reporting an interesting case of a 54-year-old man with right-side eight-and-a-half syndrome due to acute ischaemic stroke and ST-elevation myocardial infarction of the inferior wall.

Primary pneumomediastinum is the presence of air in the interstitium of the mediastinum. The exact aetiology is unclear; nevertheless, it has been reported more frequently in patients with asthma and in individuals who use recreational drugs. It is commonly preceded by a sharp rise in intrathoracic pressure as in a Valsalva-like manoeuvre. We describe a rare case of severe pneumomediastinum with a small pneumothorax related to cannabis smoking and aggravated by vigorous sexual intercourse. The patient was successfully treated conservatively due to clinical and radiological stability and the absence of secondary cause.

Background Allergic bronchopulmonary aspergillosis (ABPA) is an allergic reaction to colonisation of the lungs with the fungus Aspergillus fumigatus and affects around 10% of people with cystic fibrosis. ABPA is associated with an accelerated decline in lung function. High doses of corticosteroids are the main treatment for ABPA; although the long-term benefits are not clear, their many side effects are well-documented. A group of compounds, the azoles, have activity against Aspergillus fumigatus and have been proposed as an alternative treatment for ABPA. Of this group, itraconazole is the most active. A separate antifungal compound, amphotericin B, has been employed in aerosolised form to treat invasive infection with Aspergillus fumigatus, and may have potential for the treatment of ABPA. Antifungal therapy for ABPA in cystic fibrosis needs to be evaluated. This is an update of a previously published review. Objectives The review aimed to test the hypotheses that antifungal interventions for the treatment of ABPA in cystic fibrosis: 1. improve clinical status compared to placebo or standard therapy (no placebo); 2. do not have unacceptable adverse effects. If benefit was demonstrated, we aimed to assess the optimal type, duration and dose of antifungal therapy. Search methods We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. In addition, pharmaceutical companies were approached. Date of the most recent search of the Group's Trials Register: 29 September 2016. Selection criteria Published or unpublished randomised controlled trials, where antifungal treatments have been compared to either placebo or no treatment, or where different doses of the same treatment have been used in the treatment of ABPA in people with cystic fibrosis. Data collection and analysis Four trials were identified by the searches; none of which was judged eligible for inclusion in the review. Main results No completed randomised controlled trials were included. Authors' conclusions At present, there are no randomised controlled trials to evaluate the use of antifungal therapies for the treatment of ABPA in people with cystic fibrosis, although trials in people who do not have cystic fibrosis have shown clinical and serological evidence of improvement and a reduction in the use of corticosteroids with no increase in adverse effects. Trials with clear outcome measures are needed to properly evaluate this potentially useful treatment for cystic fibrosis.

Background Gastric cancer is worldwide the fourth more common cancer type by incidence, and the third by mortality. We analyzed three missense variants of TAS2R38 gene: rs713598 (A49P), rs1726866 (V262A), and rs10246939 (I296V). These variants and their combination in haplotypes (proline, alanine and valine/tasters or alanine, valine and isoleucine/nontasters) and diplotypes are responsible for individual differences in bitter perception. The single-nucleotide polymorphisms and the related phenotypes are known to be associated with susceptibility to Gram-negative bacterial infections, such as Helicobacter pylori, and with risk of various cancer types. An association between intermediate tasters (as defined by TAS2R38 diplotypes) and increased risk of gastric cancer was reported in a Korean population. Methods We analyzed 2616 individuals of Latin American origin, representing the whole spectrum of lesions from gastritis to gastric cancer. Results Comparing cancer cases vs. noncancers we observed a decrease in risk associated with heterozygous carriers of rs10246939 (P = 0.006) and rs1726866 (P = 0.003) when compared with homozygotes of the more common allele. Also, the analysis of diplotypes/phenotypes reflected the same association, with super-tasters showing a borderline increased risk of developing gastric cancer compared to medium-tasters [odds ratio (OR) = 1.63; 95% confidence interval (CI), 1.04-2.56; P = 0.033]. Also, nontasters showed an increased risk when compared to medium-tasters although not reaching statistical significance (OR = 1.58; 95% CI, 0.80-2.87; P = 0.203). We also tested the interactions between the TAS2R38 genotypes and H. pylori cagA status in a subset of samples and found no interaction. Conclusion In conclusion, our results suggest only a modest contribution of TAS2R38 gene genetic variability in gastric cancer etiology.

SIGNIFICANCE Reactive oxygen species (ROS) contribute to multiple aspects of peripheral nervous system (PNS) biology ranging from physiological processes (e.g. axonal outgrowth and regeneration), to pathophysiology (e.g. nerve degeneration). Although ROS are derived from multiple sources, NADPH oxidase (Nox) family members are dedicated to ROS generation. Noxs are expressed in the PNS and their overexpression is associated with detrimental effects on nerve function and contribute, at least in part, to peripheral neuropathies. Recent Advances: Of the 7 members, studies mostly focused on Nox1, Nox2, and Nox4, which are expressed in the PNS in a cell-specific manner. We have also recently identified human Nox5 in sural nerve biopsies. When maintained at homeostatic levels, Noxs regulate several aspects of peripheral nerve health, most notably neurite outgrowth and axonal regeneration following nerve lesion. While Nox2 and Nox4 dysregulation is a major source of oxidative stress in PNS disorders, including neuropathic pain and diabetic peripheral neuropathy, recent evidence also implicates Nox1 and Nox5. CRITICAL ISSUES Although there is compelling evidence for a direct role of Noxs on nerve function, little is known about their subcellular localization, intercellular regulation, and interaction. These, together with redox signaling, are considered crucial components of nerve redox status. Additionally, the lack of isoform-specific inhibitors limits conclusions about the physiological role of Noxs in the PNS and their therapeutic potential in peripheral neuropathies. FUTURE DIRECTIONS Future research using isoform-specific genetic and pharmacological approaches are therefore needed to better understand the significance of Nox enzymes in PNS (patho) physiology.

Recognizing sport-related concussion (SRC) is challenging and relies heavily on subjective symptom reports. An objective, biological marker could improve recognition and understanding of SRC. There is emerging evidence that salivary micro-ribonucleic acids (miRNAs) may serve as biomarkers of concussion; however, it remains unclear whether concussion-related miRNAs are impacted by exercise. We sought to determine whether 40 miRNAs previously implicated in concussion pathophysiology were affected by participation in a variety of contact and non-contact sports. Our goal was to refine a miRNA-based tool capable of identifying athletes with SRC without the confounding effects of exercise.This case-control study harmonized data from concussed and non-concussed athletes recruited across 10 sites. Levels of salivary miRNAs within 455 samples from 314 individuals were measured with RNA sequencing. Within-subjects testing was used to identify and exclude miRNAs that changed with either: (a) a single episode of exercise (166 samples from 83 individuals) or (b) season-long participation in contact sports (212 samples from 106 individuals). The miRNAs that were not impacted by exercise were interrogated for SRC diagnostic utility using logistic regression (172 samples from 75 concussed and 97 non-concussed individuals).Two miRNAs (miR-532-5p, miR-182-5p) decreased (adjusted p0.05) after a single episode of exercise, and 1 miRNA (miR-4510) increased only after contact sports participation. Twenty-three miRNAs changed at the end of a contact sports season. Two of these miRNAs (miR-26b-3p, miR-29c-3p) were associated (R0.50; adjusted p0.05) with the number of head impacts sustained in a single football practice. Among the 15 miRNAs not confounded by exercise or season-long contact sports participation, 11 demonstrated a significant difference (adjusted p0.05) between concussed and non-concussed participants, and 6 displayed moderate ability (AUC0.70) to identify concussion. A single ratio (miR-27a-5p/miR-30a-3p) displayed the highest accuracy (AUC = 0.810, sensitivity = 82.4%, specificity = 73.3%) for differentiating concussed and non-concussed participants. Accuracy did not differ between participants with SRC and non-SRC (z = 0.5, p = 0.60).Salivary miRNA levels may accurately identify SRC when not confounded by exercise. Refinement of this approach in a large cohort of athletes could eventually lead to a non-invasive, sideline adjunct for SRC assessment.

A fetus with features of hydrops was given intra-uterine transfusion at 27 weeks and 31 weeks of gestation. Mother had been alloimmunized with anti-D and anti-C antibodies. At birth, laboratory investigations revealed bone marrow suppression along with features of hemolytic anemia. The neonate was started on a combination of phototherapy and intravenous immunoglobulin. During the course, the neonate was transfused with one unit of packed red cells (top-up transfusion). Neonatal hyperbilirubinemia responded to phototherapy and the bone marrow activity spontaneously resumed after 3 weeks of life. In neonates with anemia at birth who have history of multiple intra-uterine transfusions, early-onset hypoproliferative anemia should be considered.

Transient loss of consciousness (TLOC) is a frequent cause of referral to an emergency room. In view of the impact on treatment and the patients’ daily life activities (e. g. profession, driving license), an accurate and timely diagnosis is of uttermost importance. This article provides key features and suggests a practical step-by-step approach of how to differentiate syncope, epileptic and psychogenic non-epileptic seizures as the commonest causes of nontraumatic TLOC.

Background Participation in sports is associated with many benefits to all aspects of health; however, it also comes with the risk of injury, particularly concussions. Self-disclosure and care seeking following a concussion are especially important because of the lack of outwardly visible signs and/or symptoms. Although recent research has explored factors affecting concussion disclosure, use of isolated methodologies limits the ability to contextualize how disclosure or nondisclosure occurs. Therefore, the purpose of this study was to describe the factors and expectations of National Collegiate Athletic Association (NCAA) athletes that may influence concussion disclosure. Methods This mixed-methods convergent parallel research study included 25 NCAA Division I athletes representing 13 sports, all of whom completed a concussion-education session with pre-/post-test surveys and a semistructured interview. Eligible athletes were at least 18 years old and on an NCAA roster. The surveys focused on previous concussion-related disclosure behaviors, knowledge, attitudes, beliefs, norms, and intentions about disclosing concussion. Interviews focused on the athletes’ experiences related to concussion disclosure. Survey data were analyzed using descriptive statistics and Mann-Whitney U tests. Interviews were analyzed using a Consensual Qualitative Research tradition. Results Participants had good concussion knowledge (median = 46), positive attitudes (median = 38), strong beliefs (median = 13), and strong intentions to disclose concussion symptoms (median = 7). None of the constructs differed by participants’ gender. Although quantitative findings were mostly positive, interview data highlighted factors that may explain why some participants are successful in disclosing concussions and why others may find disclosure difficult. Educational efforts, sport culture, and medical professional presence were the primary facilitators discussed by participants. Stigma, pressure, and a lack of team support were perceived as disclosure barriers. Conclusion The context in which concussion disclosure occurs or does not occur is vital to the success of educational interventions. Interventions must prioritize stakeholder- and team-based perspectives on concussion to establish a network supportive to disclosure.

Ancient dental calculus represents one of the most recent and innovative sources of archaeobotanical record. Exploring this matrix, diet, past ecology, and ethnobotanical practices of antique communities may be elucidated. In the present case-study, the tartar of an Imperial Roman man, likely a salt worker, found in the necropolis of Castel Malnome (Rome, Latium, Italy) and affected by bilateral temporo-mandibular joint ankylosis, was investigated. Despite his rare and extremely disabling affection, this male individual reached adulthood thanks to the forced removal of the anterior teeth, which allowed him to eat. Starches of Poeae and Triticeae tribe were detected, although the largest amount of the granules appeared gelatinized, suggesting that maybe the inhumate consumed well-cooked and semi-liquid stuff, due to his non-functional masticatory activity. Urticaceae and clover pollen grains documented unintentional aspiration or voluntary use of these plants as ingredients for meals and therapeutic decoctions. Indeed, since Roman times, written sources have documented nettle as an anti-inflammatory remedy to treat joint and muscle pains. Finally, the identification of secondary metabolites ascribable to the Brassicaceae family, Artemisia L., and Ephedra L. genera, paves the way for hypothesizing the consumption of these Mediterranean species with several nutritional and nutraceutical properties. All this evidence opens a picture window onto the life of this man, which should be well integrated into his community and natural environment despite the functional impairment.

Abstract: Lipoprotein(a)(Lp[a]) is a low-density lipoprotein-cholesterol (LDL-C)-like particle with potent pro-atherothrombotic properties. The association of Lp(a) with several circulating factors, including vitamins, remains unresolved. We performed an observational analysis using the National Health and Nutrition Examination Survey III cohort, a cohort used to monitor the nutrition status of US-citizens. We used multivariable linear regression to test associations of Lp(a) and LDL-C with levels of serum vitamins and minerals and whole-blood lead. Analyses controlled for factors known to associate with Lp(a) (age, sex, race/ethnicity, statin use, hemoglobin A1c, body mass index, hypertension, diabetes, glomerular filtration rate, alcohol intake, and saturated fat intake). LDL-C was corrected for Lp(a) mass. Multiple sensitivity tests were performed, including considering factors as categorical variables (deficient, normal, elevated). Among 7,662 subjects, Lp(a) correlated (β-coefficient) positively (change per 1 conventional unit increase) with carotenoids (lycopene (0.17(0.06,0.28), p=0.005), lutein (0.19(0.07,0.30), p=0.002), β-cryptoxanthin (0.21(0.05,0.37), p=0.01), β-carotene (0.05(0.02,0.09), p=0.003), and α-carotene (0.15(0.01,0.30), p=0.04)) and lead (0.54(0.03,1.05), p=0.04) levels when tested as continuous variables. LDL-C had similar associations. Lp(a) did not associate with vitamins A, B12, C, or E retinyl esters, folate, RBC-folate, selenium, ferritin, transferrin saturation, or calcium. With factors as categorical variables, Lp(a) but not LDL-C negatively associated with elevated vitamin B12 (−5.41(−9.50, −1.53), p=0.01) and folate (−2.86(−5.09, −0.63), p=0.01). In conclusion, Lp(a) associated similarly to LDL-C when vitamins, minerals, and lead were tested as continuous variables, while only Lp(a) correlated with vitamin B12 and folate when tested as categorical variables. These observations are hypotheses generating and require further studies to determine causality.

Phylogenetic methods are emerging as a useful tool to understand cancer evolutionary dynamics, including tumor structure, heterogeneity, and progression. Most currently used approaches utilize either bulk whole genome sequencing (WGS) or single-cell DNA sequencing (scDNA-seq) and are based on calling copy number alterations and single nucleotide variants (SNVs). Here we explore the potential of single-cell RNA sequencing (scRNA-seq) to reconstruct cancer evolutionary dynamics. scRNA-seq is commonly applied to explore differential gene expression of cancer cells throughout tumor progression. The method exacerbates the single-cell sequencing problem of low yield per cell with uneven expression levels. This accounts for low and uneven sequencing coverage and makes SNV detection and phylogenetic analysis challenging. In this paper, we demonstrate for the first time that scRNA-seq data contains sufficient evolutionary signal and can be utilized in phylogenetic analyses. We explore and compare results of such analyses based on both expression levels and SNVs called from our scRNA-seq data. Both techniques are shown to be useful for reconstructing phylogenetic relationships between cells, reflecting the clonal composition of a tumor. Without an explicit error model, standardized expression values appear to be more powerful and informative than the SNV values at a lower computational cost, due to being a by-product of standard expression analysis. Our results suggest that scRNA-seq can be a competitive alternative or useful addition to conventional scDNA-seq phylogenetic reconstruction. Our results open up a new direction of somatic phylogenetics based on scRNA-seq data. Further research is required to refine and improve these approaches to capture the full picture of somatic evolutionary dynamics in cancer.

Dental calculus and other preserved microbiome substrates are an attractive target for dietary reconstruction in past populations through a variety of physical, chemical, and molecular means. Recently, studies have attempted to reconstruct diet from archaeological dental calculus using archaeogenetic techniques. While dental calculus may provide a relatively stable environment for DNA preservation, the detection of plants and animals possibly consumed by an individual through DNA analysis is primarily hindered by microbial richness and incomplete reference databases. Moreover, high genomic similarity within eukaryotic groups 1. Introduction 2. Materials and methods 3. Results 3.1. Effects of low read counts on damage patterns 3.2. Identification of dietary reads from synthetic datasets 3.3. Identification of dietary reads from real datasets 4. Discussion and conclusions 4.1. Checklist for authors and reviewers 4.1.1. Field/storage contamination 4.1.2. Is the laboratory methodology suitable for aDNA authentication? 4.1.3. Is the database and pipeline suitable? 4.1.4. Is the taxonomic resolution analyzed sufficient for reliable interpretation? 4.1.5. Have unexpected taxa been reported and evaluated? 4.1.6. Have laboratory controls been evaluated alongside samples? 4.1.7. Has evidence of aDNA authenticity been provided? 4.1.8. Is there other evidence supporting that dietary organisms were consumed?

Introduction Streptococcus bovis/equinus complex (SBEC) is a major cause of infective endocarditis (IE), although its incidence varies greatly depending on the geographical area. The characteristics of IE caused by Streptococcus gallolyticus susp. gallolyticus are well known; there are hardly any descriptions of IE caused by other species or biotypes. Methods Retrospective cohort study, from 1990 to 2019, of all SBEC IE in adults in three Spanish hospitals, Lugo (LH), Barcelona (BH) and Ferrol (FH) where the population is mainly rural, urban and mixed, respectively. The incidence of IE was analyzed in 3 areas. Clinical characteristics of IE (277 cases, 258 biotyped) were compared according to SBEC species and biotypes. Results There are significant differences between the incidence of SBEC IE in HL (27.9/106) vs. HF and HB (8.8 and 7,1, respectively, p Conclusions IE due to SBEC has geographical variations in incidence and different clinical characteristics among biotypes. The association with CRC was high.

Background Latent tuberculosis infection (LTBI) diagnosis in a country with a low tuberculosis burden is complicated. Since the prevalence of LTBI in second generation immigrants has not been well recognized, we conducted a cross-sectional study which aimed to explore the differences in LTBI prevalence between offspring of immigrants from high tuberculosis (TB) burden countries and those whose parents were born in countries with a low TB burden. Methods Between May 2014 and April 2018 young native Israelis who were required to perform pre-occupational tuberculin skin tests (TST) (medical and paramedical personnel or teaching assistants of immigrants from high TB burden countries) and who had a TST result of 10 mm and above were tested for QuantiFERON-TB In Tube (QFT-GIT). Statistical comparisons were made between second generation immigrants and those with both parents from a low TB burden country. Results Of 102 patients, 71 were born to parents both of whom were from low-risk countries, 14 to one parent from a high-risk country and 17 to parents both of whom were from a high-risk country. The odds ratio for LTBI was 4.5 (95% CI, 1.2–17.2; p = 0.03) if both parents were born in a high-risk country compared to both parents being from a low-risk country and 4.01 (95% CI, 1.12–14.3; p = 0.03) higher compared to persons for whom at least one parent was born in a low-risk country. Conclusion The risk for latent TB is significantly higher in second generation immigrants if both parents were born in a high-risk country. IGRA should be considered before treatment to patients with a positive TST if at least one parent was born in a low-risk country in order to confirm LTBI.

PURPOSE Immunohistochemistry (IHC) is a newer technique for assessing the estrogen receptor (ER) status of breast cancers, with the potential to overcome many of the shortcomings associated with the traditional ligand-binding assay (LBA). The purpose of this study was to evaluate the ability of ER status determination by IHC, compared with LBA, to predict clinical outcome—especially response to adjuvant endocrine therapy—in a large number of patients with long-term clinical follow-up. PATIENTS AND METHODS ER status was evaluated in 1,982 primary breast cancers by IHC on formalin-fixed paraffin-embedded tissue sections, using antibody 6F11 and standard methodology. Slides were scored on a scale representing the estimated proportion and intensity of positive-staining tumor cells (range, 0 to 8). Results were compared with ER values obtained by the LBA in the same tumors and to clinical outcome. RESULTS An IHC score of greater than 2 (corresponding to as few as 1% to 10% weakly positive cells) was used to define ER positivity on the basis of a univariate cut-point analysis of all possible scores and disease-free survival (DFS) in patients receiving any adjuvant endocrine therapy. Using this definition, 71% of all tumors were determined to be ER-positive by IHC, and the level of agreement with the LBA was 86%. In multivariate analyses of patients receiving adjuvant endocrine therapy alone, ER status determined by IHC was better than that determined by the LBA at predicting improved DFS (hazard ratios/ P = 0.474/.0008 and 0.707/.3214, respectively) and equivalent at predicting overall survival (0.379/.0001 and 0.381/.0003, respectively). CONCLUSION IHC is superior to the LBA for assessing ER status in primary breast cancer because it is easier, safer, and less expensive, and has an equivalent or better ability to predict response to adjuvant endocrine therapy.

Periodontitis is an oral chronic inflammatory disease. Inhibiting tissue destruction and promoting tissue regeneration are important means for the treatment of periodontitis. Metformin not only has hypoglycemic effect but also has anti-inflammatory effect. Metformin has been shown to inhibit oxidative stress and activate autophagy through AMPK/mTOR pathway. High mobility group box 1 (HMGB1) has been implicated in the pathogenesis of many inflammatory diseases including periodontitis, it can participate in the induction of oxidative stress. HMGB1 is an autophagy regulator under oxidative stress, which can activate mTOR pathway. However, it is not clear whether metformin is related to HMGB1 and its mechanism in the process of periodontitis. Cell viability and expression of inflammatory cytokines were clarified by Cell Counting Kit-8, real-time PCR and enzyme-linked immunosorbent assay. Western blot and immunofluorescence were conducted to determine HMGB1 intracellular localization and expression of autophagy-associated proteins in vitro. Experimental periodontitis mice model was induced by administering a ligature. Immunohistochemistry was performed to detect the expression and localization of HMGB1 in vivo. The results of CCK-8, real-time PCR, enzyme-linked immunosorbent assay, Western blot and immunofluorescence showed lipopolysaccharide (LPS) treatment inhibited cell viability, and increased HMGB1 expression at a dose-independent manner. Metformin can reduce the effect of LPS. It also improves autophagy pathway inhibited by LPS and down-regulates mTOR expression. In addition, metformin attenuated alveolar bone resorption induced by ligation. This study provides new evidence for that metformin is a potential drug for the treatment of periodontitis and HMGB1 may be a potential target for periodontal intervention.

Introduction: Glioblastoma multiforme (GBM) is an aggressive case of primary brain cancer which remains among the most fatal tumors worldwide. Although, some in vitro and in vivo models have been developed for a better understanding of GBM behavior; a natural model of GBM would improve the efficiency of experimental models of human GBM tumors. We aimed the present study to examine the survival and durability of U87 cells in the brain of wild-type rats. Methods: U87 cells were intracranially implanted in twenty-one wild-type rats. Tumor size and morphology as well as infiltration of immune cells were investigated at three-time points by H&E and immunohistochemistry (IHC). Results: The results demonstrated that the inoculation of GBM cells led to the infiltration of host defense system cells which caused immunological regression of the tumor mass after six weeks. While the tumors successfully developed without any sign of host defense invasion in the second week of GBM inoculation. Also, a decrease in tumor size and infiltration of immune system cells were observed in the fourth week. Conclusion: These data remarkably suggest that time plays a crucial role in activating the immune system against human GBM tumors in rats; it shows that the regression of tumor mass depends on a time slope.

Background: The procancer effect of TEA domain transcription factor 4 (TEAD4) has been gradually discovered. However, its expression in esophageal cancer (EC) cells and its effect on proliferation ...

Long non-coding RNAs (lncRNAs) are a novel class of non-coding RNA (ncRNA), that have been studied extensively in the field of tumor research in recent years. In the case of tumor-associated lncRNAs, lncRNA cytoskeleton regulator RNA (CYTOR) displays extensive functions in tumorigenesis, including invasion, metastasis, malignant proliferation, glycolysis, and inflammatory response. Moreover, the dysregulation of CYTOR is closely related to clinicopathological characteristics, such as tumor stage, lymph node metastasis and infiltration, and poor prognosis of tumor patients. In this review, we provide a novel strategy to summarize the biological functions and clinical value of CYTOR in tumors through an overview of the literature combined with gene set enrichment analysis. A deeper understanding of the role of CYTOR in tumorigenesis may provide new diagnostic, prognostic and therapeutic markers for human tumors.

Introduction: It is reported that migraine may be a risk factor for brain cancers. Since one of the best ways to assess this possible relationship is to study the molecular mechanism, here the common central dysregulated proteins between these diseases are investigated via network analysis. Methods: The dysregulated proteins of migraine and gliosarcoma are extracted from the STRING database and interacted via Cytoscape software, version 3.7.2. to form two separate networks. Central nodes of the networks are compared to find the common central district proteins. First neighbors of the common central proteins are studied. Results: The number of 11 hub bottlenecks was identified for each of the migraine and gliosarcoma cancer networks. Albumin (ALB) and interleukin 6 (IL6) were introduced as common differentially expressed central proteins. Kininogen 1 (KNG1), vascular endothelial growth factor A (VEGFA), and neurofibromatosis type I (NF1) the first neighbors of ALB-IL6 were connected to the central nodes of networks of the two studied diseases. Conclusion: ALB and IL6 can be considered molecular links between migraine and brain cancers.

A 23-year-old man with a history of migraine and focal seizures, developed painless visual loss in the left eye associated with optic disk edema. There was no recent history of cat exposure except for a cat that lives outside. Initial laboratory studies were negative. magnetic resonance imaging brain and orbits without and with fat suppression and intravenous contrast was normal. The patient admitted to routinely skinning, processing and consuming deer while not wearing gloves, and he also frequently had cuts on his hands while doing so. The serum Toxoplasma gondii IgG antibody returned at400 (0-7.1 IU/mL) with the IgM at 10.4 (0-7.9 AU/mL).

Anaemia is a common complication of chronic kidney disease. The most important contributory factor is an abnormally low circulating concentration of erythropoietin, which is produced by the kidney peritubular cells. Anaemia of kidney disease is likely to develop once the glomerular filtration rate (GFR) is

Background: Stress induces secretion of cathecolamines and glucocorticoids, which may produce liver injury. Followed by the production of inflammatory mediators, it causes apoptosis. Centella asiatica (CeA) has anti-inflammatory and hepatoprotective effects. The present study aims to determine the role of CeA in the attenuation of liver pro-inflammatory mediator expression in rats with electrical foot shock stress model. Materials and Methods: Twenty-four Sprague-Dawley rats were randomized into four groups consisted of six rats each: (1) Control group, (2) CeA-treated group, (3) Stress group, and (4) CeA + stress group. Reverse transcriptase PCR of inflammatory and apoptosis markers as well as Real-Time PCR of β2-adrenergic receptor were performed from liver tissues. Results: Electrical foot shock stress induced up-regulation of NFκB and TNF-α mRNA expressions as pro-inflammatory mediators, compared to control group. This alteration was followed by up-regulation of BAX and β2-adrenergic receptor, as well as the down-regulation of BCl2 compared to control. CeA treatment prevented enhancement of NFκB, TNF-α, TLR-4 and β-adrenergic receptor mRNA expressions, which was followed by down-regulation of BAX and up-regulation of BCl-2, compared to stress group. Conclusion: CeA prevents secretion of pro-inflammatory chemokines and cytokines as well as apoptotic markers in liver cells through the activation of β2-adrenergic receptor.

Mosquitoes serve as the major vector transmitting malaria, dengue, yellow fever and several other diseases of human concern. Rising in mosquito-borne diseases and consequent fatalities throughout the world has made the management of mosquitoes of paramount importance. With the use of various insecticidal agents and their indiscriminate application in the fields for vector control; other issues such as multiple insecticide resistance, lethality to non-specific targets and adverse effects on human and environmental health have emerged making the situation more critical. Hence, the focus of researchers has diverted to the use of Insect Growth Regulators (IGRs) that affect the growth and development of the insects without inducing any appreciable toxic effects. The paper comprehensively reviews various IGRs and their potential use against insect pests and mosquito vectors. A special emphasis has been laid on the utilization of diflubenzuron, its larvicidal potency and growth regulatory effects against mosquitoes. The paper also delivers a detailed discussion on various approaches governing with the application of diflubenzuron, a chitin synthesis inhibitor, for its potent effects over a wide range of other insect species, low toxicity to humans, safety to other non-target animals, negligible deleterious environmental impact along with the possible development of resistance in the mosquitoes, thereby providing insights and the direction for the future in terms of the innovative and technological perspective. Keeping in view the role of multifarious mechanisms in the development of resistance; use of various synergistic compounds, such as hydrolase inhibitors - profenofos and S,S,S-tributyl phosphorotrithioate; glutathione S-transferase inhibitor – diethylmaleate; and oxidase inhibitor - piperonyl butoxide (PBO); has been recommended in combination with IGRs to enhance their efficacy, and reduce or reverse the resistance in target mosquitoes. Another compound, verapamil, has been found extremely efficient in imparting synergistic effect to diflubenzuron by inhibiting P-glycoproteins, a transporter of the insecticides causing their efflux from the cell. Recommendations have been made for safe and effective mosquito control measures, adequate policies and increased awareness about the mosquito-borne diseases among the masses. In addition, regular surveillance of mosquitoes is endorsed for the formulation of an efficient mosquito management strategy.

Background: Temozolomide (TMZ) resistance plays a critical role in the treatment of glioma. This research tries to explore how circRNAs affect the chemosensitivity of glioma cells. Materials and Methods: In this study, the authors performed gene sequencing and selected circRNAs specifically expressed in TMZ-R cells and used them as target genes for subsequent studies. By knocking out the target gene, the authors clarify its effect on TMZ-R glioma proliferation, invasion, migration, and cell apoptosis; and through tumor-burdened animals, the authors explore the effect of the target gene in an in vivo environment. Results: In this research, the authors revealed that circ-GLIS3 was significantly upregulated in TMZ-R glioma cells. Functionally, knocking down circ-GLIS3 could inhibit proliferation, invasion, and migration abilities of TMZ-R glioma cells. Moreover, downregulation of circ-GLIS3 could induce cell cycle arrest and apoptosis, while miR-548m inhibition and MED31 mRNA could reverse this progress. In the in vivo condition, silencing of circ-GLIS3 could induce cell apoptosis and suppressed tumor growth. Mechanistically, circ-GLIS3 positively upregulated MED31 expression by sponging miR-548m. Conclusions: All these research findings demonstrate that circ-GLIS3 accelerates TMZ-R glioma progression through the miR-548m/MED31 axis.

Ferrous gluconate has been widely used in the treatment of iron deficiency anemia due to its good therapeutic effect, high utilization, and low toxicity. However, the improper management of expired waste ferrous gluconate may also result in the flow of excessive ferrous ion into the environment, which may do harm to the organisms in the world. For this purpose, expired waste ferrous gluconate was firstly recycled in the form of cobalt ferrite (CoFe2O4)/carbon (C) by a fluid method and a post-calcination at the different temperatures of 400 and 500°C, and the effect of the calcination temperature on the morphology, micro-structure, and supercapacitive performances was also studied. The results showed that the obtained dark-brown CoFe2O4/C powders exhibited the loose mesoporous tremella-like morphology and satisfactory electrochemical supercapacitive performances, in which CFO-400 delivered higher electrochemical performances than CFO-500 due to lower crystallinity, higher electrical conductivity, and higher surface area. For example, the specific capacitance of CFO-400 electrode was as high as about 503 F/g at 0.5 A/g in the three-electrode system, and it remained 106 F/g after 5000 cycles at 5.0 A/g with 86% capacity retention in the symmetrical two-electrode capacitor, showing satisfactory long cycle stability. No doubt, these results provided a new successful recovery strategy for the circular economy of expired ferrous gluconate.

Background: Methadone maintenance treatment (MMT) is an effective treatment for opioid use disorder. However, subtherapeutic dosing may lead to continued opioid use by failing to suppress opioid withdrawal and craving. Preclinical and pilot experimental research suggests that cannabinoids may reduce opioid withdrawal and craving. We sought to test whether the association between low methadone dose and illicit opioid use differs according to concurrent cannabis use patterns. Methods: Data for this study were derived from two community-recruited cohorts of people (≥18 years old) who use illicit drugs in Vancouver, Canada. We used generalized estimating equations to estimate the adjusted association between lower daily MMT dose (

Introduction: Cannabis products containing delta-8-THC became widely available in most of the United States in late 2020 and rapidly became a significant source of revenue for hemp processing companies, especially in states where use of delta-9-THC remains illegal or requires professional authorization for medical use. Scientific research on the use of delta-8-THC is scarce, previous clinical studies included a combined total of 14 participants, leading some state governments to prohibit it until its properties and effects are better understood. Methods: Researchers developed an online survey for delta-8-THC consumers addressing a broad range of issues regarding delta-8-THC, including use for the treatment of health and medical conditions. Previous survey studies on the medical use of cannabis and cannabis products informed survey components. Results: Patterns of delta-8-THC use had both similarities with and differences from the use of delta-9-THC cannabis and products. Administration methods were primarily edibles (64%) and vaping concentrates (48%). About half of the participants (51%) used delta-8-THC to treat a range of health and medical conditions, primarily anxiety or panic attacks (69%), stress (52%), depression or bipolar disorder (46%), and chronic pain (41%). Participants compared delta-8-THC very favorably with both delta-9-THC and pharmaceutical drugs and reported substantial levels of substitution for both. Most participants did not inform their primary care provider of their delta-8-THC use (78%) and were not confident of their primary care provider's ability to integrate medical cannabis into their treatment (70%). Knowledge of effective dosages was low, and participants' knowledge of delta-8-THC was primarily from the Internet and their own experiences. Conclusion: Harm reduction is a central component of public health. Although the legal environment is becoming more restrictive for delta-8-THC in comparison to delta-9-THC, results suggest that delta-8-THC may be equally effective for desired purposes of cannabis use and lower in undesirable or adverse effects. All policies and practices should be informed by empirical evidence. Considerable research will be needed to systematically verify the patterns reported by participants, and collaborations among academic researchers, government, and the cannabis industry may be valuable in developing the knowledge base for delta-8-THC and other cannabinoids.

Background A subset of patients with estrogen receptor (ER)-positive, HER2-negative, and node-negative breast cancer experience recurrences. Predicting patients who will have recurrences within 5 years of surgery is essential so that patients can be selected to receive adjuvant chemotherapy. The 95-gene classifier (95-GC) has been validated as a method to differentiate patients into high and low-risk groups for early recurrence. Methods In this study, we performed 95-GC analysis on 56 formalin-fixed paraffin-embedded (FFPE) tissue samples from patients who underwent surgery for ER-positive, HER2-negative, and node-negative breast cancer and did not receive adjuvant chemotherapy. We associated the obtained high- and low-risk groups with clinicopathological characteristics and recurrence-free survival (RFS).Results We classified 12 out of 56 patients into the high-risk recurrence group. We found significantly higher KI67 scores in patients in the high-risk group. Other clinicopathological characteristics were not associated with the 95-GC risk groups. Patients in the 95-GC low-risk group had a significantly better prognosis than those in the high-risk group (p = 0.0387). The 5-year RFS rate was 97.6% in the low-risk group and 74.1% in the high-risk group, while the 10-year RFS rates were 90.1% and 74.1%, respectively.Conclusions Our study shows that the 95-GC score can accurately predict RFS within 5 years of surgery for ER-positive, HER2-negative, and node-negative breast cancer using FFPE tissue samples. These prediction models could help assign patients to the most effective treatment regimen.