LTK and ALK promote neuronal polarity and cortical migration by inhibiting IGF1R activity.

The establishment of axon-dendrite polarity is fundamental for radial migration of neurons, cortical patterning, and formation of neuronal circuits. Here, we show that the receptor tyrosine kinases, Ltk and Alk, are required for proper neuronal polarization. In isolated primary mouse embryonic neurons, the loss of Ltk and/or Alk causes a multiple axon phenotype. In mouse embryos and newborn pups, the absence of Ltk and Alk delays neuronal migration and subsequent cortical patterning. In adult cortices, neurons with aberrant neuronal projections are evident and axon tracts in the corpus callosum are disrupted. Mechanistically, we show that the loss of Alk and Ltk increases the cell-surface expression and activity of the insulin-like growth factor 1 receptor (Igf-1r), which activates downstream PI3 kinase signaling to drive the excess axon phenotype. Our data reveal Ltk and Alk as new regulators of neuronal polarity and migration whose disruption results in behavioral abnormalities.

Instagram for peer teaching: opportunity and challenge.

Medical education is increasingly being delivered beyond the boundaries of the classroom. Online learning and peer teaching are particularly popular among educators to complement traditional, didactic teaching methods. In light of the COVID-19 pandemic, students at the Queen's University Belfast's (QUB) General Practice Society started creating daily multiple-choice questions (MCQs) on Instagram to help continue learning while placements were suspended. There were high levels of engagement with the MCQs, with students reporting the content to be both relevant and useful for their learning. The project also allowed us to gain early experience of teaching, furthered our own learning and helped develop key skills (e.g. providing constructive feedback, creativity, self-directed learning) important for both our professional and personal development. Nonetheless, there are few published examples of the use of Instagram within medical education. Further work needs to be carried out to summarise projects delivered on the platform, train educators in using Instagram, and encourage students to get involved in finding further, novel methods of delivering medical education.

Onset of benign paroxysmal positional vertigo after total laparoscopic hysterectomy in the Trendelenburg position.

Herein is reported the case of a 51-year-old woman who underwent total laparoscopic hysterectomy in the steep Trendelenburg position who developed postoperative benign paroxysmal positional vertigo. The etiology of benign paroxysmal positional vertigo is examined and the Trendelenburg position during surgery as the triggering factor is explored.

NUAK1 promotes organ fibrosis via YAP and TGF-ß/SMAD signaling.

Fibrosis is a central pathway that drives progression of multiple chronic diseases, yet few safe and effective clinical antifibrotic therapies exist. In most fibrotic disorders, transforming growth factor-ß (TGF-ß)-driven scarring is an important pathologic feature and a key contributor to disease progression. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are two closely related transcription cofactors that are important for coordinating fibrogenesis after organ injury, but how they are activated in response to tissue injury has, so far, remained unclear. Here, we describe NUAK family kinase 1 (NUAK1) as a TGF-ß-inducible profibrotic kinase that is up-regulated in multiple fibrotic organs in mice and humans. Mechanistically, we show that TGF-ß induces a rapid increase in NUAK1 in fibroblasts. NUAK1, in turn, can promote profibrotic YAP and TGF-ß/SMAD signaling, ultimately leading to organ scarring. Moreover, activated YAP and TAZ can induce further NUAK1 expression, creating a profibrotic positive feedback loop that enables persistent fibrosis. Using mouse models of kidney, lung, and liver fibrosis, we demonstrate that this fibrogenic signaling loop can be interrupted via fibroblast-specific loss of NUAK1 expression, leading to marked attenuation of fibrosis. Pharmacologic NUAK1 inhibition also reduced scarring, either when initiated immediately after injury or when initiated after fibrosis was already established. Together, our data suggest that NUAK1 plays a critical, previously unrecognized role in fibrogenesis and represents an attractive target for strategies that aim to slow fibrotic disease progression.

Appropriateness of antimicrobial prescribing in the high-burden emergency department of a tertiary hospital in Malaysia.

Background Appropriate antimicrobial prescribing in the emergency department (ED) is a challenge due to diagnostic uncertainty, time pressure, and clinical inertia. Objective To assess the appropriateness of antimicrobial prescribing in the ED. Setting This study was conducted in the inpatient ED of a tertiary hospital in Malaysia. Method We conducted a 6-month retrospective antimicrobial prescriptions analysis among ED patients who received intravenous antimicrobial. Antimicrobial prescriptions of conveniently selected adult patients were evaluated with the medication appropriateness index. Main outcome measure Appropriateness of antimicrobial prescribing was the primary outcome measure. Results We analysed 310 patients with 326 antimicrobial prescriptions. Ceftriaxone (41.1%, n = 134) and amoxicillin-clavulanate (36.5%, n = 119) were the most common antimicrobials prescribed. Respiratory infections (71.5%, n = 233) was the main indication for antimicrobial therapy in the ED. All antimicrobials prescribed were indicated as per the Malaysian antimicrobial guidelines. The overall rate of inappropriate antimicrobial prescribing was 53.1% (n = 173). Thirty-two (9.8%) antimicrobials were prescribed with inappropriate doses; the majority was related to beta-lactam/beta-lactamase dose (p = 0.002). One hundred and forty-three (43.9%) antimicrobials prescribed had alternatives with similar efficacy but were less costly; which referring to ceftriaxone usage (p < 0.001). Conclusions The inappropriate antimicrobial prescribing in the emergency department is prevalent. This emphasises the importance of conducting antimicrobial stewardship initiative in the ED to improve the appropriate dosing of beta-lactam/beta-lactamase inhibitors as well as the judicious use of ceftriaxone.

Integrating preventive dental care into general Paediatric practice for Indigenous communities: paediatric residents' perceptions.

This qualitative study aimed to explore paediatric residents' perceptions of the feasibility of incorporating preventive dental care into a general paediatric outreach clinic for a First Nations community. Four focus groups were conducted with paediatric residents and attending paediatricians. Interviews were recorded, transcribed verbatim and analysed using a basic interpretive qualitative approach. Three major themes emerged from the data: advantages of integration, barriers to integration and strategies for integration. Comprehensive care and service delivery were the two identified advantages of integration. Three categories of barriers emerged including patient and caregiver-related, resident-related and setting-related barriers. Training and practice, patient education, support and policy were the suggested strategies for successful integration. Providers were found to be open to integrating preventive dental care into their practice. However, barriers impeded the success of this integration. Multiple strategies including oral health care training for medical providers, office support and policy changes would facilitate successful integration.

Integrated copy number and miRNA expression analysis in triple negative breast cancer of Latin American patients.

Triple negative breast cancer (TNBC), a clinically aggressive breast cancer subtype, affects 15-35% of women from Latin America. Using an approach of direct integration of copy number and global miRNA profiling data, performed simultaneously in the same tumor specimens, we identified a panel of 17 miRNAs specifically associated with TNBC of ancestrally characterized patients from Latin America, Brazil. This panel was differentially expressed between the TNBC and non-TNBC subtypes studied (p ≤ 0.05, FDR ≤ 0.25), with their expression levels concordant with the patterns of copy number alterations (CNAs), present mostly frequent at 8q21.3-q24.3, 3q24-29, 6p25.3-p12.2, 1q21.1-q44, 5q11.1-q22.1, 11p13-p11.2, 13q12.11-q14.3, 17q24.2-q25.3 and Xp22.33-p11.21. The combined 17 miRNAs presented a high power (AUC = 0.953 (0.78-0.99);95% CI) in discriminating between the TNBC and non-TNBC subtypes of the patients studied. In addition, the expression of 14 and 15 of the 17miRNAs was significantly associated with tumor subtype when adjusted for tumor stage and grade, respectively. In conclusion, the panel of miRNAs identified demonstrated the impact of CNAs in miRNA expression levels and identified miRNA target genes potentially affected by both CNAs and miRNA deregulation. These targets, involved in critical signaling pathways and biological functions associated specifically with the TNBC transcriptome of Latina patients, can provide biological insights into the observed differences in the TNBC clinical outcome among racial/ethnic groups, taking into consideration their genetic ancestry.

A feed forward loop enforces YAP/TAZ signaling during tumorigenesis.

In most solid tumors, the Hippo pathway is inactivated through poorly understood mechanisms that result in the activation of the transcriptional regulators, YAP and TAZ. Here, we identify NUAK2 as a YAP/TAZ activator that directly inhibits LATS-mediated phosphorylation of YAP/TAZ and show that NUAK2 induction by YAP/TAZ and AP-1 is required for robust YAP/TAZ signaling. Pharmacological inhibition or loss of NUAK2 reduces the growth of cultured cancer cells and mammary tumors in mice. Moreover, in human patient samples, we show that NUAK2 expression is elevated in aggressive, high-grade bladder cancer and strongly correlates with a YAP/TAZ gene signature. These findings identify a positive feed forward loop in the Hippo pathway that establishes a key role for NUAK2 in enforcing the tumor-promoting activities of YAP/TAZ. Our results thus introduce a new opportunity for cancer therapeutics by delineating NUAK2 as a potential target for re-engaging the Hippo pathway.

Differentially expressed miRNAs in triple negative breast cancer between African-American and non-Hispanic white women.

Triple Negative Breast Cancer (TNBC), a clinically aggressive subtype of breast cancer, disproportionately affects African American (AA) women when compared to non-Hispanic Whites (NHW). MiRNAs(miRNAs) play a critical role in these tumors, through the regulation of cancer driver genes. In this study, our goal was to characterize and compare the patterns of miRNA expression in TNBC of AA (n = 27) and NHW women (n = 30). A total of 256 miRNAs were differentially expressed between these groups, and distinct from the ones observed in their respective non-TNBC subtypes. Fifty-five of these miRNAs were mapped in cytobands carrying copy number alterations (CNAs); 26 of them presented expression levels concordant with the observed CNAs. Receiving operating characteristic (ROC) analysis showed a good power (AUC ≥ 0.80; 95% CI) for over 65% of the individual miRNAs and a high combined power with superior sensitivity and specificity (AUC = 0.88 (0.78-0.99); 95% CI) of the 26 miRNA panel in discriminating TNBC between these populations. Subsequent miRNA target analysis revealed their involvement in the interconnected PI3K/AKT, MAPK and insulin signaling pathways. Additionally, three miRNAs of this panel were associated with early age at diagnosis. Altogether, these findings indicated that there are different patterns of miRNA expression between TNBC of AA and NHW women and that their mapping in genomic regions with high levels of CNAs is not merely physical, but biologically relevant to the TNBC phenotype. Once validated in distinct cohorts of AA women, this panel can potentially represent their intrinsic TNBC genome signature.

Local molecular analysis of indeterminate thyroid nodules.

BACKGROUND: Thyroid nodules are common but only a minority are malignant. Molecular testing can assist in helping determine whether indeterminate nodules are suspicious for malignancy or benign. The objective of the study was to determine if the analysis of mutations (BRAF, NRAS, KRAS and HRAS) using readily available molecular techniques can help better classify indeterminate thyroid nodules. METHODS: A retrospective cohort of consecutive patients undergoing diagnostic thyroid surgery were analyzed for the presence or absence of specific mutations known to be associated with thyroid malignancy in FNA samples. Markers chosen were BRAF, NRAS, KRAS and HRAS. All were locally available and currently in use at our centre for other clinical indications. Results from the molecular analysis were then compared to the histopathology from thyroidectomy specimens to determine the sensitivity and specificity of these molecular techniques to classify indeterminate thyroid nodules. RESULTS: Sixty consecutive patients with indeterminate FNAs were recruited. Twenty-three patients had malignant tumors while 37 specimens were benign. Multiple different mutations were identified in the FNA samples. Overall 18 cases had a positive mutation (10 malignant and 8 benign). The sensitivity of BRAF, HRAS, KRAS, and NRAS was 8.7, 8.7, 8.7, and 17.4 respectively while the specificity was100, 83.7, 100 and 94.6. CONCLUSION: While molecular analysis remains promising, it requires further refinement. Several markers showed promise as good "rule-in" tests.

Nasal packing after septoplasty: cardiopulmonary impact.

IMPORTANCE: Bilateral anterior nasal packing is used after septoplasty with the goals of decreasing the risk of postoperative bleeding and adhesions. However, multiple studies caution against the use of nasal packing because of the risk of cardiopulmonary complications. OBJECTIVE: To evaluate the cardiopulmonary risks associated with bilateral anterior nasal packing after septoplasty. EVIDENCE REVIEW: A literature review was conducted by 2 independent reviewers using EMBASE, Ovid, Medline, PubMed, Google Scholar, Cochrane Central Register of Controlled Trials (CENTRAL), and reference list review from January 1966 to September 2012 to identify studies assessing nasal packing after septoplasty. The studies were reviewed and assigned an Oxford level of evidence grade, Detsky score, and Methodological Index for Nonrandomized Studies (MINORS) score. Data were extracted for arterial blood gases, oxygen desaturations, oxygen saturations, and adverse outcomes. Pooled estimates for randomized studies were performed when possible. FINDINGS: Fourteen studies conducted between 1973 and 2011 were included: 2 randomized clinical trials (RCTs) with a total of 119 patients and 12 prospective observational studies with a total of 356 patients. Nine studies showed a significant change within 1 of the cardiopulmonary parameters investigated. However, there was no consistency in changes across both observational and randomized studies. Furthermore, pooled estimates for cardiopulmonary parameters were all nonsignificant: standard mean differences of the pooled results of the RCTs were 0.05 (95% CI, -0.31 to 0.41) for arterial pH, 0.08 (95% CI, -0.30 to 0.46) for Paco2, and -0.32 (95% CI, -1.28 to 0.63) for Pao2. There were no major cardiopulmonary complications after nasal packing. CONCLUSIONS AND RELEVANCE: Bilateral anterior nasal packing does not seem to cause adverse cardiopulmonary changes after septoplasty.

Is nasal packing necessary after septoplasty? A meta-analysis.

BACKGROUND: Nasal packing is routinely used after septoplasty because it is believed to decrease risk of postoperative bleeding, hematomas, and adhesions. Multiple studies have shown, however, that there are numerous complications associated with nasal packing. The purpose of this work was to perform a meta-analysis on the existing literature to evaluate the role of nasal packing after septoplasty. METHODS: Two independent reviewers conducted a literature search using EMBASE, OVID, Medline, PubMed, Google scholar, Cochrane Library, and reference list review from 1966 to August 2010 to identify studies assessing nasal packing after septoplasty. All papers were reviewed for study design, results, and were assigned an Oxford level of evidence grade, Detsky score, and Methodological Index for Nonrandomized Studies (MINORS) score. RESULTS: Sixteen papers were identified that met the inclusion criteria. Eleven papers were randomized control trials, 3 were prospective, and 2 were retrospective studies. Nasal packing did not show benefit in reducing postoperative bleeding, hematomas, septal perforations, adhesions, or residual deviated nasal septum. There was, however, an increase in postoperative infections. Two studies using fibrin products as nasal packing showed a decreased bleeding rate. CONCLUSION: Nasal packing after septoplasty does not show any postoperative benefits. Fibrin products show a possibility of decreasing postoperative bleeding. Routine use of nasal packing after septoplasty is not warranted. This is the first meta-analysis conducted on this topic.

Castration differentially affects spatial working and reference memory in male rats.

A male advantage for spatial learning and memory tasks is well documented among humans and rodents. A possible physiological cause for this male advantage is activational effects of androgens among males. The spatial memory of eight castrated and eight sham-castrated adult male rats was compared using a working-reference memory version of the eight-arm radial arm maze followed by a reference memory version of the Morris water maze. After maze testing, blood was collected from each rat, and testosterone levels were determined using radioimmunoassay. In the radial arm maze, castrates committed significantly more working memory errors and significantly fewer reference memory errors than did shams. In the water maze, no statistically significant differences were found for acquisition or retention. There was a trend for shams with higher testosterone levels to have better retention in the water maze, but this seemed to be due to higher levels of perseverance rather than better reference memory. Castration may have affected performance in the radial arm maze and not in the water maze because the radial arm maze was a more difficult task or because the water maze was aversively motivated while the radial arm maze was appetitively motivated. Our results indicate that androgens improve working memory and may impair reference memory, but the effects of androgens on reference memory seem to be task dependent.