asis for developing a bespoke COVID-19 prognostication tool.Perineuronal nets (PNNs) are an extracellular matrix structure rich in chondroitin sulfate proteoglycans (CSPGs), which preferentially encase parvalbumin-containing (PV+) interneurons. PNNs restrict cortical network plasticity but the molecular mechanisms involved are unclear. We found that reactivation of ocular dominance plasticity in the adult visual cortex induced by chondroitinase ABC (chABC)-mediated PNN removal requires intact signaling by the neurotrophin receptor TRKB in PV+ neurons. Additionally, we demonstrate that chABC increases TRKB phosphorylation (pTRKB), while PNN component aggrecan attenuates brain-derived neurotrophic factor (BDNF)-induced pTRKB in cortical neurons in culture. We further found that protein tyrosine phosphatase σ (PTPσ, PTPRS), receptor for CSPGs, interacts with TRKB and restricts TRKB phosphorylation. PTPσ deletion increases phosphorylation of TRKB in vitro and in vivo in male and female mice, and juvenile-like plasticity is retained in the visual cortex of adult PTPσ-deficNs, interacts with TRKB and inhibits its phosphorylation, and chondroitinase treatment or deletion of PTPσ increases TRKB phosphorylation. Antidepressant fluoxetine disrupts the interaction between TRKB and PTPσ, thereby increasing TRKB phosphorylation. Thus, juvenile-like plasticity induced by both chondroitinase and antidepressant treatment is mediated by TRKB activation in PV+ interneurons.The retrieval of fear memory induces two opposite memory process, i.e., reconsolidation and extinction. Brief retrieval induces reconsolidation to maintain or enhance fear memory, while prolonged retrieval extinguishes this memory. Although the mechanisms of reconsolidation and extinction have been investigated, it remains unknown how fear memory phases are switched from reconsolidation to extinction during memory retrieval. Here, we show that an extracellular signal-regulated kinase (ERK)-dependent memory transition process after retrieval regulates the switch of memory phases from reconsolidation to extinction by preventing induction of reconsolidation in an inhibitory avoidance (IA) task in male mice. First, the transition memory phase, which cancels the induction of reconsolidation, but is insufficient for the acquisition of extinction, was identified after reconsolidation, but before extinction phases. Second, the reconsolidation, transition, and extinction phases after memory retrieval showed distinct mand extinction. Reconsolidation maintains/enhances fear memory, while extinction weakens fear memory. It remains unknown how memory phases are switched from reconsolidation to extinction during retrieval. Here, we identified an active memory transition process functioning as a switch that inhibits reconsolidation. This memory transition phase showed a transient increase of extracellular signal-regulated kinase (ERK) phosphorylation in the amygdala, hippocampus and medial prefrontal cortex (mPFC). Interestingly, inhibition of ERK in these regions at the transition phase disinhibited the reconsolidation-mediated enhancement of inhibitory avoidance (IA) memory. These findings suggest that the transition memory process actively regulates the switch of fear memory phases of fear memory by preventing induction of reconsolidation through the activation of the ERK-signaling pathway.A multidimensional inflammatory response ensues after status epilepticus (SE), driven partly by cyclooxygenase-2-mediated activation of prostaglandin EP2 receptors. The inflammatory response is typified by astrocytosis, microgliosis, erosion of the blood-brain barrier (BBB), formation of inflammatory cytokines, and brain infiltration of blood-borne monocytes. Our previous studies have shown that inhibition of monocyte brain invasion or systemic administration of an EP2 receptor antagonist relieves multiple deleterious consequences of SE. Here we identify those effects of EP2 antagonism that are reproduced by conditional ablation of EP2 receptors in immune myeloid cells and show that systemic EP2 antagonism blocks monocyte brain entry in male mice. The induction of hippocampal IL-6 after pilocarpine SE was nearly abolished in EP2 conditional KO mice. Serum albumin levels in the cortex, a measure of BBB breakdown, were significantly higher after SE in EP2-sufficient mice but not in EP2 conditional KOs. EP2 definces of seizures. However, the relevant EP2-expressing cell types remain unclear. Here we identify peripheral innate immune cells as a driver of the EP2-related negative consequences of seizures. Removal of EP2 from peripheral immune cells was beneficial, abolishing production of a key inflammatory cytokine, accelerating weight regain, and limiting behavioral deficits. These findings provide evidence that EP2 engagement on peripheral immune and brain endothelia contributes to the deleterious effects of SE, and will assist in the development of beneficial therapies to enhance quality of life in individuals who suffer prolonged seizures.

Neurally adjusted ventilatory assist (NAVA) involves an intricate interaction between patient, clinician and technology. To improve our understanding of this complex intervention and to inform future trials, this survey aimed to examine clinician attitudes, beliefs and barriers to NAVA use in critically ill adults within an institution with significant NAVA experience.

A survey of nurses, doctors and physiotherapists in four Intensive Care Units (ICUs) of one UK university-affiliated hospital (75 NAVA equipped beds). The survey consisted of 39 mixed open and structured questions. The hospital had 8 years of NAVA experience prior to the survey.

Of 466 distributed questionnaires, 301 (64.6%) were returned from 236 nurses (78.4%), 53 doctors (17.6%) and 12 physiotherapists (4.0%). Overall, 207/294 (70.4%) reported clinical experience. Most agreed that NAVA was safe (136/177, 76.8%) and clinically effective (99/176, 56.3%) and most perceived 'improved synchrony’, 'improved comfort’ and 'monitoring the diaphsurvey describes technical concerns, low confidence and a perception of difficulty above that associated with PSV. In this context, high-quality training and usage algorithms are critically important to the design and of future trials, to clinician acceptance and to the clinical implementation and future success of NAVA.

Prostate cancer (PCa) is a major health problem worldwide. Taxol derivatives-based chemotherapies or immunotherapies are usually proposed depending on the symptomatic status of the patient. In the case of immunotherapy, tumors develop robust immune escape mechanisms that abolish any protective response, and to date why prostate cancer is one of the most resistant diseases remains unresolved.

By using a combination of clinical data to study the transcriptome of metastasis samples from patients with castration-refractory prostate cancer, and state of the art cellular and molecular biology assays in samples from tumor-bearing mice that have been submitted to surgical resection of the tumor before receiving a vaccination, we answered several essential questions in the field of immunotherapy for prostate cancer. We also used two different methods to inhibit the expression of galectin-3 (Gal-3) in tumor cells a stable RNA interference method to control the expression of this galectin efficiently only in tumor cth non-cytotoxic effect on leukocyte survival could be used before immunotherapy for all patients with PCa to reduce the expression of this critical negative immune checkpoint, pre-conditioning the tumor-microenvironment to activate an antitumor immune response and promote tumor-free outcome.

Thus, Gal-3 expression by PCa cells is a crucial inhibitor for the success of immunotherapy, and low doses of docetaxel with non-cytotoxic effect on leukocyte survival could be used before immunotherapy for all patients with PCa to reduce the expression of this critical negative immune checkpoint, pre-conditioning the tumor-microenvironment to activate an antitumor immune response and promote tumor-free outcome.

Adenoviral vectors emerged as important platforms for cancer immunotherapy. Vaccination with adenoviral vectors is promising in this respect, however, their specific mechanisms of action are not fully understood. Here, we assessed the development and maintenance of vaccine-induced tumor-specific CD8

T cells elicited upon immunization with adenoviral vectors.

Adenoviral vaccine vectors encoding the full-length E7 protein from human papilloma virus (HPV) or the immunodominant epitope from E7 were generated, and mice were immunized intravenously with different quantities (10

, 10

or 10

infectious units). The magnitude, kinetics and tumor protection capacity of the induced vaccine-specific T cell responses were evaluated.

The adenoviral vaccines elicited inflationary E7-specific memory CD8

T cell responses in a dose-dependent manner. The magnitude of these vaccine-specific CD8

T cells in the circulation related to the development of E7-specific CD8

tissue-resident memory T (T

) cells, which were maintained for months in multiple tissues after vaccination. The vaccine-specific CD8

T cell responses conferred long-term protection against HPV-induced carcinomas in the skin and liver, and this protection required the induction and accumulation of CD8

T

cells. Moreover, the formation of CD8

T

cells could be enhanced by temporal targeting CD80/CD86 costimulatory interactions via CTLA-4 blockade early after immunization.

Together, these data show that adenoviral vector-induced CD8

T cell inflation promotes protective T

cell populations, and this can be enhanced by targeting CTLA-4.

Together, these data show that adenoviral vector-induced CD8+ T cell inflation promotes protective TRM cell populations, and this can be enhanced by targeting CTLA-4.Ewing sarcoma (ES) is thought to arise from mesenchymal stem cells and is the second most common bone sarcoma in pediatric patients and young adults. Given the dismal overall outcomes and very intensive therapies used, there is an urgent need to explore and develop alternative treatment modalities including immunotherapies. In this article, we provide an overview of ES biology, features of ES tumor microenvironment (TME) and review various tumor-associated antigens that can be targeted with immune-based approaches including cancer vaccines, monoclonal antibodies, T cell receptor-transduced T cells, and chimeric antigen receptor T cells. We highlight key reasons for the limited efficacy of various immunotherapeutic approaches for the treatment of ES to date. These factors include absence of human leukocyte antigen class I molecules from the tumor tissue, lack of an ideal surface antigen, and immunosuppressive TME due to the presence of myeloid-derived suppressor cells, F2 fibrocytes, and M2-like macrophages. Lastly, we offer insights into strategies for novel therapeutics development in ES. These strategies include the development of gene-modified T cell receptor T cells against cancer-testis antigen such as XAGE-1, surface target discovery through detailed profiling of ES surface proteome, and combinatorial approaches. In summary, we provide state-of-the-art science in ES tumor immunology and immunotherapy, with rationale and recommendations for future therapeutics development.This manuscript concerns the ethical aspects of the clinical autopsy procedure. Much of the literature on this topic addresses some of the multifaceted issues potentially involved religious beliefs and/or cultural traditions coming to bear on the management of autopsies, relations between families and healthcare personnel (physicians and technicians) involved in conducting an autopsy, ethical implications of regulations to follow and procedures for obtaining biological samples for further diagnostics or research. All these issues have ethical implications, particularly in today’s globalised cultural domain. To preserve for future generations the teaching and scientific value of the clinical autopsy, scientific societies and academic institutions should endorse educational efforts to promote the ethical management of autopsy procedures.DICER1 is a highly conserved RNaseIII endoribonuclease that has a critical role in the biogenesis of microRNAs (miRNAs). miRNAs are small regulatory RNAs responsible for post-transcriptional gene silencing, controlling more than half of human protein-coding genes. This is achieved through the targeting and regulation of complementary RNA transcripts and has a well-documented role in post-transcriptional gene regulation and transposon repression. DICER1 deficiency results in dysregulation of miRNAs, changing the expression of many genes. DICER1 syndrome represents a collection of benign and malignant tumours arising from an autosomally inherited germline mutation leading to an inherited predisposition to cancer. The syndrome represents an unusual form of Knudson’s two-hit hypothesis, where individuals with a pathogenic germline DICER1 variant acquire a second trans-somatic missense DICER1 mutation. This somatic mutation appears to have to occur in one of five hotspots codons and may contribute towards the incomplete penetrance observed within DICER1 syndrome families. In this case, DICER1 is haploinsuffcient with only one deletion required and partial loss of function being advantageous to tumours over complete loss of function. As increasing data emerge reaffirming the pivotal role of DICER1 in the maintenance of human physiology, DICER1 is likely to become an increasingly attractive target for novel therapeutic strategies.

Histological examination of the rib is of critical value in perinatal pathology and points to the health of the child preceding death. The rib is considered ideal because it is the most rapidly growing long bone in infants and demonstrates growth arrest at onset of the insult. We aimed to identify (1) changes in the perichondrial ring (PR) in the rib of infants and children up to 16 months of age dying suddenly at our institution and (2) any association with presence of histological changes of vitamin D deficiency (VDD)/metabolic bone disease (MBD) in the growth plate.

Retrospective review of the PR histology and comparison with the presence or absence of histological features of VDD in the growth plate of 167 cases. The cases were anonymised and divided in six age/gender categories.

Periphyseal abnormalities were only seen in 38% of the cases; of whom 33% had established and 67% had mild changes. Only 14.5% of cases with established histological appearance of VDD at the growth plate had significant PR abnormality; of whom majority (83%) were ≤3 months of age and none ≥9 months old, reflecting a temporal relation with birth and beyond the perinatal period.

The histological changes in the PR are significantly associated with histological changes of VDD/MBD at the rib growth plate with an OR of 3.04.

The histological changes in the PR are significantly associated with histological changes of VDD/MBD at the rib growth plate with an OR of 3.04.

Both glucose and triglyceride production are increased in type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). For decades, the leading hypothesis to explain these paradoxical observations has been selective hepatic insulin resistance wherein insulin drives de novo lipogenesis (DNL) while failing to suppress glucose production. Here, we aimed to test this hypothesis in humans.

We recruited obese subjects who met criteria for bariatric surgery with (

= 16) or without (

= 15) NAFLD and assessed

) insulin-mediated regulation of hepatic and peripheral glucose metabolism using hyperinsulinemic-euglycemic clamps with [6,6-

H

]glucose,

) fasting and carbohydrate-driven hepatic DNL using deuterated water (

H

O), and

) hepatocellular insulin signaling in liver biopsy samples collected during bariatric surgery.

Compared with subjects without NAFLD, those with NAFLD demonstrated impaired insulin-mediated suppression of glucose production and attenuated-not increased-glucose-stimulated/high-insulin lipogenesis. Fructose-stimulated/low-insulin lipogenesis was intact. Hepatocellular insulin signaling, assessed for the first time in humans, exhibited a proximal block in insulin-resistant subjects Signaling was attenuated from the level of the insulin receptor through both glucose and lipogenesis pathways. The carbohydrate-regulated lipogenic transcription factor

was increased in subjects with NAFLD.

Acute increases in lipogenesis in humans with NAFLD are not explained by altered molecular regulation of lipogenesis through a paradoxical increase in lipogenic insulin action; rather, increases in lipogenic substrate availability may be the key.

Acute increases in lipogenesis in humans with NAFLD are not explained by altered molecular regulation of lipogenesis through a paradoxical increase in lipogenic insulin action; rather, increases in lipogenic substrate availability may be the key.

Leucine-rich α-2 glycoprotein 1 (LRG1) is a circulating protein potentially involved in several pathways related to pathogenesis of heart failure (HF). We aimed to study whether plasma LRG1 is associated with risks of incident HF and hospitalization attributable to HF (HHF) in individuals with type 2 diabetes.

A total of 1,978 individuals with type 2 diabetes were followed for a median of 7.1 years (interquartile range 6.1-7.6). Association of LRG1 with HF was studied using cause-specific Cox regression models.

In follow-up, 191 incident HF and 119 HHF events were identified. As compared with quartile 1, participants with LRG1 in quartiles 3 and 4 had 3.60-fold (95% CI 1.63-7.99) and 5.99-fold (95% CI 2.21-16.20) increased risk of incident HF and 5.88-fold (95% CI 1.83-18.85) and 10.44-fold (95% CI 2.37-45.98) increased risk of HHF, respectively, after adjustment for multiple known cardiorenal risk factors. As a continuous variable, 1 SD increment in natural log-transformed LRG1 was associated with 1.78-fold (95% CI 1.33-2.38) adjusted risk of incident HF and 1.92-fold (95% CI 1.27-2.92) adjusted risk of HHF. Adding LRG1 to the clinical variable-based model improved risk discrimination for incident HF (area under the curve [AUC] 0.79-0.81;

= 0.02) and HHF (AUC 0.81-0.84;

= 0.02).

Plasma LRG1 is associated with risks of incident HF and HHF, suggesting that it may potentially be involved in pathogenesis of HF in individuals with type 2 diabetes. Additional studies are warranted to determine whether LRG1 is a novel biomarker for HF risk stratification.

Plasma LRG1 is associated with risks of incident HF and HHF, suggesting that it may potentially be involved in pathogenesis of HF in individuals with type 2 diabetes. Additional studies are warranted to determine whether LRG1 is a novel biomarker for HF risk stratification.Immunocytokines hold great potential as anticancer agents, as they use a specific antitumor antibody to deliver an immune-activating cytokine directly to the immunosuppressive tumor microenvironment (TME). We have developed a novel immunocytokine (KD033) composed of a fully human, high-affinity antiprogrammed death-ligand 1 (PD-L1) linked to the sushi-domain of the human IL-15/IL-15 receptor alpha (IL-15/IL-15Rα) complex. A murine PD-L1 cross-reactive KD033 surrogate (srKD033) and a nontargeting antibody (ntKD033) were also developed to investigate mechanism of action in murine tumor models. Efficacy analyses showed a robust antitumor effect of single-dose srKD033 in several diverse syngeneic murine tumor models. In a CT26 murine colon tumor model, single-dose srKD033 produced durable antitumor immunity as evidenced by resistance to subsequent tumor rechallenges. Mice responding to srKD033 treatment showed increased retention of PD-L1/IL-15 in the TME which likely facilitated prolonged IL-15-induced expansion of cytotoxic cells. Importantly, target-based PD-L1/IL-15 delivery via srKD033 was well-tolerated and induced significant antitumor activity in murine carcinoma models that are non- or minimally responsive to IL-15 or anti-PD-L1/PD-1 monotherapy.Liver kinase B1 (LKB1)-inactivated tumors are vulnerable to the disruption of pyrimidine metabolism, and leflunomide emerges as a therapeutic candidate because its active metabolite, A77-1726, inhibits dihydroorotate dehydrogenase, which is essential for de novo pyrimidine biosynthesis. However, it is unclear whether leflunomide inhibits LKB1-inactivated tumors in vivo, and whether its inhibitory effect on the immune system will promote tumor growth. Here, we carried out a comprehensive analysis of leflunomide treatment in various LKB1-inactivated murine xenografts, patient-derived xenografts, and genetically engineered mouse models. We also generated a mouse tumor-derived cancer cell line, WRJ388, that could metastasize to the lung within a month after subcutaneous implantation in all animals. This model was used to assess the ability of leflunomide to control distant metastasis. Leflunomide treatment shrank a HeLa xenograft and attenuated the growth of an H460 xenograft, a patient-derived xenograft, and lung adenocarcinoma in the immune-competent genetically engineered mouse models. Interestingly, leflunomide suppressed tumor growth through at least three different mechanisms. It caused apoptosis in HeLa cells, induced G1 cell-cycle arrest in H460 cells, and promoted S-phase cell-cycle arrest in WRJ388 cells. Finally, leflunomide treatment prevented lung metastasis in 78% of the animals in our novel lung cancer metastasis model. In combination, these results demonstrated that leflunomide utilizes different pathways to suppress the growth of LKB1-inactivated tumors, and it also prevents cancer metastasis at distant sites. Therefore, leflunomide should be evaluated as a therapeutic agent for tumors with LKB1 inactivation.

In human papillomavirus (HPV)-based cervical screening programs, management of HPV-positive women with normal cytology is debated. Longitudinal information on HPV type persistence may be employed for risk stratification.

We assessed the risk of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) after repeatedly testing positive for the same HPV type(s) in the randomized population-based screening study Amsterdam (POBASCAM). We compared 18-month CIN3+ risks in HPV-positive women (intervention,

= 1,066) to those in HPV-positive/cytology-negative women who tested HPV-positive in the next screening round (control,

= 111) five years later, stratified for HPV type concordance.

The 18-month CIN3+ risk was 15% in HPV-positive women in the intervention group, 40% in the control group after two-round type concordance (relative risk 2.6, 95% confidence interval 1.9-3.4), and 20% in the control group after a type switch (1.3, 0.5-3.2). The relative increase in CIN3+ risk after two-round type concordance was similar in <35-year-old (3.0, 2.0-4.4) and older women (2.2, 1.4-3.5), and was high in high-risk HPV-positive women who were HPV16/18/31/33/45-negative in both rounds (9.9, 4.4-21.9).

Five-year HPV type concordance signals high CIN3+ risk and warrants referral for colposcopy without additional cytology triage.

HPV screening programs become highly efficient when HPV-positive women with negative triage testing at baseline are offered repeat HPV genotyping after five years.

HPV screening programs become highly efficient when HPV-positive women with negative triage testing at baseline are offered repeat HPV genotyping after five years.

Iron is both essential to life and potentially toxic at higher levels. Epidemiologic studies of iron and breast cancer are sparse, with substantial heterogeneity found in a recent meta-analysis. Evidence based on a comprehensive set of iron biomarkers and a large sample size could help clarify relationships between iron body stores and breast cancer risk.

A case-cohort sample of 6,008 women, including 3,011 incident cases, has been followed for a median of 7.9 years. We estimated breast cancer HRs with Cox models, including age as the primary time scale and including in turn iron, ferritin, percent transferrin saturation, and their first principal component (PC) both as categorical (quartiles) and continuous measures.

Adjusted HRs for the highest versus lowest quartiles of iron, ferritin, and transferrin saturation (95% confidence interval) were 1.06 (0.90-1.25), 1.03 (0.87-1.23), and 0.94 (0.80-1.12), respectively, and 1.06 (0.90-1.25) for the first principal component (PC). Associations were similar when follow-up time was restricted to ≤4 or >2 years.

analyses suggested low iron stores were associated with reduced breast cancer risk, in both pre- and postmenopause and the obese.

A study with one of the largest sample sizes to date and with all three measures of circulating iron, ferritin, and transferrin saturation does not support a strong association between elevated iron stores and breast cancer risk. Further investigation of low iron may be warranted.

These results do not support a strong association between iron overload and breast cancer incidence.

These results do not support a strong association between iron overload and breast cancer incidence.

The association of aspirin use with prostate cancer has been investigated, but few studies included African-American men. Here, we analyzed the relationship of aspirin intake with prostate cancer risk and mortality among African-American men in the Southern Community Cohort Study (SCCS).

SCCS recruited 22,426 African-American men between 2002 and 2009. Aspirin use was assessed at enrollment. Our exposures of interest were any aspirin use (regular strength, low-dose or baby aspirin, or half tablets of aspirin) and regular strength aspirin. Each exposure variable was compared with nonusers. Associations between aspirin use and prostate cancer risk and mortality were examined with Cox proportional hazards models.

At enrollment, 5,486 men (25.1%) reported taking any aspirin and 2,634 men (12.1%) reported regular strength aspirin use. During follow-up (median, 13 years), 1,058 men developed prostate cancer, including 103 prostate cancer-specific deaths. Aspirin use was not associated with prostate cancer development [adjusted HR, 1.07; 95% confidence interval (CI), 0.92-1.25 for any aspirin use and HR, 0.97; 95% CI, 0.78-1.19 for regular strength aspirin], but was suggestively associated with reduced prostate cancer mortality (HR, 0.66; 95% CI, 0.39-1.14 for any aspirin use and HR, 0.41; 95% CI, 0.17-1.00 for regular strength aspirin).

Aspirin use at enrollment was tentatively associated with reduced prostate cancer mortality, but not risk, among African-American men in SCCS.

Prospective SCCS data suggest that aspirin use may help prevent lethal prostate cancer among this high-risk group of men.

Prospective SCCS data suggest that aspirin use may help prevent lethal prostate cancer among this high-risk group of men.Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread rapidly in Manaus, the capital of Amazonas state in northern Brazil. The attack rate there is an estimate of the final size of the largely unmitigated epidemic that occurred in Manaus. We use a convenience sample of blood donors to show that by June 2020, 1 month after the epidemic peak in Manaus, 44% of the population had detectable immunoglobulin G (IgG) antibodies. Correcting for cases without a detectable antibody response and for antibody waning, we estimate a 66% attack rate in June, rising to 76% in October. This is higher than in São Paulo, in southeastern Brazil, where the estimated attack rate in October was 29%. These results confirm that when poorly controlled, COVID-19 can infect a large proportion of the population, causing high mortality.Here, we review fish rheotaxis (orientation to flow) with the goal of placing it within a larger behavioral and multisensory context. Rheotaxis is a flexible behavior that is used by fish in a variety of circumstances to search for upstream sources of current-borne odors, to intercept invertebrate drift and, in general, to conserve energy while preventing downstream displacement. Sensory information available for rheotaxis includes water-motion cues to the lateral line and body-motion cues to visual, vestibular or tactile senses when fish are swept downstream. Although rheotaxis can be mediated by a single sense, each sense has its own limitations. For example, lateral line cues are limited by the spatial characteristics of flow, visual cues by water visibility, and vestibular and other body-motion cues by the ability of fish to withstand downstream displacement. The ability of multiple senses to compensate for any single-sense limitation enables rheotaxis to persist over a wide range of sensory and flow conditions. Here, we propose a mechanism of rheotaxis that can be activated in parallel by one or more senses; a major component of this mechanism is directional selectivity of central neurons to broad patterns of water and/or body motions. A review of central mechanisms for vertebrate orienting behaviors and optomotor reflexes reveals several motorsensory integration sites in the CNS that could be involved in rheotaxis. As such, rheotaxis provides an excellent opportunity for understanding the multisensory control of a simple vertebrate behavior and how a simple motor act is integrated with others to form complex behaviors.Homologous chromosomes pair with each other during meiosis, culminating in the formation of the synaptonemal complex (SC), which is coupled with meiotic recombination. In this study, we showed that a meiosis-specific depletion mutant of a cullin (Cdc53) in the SCF (Skp-Cullin-F-box) ubiquitin ligase, which plays a critical role in cell cycle regulation during mitosis, is deficient in SC formation. However, the mutant is proficient in forming crossovers, indicating the uncoupling of meiotic recombination with SC formation in the mutant. Furthermore, the deletion of the PCH2 gene encoding a meiosis-specific AAA+ ATPase suppresses SC-assembly defects induced by CDC53 depletion. On the other hand, the pch2 cdc53 double mutant is defective in meiotic crossover formation, suggesting the assembly of SC with unrepaired DNA double-strand breaks. A temperature-sensitive mutant of CDC4, which encodes an F-box protein of SCF, shows meiotic defects similar to those of the CDC53-depletion mutant. These results suggest that SCFCdc4, probably SCFCdc4-dependent protein ubiquitylation, regulates and collaborates with Pch2 in SC assembly and meiotic recombination.Bacterial artificial chromosome (BAC)-based transgenes have emerged as a powerful tool for controlled and conditional interrogation of protein function in higher eukaryotes. Although homologous recombination-based recombineering methods have streamlined the efficient integration of protein tags onto BAC transgenes, generating precise point mutations has remained less efficient and time-consuming. Here, we present a simplified method for inserting point mutations into BAC transgenes requiring a single recombineering step followed by antibiotic selection. This technique, which we call exogenous/synthetic intronization (ESI) mutagenesis, relies on co-integration of a mutation of interest along with a selectable marker gene, the latter of which is harboured in an artificial intron adjacent to the mutation site. Cell lines generated from ESI-mutated BACs express the transgenes equivalently to the endogenous gene, and all cells efficiently splice out the synthetic intron. Thus, ESI mutagenesis provides a robust and effective single-step method with high precision and high efficiency for mutating BAC transgenes.Cancer Grand Challenges is a unique funding platform that dares global, multidisciplinary teams of researchers to come together, think differently, and tackle some of the toughest challenges in cancer research. Here, we discuss the nine intractable challenges currently open for application.

Patient ambulation is frequently recommended to help prevent venous thromboembolism during hospital admission. Our objective was to synthesize the evidence for ambulation as a prophylaxis for venous thromboembolism in hospital.

We conducted a systematic review. We searched MEDLINE, Embase, Scopus, Web of Science and Cochrane Central Register of Controlled Trials indexed from their inception through April 2020 for studies of adult patients admitted to hospital, in which ambulation or mobilization alone or concomitant with prophylaxis was indicated for prevention of venous thromboembolism. We searched ClinicalTrials.gov for unpublished trials. We included randomized controlled trials (RCTs) and observational studies. Two reviewers independently screened articles and assessed risk of bias using 2 validated tools. We scored studies on quality of reporting, internal and external validity and study power; combined scores determined the overall quality.

Eighteen articles met the inclusion criteria 8 retrospectve prophylaxis for venous thromboembolism. Ambulation should not be considered an adequate prophylaxis for venous thromboembolism, nor as an adequate reason to discontinue pharmacologic prophylaxis for venous thromboembolism during a patient’s hospital admission.

Bill C-14, the legislation that legalized medical assistance in dying (MAiD) in Canada in 2016, outlines eligibility criteria and includes both a mandated 10-day reflection period and a requirement that the patient have capacity to consent at the time MAiD is provided. We examined clinical factors associated with shortened reflection periods or loss of capacity before provision of MAiD.

This retrospective database review involved patients who requested MAiD at a tertiary care hospital in Toronto, Canada, between June 2016 and April 2019. We used logistic regression analyses to examine the association between the combined outcome of unanticipated loss of decisional capacity, shortening of the reflection period or death and the clinical risk factors of interest (age, sex, location of MAiD request [inpatient v. outpatient], score on palliative performance scale [PPS] and diagnosis [cancer v. noncancer]). We generated receiver operating characteristic curves to identify the PPS score (encompassing 5 functionang the risk of these outcomes. For patients with a PPS score of 40% or below, close monitoring is warranted, potentially with plans made to allow rapid provision of MAiD should their clinical condition deteriorate.

The PPS score at the time of MAiD request was strongly associated with loss of capacity or shortening of the reflection period, with lower scores incrementally increasing the risk of these outcomes. For patients with a PPS score of 40% or below, close monitoring is warranted, potentially with plans made to allow rapid provision of MAiD should their clinical condition deteriorate.

There is high risk of transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in congregate settings, including shelters. This study describes a coronavirus disease 2019 (COVID-19) outbreak and corresponding reported symptomatology at a shelter in Toronto.

This clinical and epidemiologic analysis focuses on a COVID-19 outbreak at a dedicated refugee shelter in downtown Toronto. All adult residents on site at the shelter were offered SARS-CoV-2 testing on Apr. 20, 2020. At the time of testing, residents were screened for 3 typical COVID-19 symptoms (fever, cough and shortness of breath). Among those who tested positive, a more comprehensive clinical assessment was conducted 1 day after testing and a standardized 15-item symptom screen was administered by telephone 14 days after testing. We report rates of positive test results and clinical symptoms with each assessment interval.

Of the 63 adult residents on site at the shelter, 60 agreed to be tested. Among those tested, 41.7% (

= 25) were positive for SARS-CoV-2 infection. Of those who tested positive (

= 25), 20.0% (

= 5) reported fever, cough or shortness of breath at the time of testing. On more detailed assessment 1 day later, 70.8% (17/24) reported a broader range of symptoms. During the 14 days after testing, 87.5% (21/24) reported symptoms of infection.

We found a high rate of SARS-CoV-2 infection in this shelter population. Our study underscores the high risk of SARS-CoV-2 transmission in congregate living settings and the importance of mobilizing timely testing and management of symptomatic, paucisymptomatic and asymptomatic residents in shelters.

We found a high rate of SARS-CoV-2 infection in this shelter population. Our study underscores the high risk of SARS-CoV-2 transmission in congregate living settings and the importance of mobilizing timely testing and management of symptomatic, paucisymptomatic and asymptomatic residents in shelters.

Most often in Canada, the evaluation and management of abnormal uterine bleeding occurs under general anesthesia in the operating room. We aimed to assess the potential cost-effectiveness of an outpatient uterine assessment and treatment unit (UATU) compared with the current standard of care when diagnosing and treating abnormal uterine bleeding in women.

We performed a cost-effectiveness analysis and developed a probabilistic decision tree model to simulate the total costs and outcomes of women receiving outpatient UATU or usual care over a 1-year time horizon (Apr. 1, 2014, to Mar. 31, 2017) at a tertiary care hospital in Ontario, Canada. Probabilities, resource use and time to diagnosis and treatment were obtained from a retrospective chart review of 200 randomly selected women who presented with abnormal uterine bleeding. Results were expressed as overall cost and time savings per patient. Costs are reported in 2018 Canadian dollars.

Compared with usual care, care in the UATU was associated with a decrease in overall cost ($1332, 95% confidence interval [CI] -$1742 to -$1008) and a decrease in overall time to treatment (-75, 95% CI -89 to -63, d). The point at which the UATU would no longer be cost saving is if the additional cost to operate and maintain the UATU is greater than $1600 per patient.

From the perspective of Canada’s health care system, an outpatient UATU is more cost effective than usual care and saves time. Future studies should focus on the relative efficacy of a UATU and the total budget required to operate and maintain a UATU.

From the perspective of Canada’s health care system, an outpatient UATU is more cost effective than usual care and saves time. Future studies should focus on the relative efficacy of a UATU and the total budget required to operate and maintain a UATU.

To describe how the primary healthcare (PHC) in Iceland changed its strategy to handle the COVID-19 pandemic.

Descriptive observational study.

Reykjavik, the capital of Iceland.

The Reykjavik area has a total of 233 000 inhabitants.

The number and the mode of consultations carried out. Drug prescriptions and changes in the 10 most common diagnoses made in PHC. Laboratory tests including COVID-19 tests. Average numbers in March and April 2020 compared with the same months in 2018 and 2019.

Pragmatic strategies and new tasks were rapidly applied to the clinical work to meet the foreseen healthcare needs caused by the pandemic. The number of daytime consultations increased by 35% or from 780 to 1051/1000 inhabitants (p<0.001) during the study period. Telephone and web-based consultations increased by 127% (p<0.001). The same tendency was observed in out-of-hours services. The number of consultations in maternity and well-child care decreased only by 4% (p=0.003). Changes were seen in the 10 most common diagnoses. Most noteworthy, apart from a high number of COVID-19 suspected disease, was that immunisation, depression, hypothyroidism and lumbago were not among the top 10 diagnoses during the epidemic period. The number of drug prescriptions increased by 10.3% (from 494 to 545 per 1000 inhabitants, p<0.001). The number of prescriptions from telephone and web-based consultations rose by 55.6%. No changes were observed in antibiotics prescriptions.

As the first point of contact in the COVID-19 pandemic, the PHC in Iceland managed to change its strategy swiftly while preserving traditional maternity and well-child care, indicating a very solid PHC with substantial flexibility in its organisation.

As the first point of contact in the COVID-19 pandemic, the PHC in Iceland managed to change its strategy swiftly while preserving traditional maternity and well-child care, indicating a very solid PHC with substantial flexibility in its organisation.

Breast and cervical cancers pose a major public health burden globally, with disproportionately high incidence, morbidity and mortality in low- and middle-income countries (LMICs). The majority of women diagnosed with cancer in LMICs present with late-stage disease, the treatment of which is often costlier and less effective. While interventions to improve the timely diagnosis of these cancers are increasingly being implemented in LMICs, there is uncertainty about their role and effectiveness. The aim of this review is to systematically synthesise available evidence on the nature and effectiveness of interventions for improving timely diagnosis of breast and cervical cancers in LMICs.

A comprehensive search of published and relevant grey literature will be conducted. The following electronic databases will be searched MEDLINE (via PubMed), Cochrane Library, Scopus, CINAHL, Web of Science and the International Clinical Trials Registry Platform (ICTRP). Evidence will be synthesised in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA). Two reviewers will independently screen the search outputs, select studies using predefined inclusion criteria and assess each included study for risk of bias. If sufficient data are available and studies are comparable in terms of interventions and outcomes, a meta-analysis will be conducted. Where studies are not comparable and a meta-analysis is not appropriate, a narrative synthesis of findings will be reported.

As this will be a systematic review of publicly available data, with no primary data collection, it will not require ethical approval. Findings will be disseminated widely through a peer-reviewed publication and forums such as conferences, workshops and community engagement sessions. This review will provide a user-friendly evidence summary for informing further efforts at developing and implementing interventions for addressing delays in breast and cervical cancer diagnosis in LMICs.

CRD42020177232.

CRD42020177232.

This scoping review aimed to explore and describe the research on associations between person-centred care (PCC) and healthcare provider outcomes, for example, job satisfaction and work-related health.

Scoping review.

Studies were included if they were empirical studies that analysed associations between PCC measurement tools and healthcare providers outcomes.

Searches in PubMed, CINAHL, Psychinfo and SCOPUS databases were conducted to identify relevant studies published between 2001 and 2019. Two authors independently screened studies for inclusion.

Eighteen studies fulfilled the inclusion criteria. Twelve studies were cross-sectional, four quasi-experimental, one longitudinal and one randomised controlled trial. The studies were carried out in Sweden, The Netherlands, the USA, Australia, Norway and Germany in residential care, nursing homes, safety net clinics, a hospital and community care. The healthcare provider outcomes consisted of job satisfaction, burnout, stress of conscience, psychosocial work environment, job strain and intent to leave. The cross-sectional studies found significant associations, whereas the longitudinal studies revealed no significant effects of PCC on healthcare provider outcomes over time.

Most studies established a positive association between PCC and healthcare provider outcomes. However, due to the methodological variation, a robust conclusion could not be generated. Further research is required to establish the viability of implementing PCC for the improvement of job satisfaction and work-related health outcomes through rigorous and consistent research.

Most studies established a positive association between PCC and healthcare provider outcomes. However, due to the methodological variation, a robust conclusion could not be generated. Further research is required to establish the viability of implementing PCC for the improvement of job satisfaction and work-related health outcomes through rigorous and consistent research.

Asymptomatic carriers (AC) of the new SARS-CoV-2 represent an important source of spread for COVID-19. Early diagnosis of these cases is a powerful tool to control the pandemic. Our objective was to characterise patients with AC status and identify associated sociodemographic factors.

Using a cross-sectional design and the national database of daily occurrence of COVID-19, we characterised both socially and demographically all ACs. Additional correspondence analysis and logistic regression model were performed to identify characteristics associated with AC state (OR, 95% CI).

76.162 ACs (12.1%; 95% CI 12.0% to 12.2%) were identified, mainly before epidemiological week 35. Age≤26 years (1.18; 1.09 to 1.28), male sex (1.51; 1.40 to 1.62), cases imported from Venezuela, Argentina, Brazil, Germany, Puerto Rico, Spain, USA or Mexico (12.6; 3.03 to 52.5) and autochthonous cases (22.6; 5.62 to 91.4) increased the risk of identifying ACs. We also identified groups of departments with moderate (1.23; 1.13 to 1.34) and strong (19.8; 18.6 to 21.0) association with ACs.

Sociodemographic characteristics strongly associated with AC were identified, which may explain its epidemiological relevance and usefulness to optimise mass screening strategies and prevent person-to-person transmission.

Sociodemographic characteristics strongly associated with AC were identified, which may explain its epidemiological relevance and usefulness to optimise mass screening strategies and prevent person-to-person transmission.

Increased demands are placed on emergency services and their role and ability to act in incidents in challenging environments, for example, road tunnels. Collaboration between officers from emergency services (fire brigade, police and ambulance services) is important for an effective rescue effort. In Gothenburg, Sweden, a position as a senior ambulance officer (SAO) within the emergency medical services (EMS) has been introduced to support the regular force during major incidents. The aim of this paper was to explore the perceptions and experiences of the SAO’s new management role in challenging incidents, such as those occurring in road tunnels.

A qualitative interview study.

The study was carried out from February to June 2019 in Gothenburg, Sweden, which is a municipality with several road tunnels and a population of approximately 580 000 people. SAOs collaborate with the corresponding function within the police and fire brigade, both having senior officers at major incident sites.

Twelve SAOs.

ew SAO role not only seems to improve the prehospital medical management, but also makes the EMS command structure during challenging incidents symmetrical with the fire brigade and police command structure. The implementation of national guidelines is desirable and is requested by the SAOs.

Suicide remains a major public health issue around the world. People bereaved by suicide are a vulnerable group who are at considerable risk of developing mental and physical health problems, such as complicated grief, post-traumatic stress disorder or cardiovascular disease. Many unanswered questions remain, in particular, in terms of their use of healthcare services. This protocol describes how we aim to systematically scope the existing literature on the professional follow-up and health service use by families bereaved by suicide. The scoping review will help to identify research gaps in the literature and aid in the planning and commission of future research. We will provide a summary of research findings.

We will use the scoping review framework provided by the Joanna Briggs Institute. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews will be used as a guide for reporting our results. We plan to conduct an extensive literature search using relevant health-related databases (MEDLINE, Embase, PsycINFO and CINAHL) and Web of Science. Two independent reviewers will screen the articles in a two-stage process (1) titles and abstracts and (2) full-text documents.

This scoping review will identify and consider only previously published research. Hence, no ethical approval is considered necessary. We will disseminate the results in a scientific journal and at conferences, as well as through user organisations for people bereaved by suicide and social media.

This scoping review will identify and consider only previously published research. Hence, no ethical approval is considered necessary. We will disseminate the results in a scientific journal and at conferences, as well as through user organisations for people bereaved by suicide and social media.

Over a third of the world’s population relies on solid fuels as their primary energy source. These fuels have damaging effects on health, air quality and forest resources. Interventions to promote access to cleaner solid fuel cookstoves and clean fuels have existed for decades. However, the adoption by local communities has largely failed, which led to a waste of resources and suboptimal outcomes. Therefore, the objective of this umbrella review is to identify factors that determine implementation success for cleaner cooking interventions in low-resource settings and weigh their level of confidence in the evidence.

We identified systematic and narrative reviews examining factors that influence the acquisition, initial adoption or sustained use of cleaner solid fuel cookstoves and clean fuels at any scale by a literature search in PubMed, Embase, Global Health Database, Cochrane, PsycINFO, Emcare, Web of Science and CINAHL, without date or language restrictions. The search was conducted on 23 October 2017 s in low-income and middle-income countries to improve implementation success. These tools should be pilot-tested and promoted among regional and global initiatives.

CRD42018088687.

CRD42018088687.

To examine proton pump inhibitor (PPI) and histamine-2 receptor antagonist (H2RA) prescribing patterns over a 29-year period by quantifying annual prevalence and prescribing intensity over time.

Population-based cross-sectional study.

More than 700 general practices contributing data to the UK Clinical Practice Research Datalink (CPRD).

Within a cohort of 14 242 329 patients registered in the CPRD, 3 027 383 patients were prescribed at least one PPI or H2RA from 1 January 1990 to 31 December 2018.

Annual prescription rates were estimated by dividing the number of patients prescribed a PPI or H2RA by the total CPRD population. Change in prescribing intensity (number of prescriptions per year divided by person-years of follow-up) was calculated using negative binomial regression.

From 1990 to 2018, 21.3% of the CPRD population was exposed to at least one acid suppressant drug. During that period, PPI prevalence increased from 0.2% to 14.2%, while H2RA prevalence remained low (range 1.2%-3.4%). Yearly prescribing intensity to PPIs increased during the first 15 years of the study period but remained relatively constant for the remainder of the study period.