Cytoplasmic TDP-43 accumulation drives changes in C-bouton number and size in a mouse model of sporadic Amyotrophic Lateral Sclerosis.

An altered neuronal excitability of spinal motoneurones has consistently been implicated in Amyotrophic Lateral Sclerosis (ALS) leading to several investigations of synaptic input to these motoneurones. One such input that has repeatedly been shown to be affected is a population of large cholinergic synapses terminating mainly on the soma of the motoneurones referred to as C-boutons. Most research on these synapses during disease progression has used transgenic Superoxide Dismutase 1 (SOD1) mouse models of the disease which have not only produced conflicting findings, but also fail to recapitulate the key pathological feature seen in ALS; cytoplasmic accumulations of TAR DNA-binding protein 43 (TDP-43). Additionally, they fail to distinguish between slow and fast motoneurones, the latter of which have more C-boutons, but are lost earlier in the disease. To circumvent these issues, we quantified the frequency and volume of C-boutons on traced soleus and gastrocnemius motoneurones, representing predominantly slow and fast motor pools respectively. Experiments were performed using the TDP-43ΔNLS mouse model that carries a transgenic construct of TDP-43 devoid of its nuclear localization signal, preventing its nuclear import. This results in the emergence of pathological TDP-43 inclusions in the cytoplasm, modelling the main pathology seen in this disorder, accompanied by a severe and lethal ALS phenotype. Our results confirmed changes in both the number and volume of C-boutons with a decrease in number on the more vulnerable, predominantly fast gastrocnemius motoneurones and an increase in number on the less vulnerable, predominantly slow soleus motoneurones. Importantly, these changes were only found in male mice. However, both sexes and motor pools showed a decrease in C-bouton volume. Our experiments confirm that cytoplasmic TDP-43 accumulation is sufficient to drive C-bouton changes.

Control of Severe, Life-Threatening External Bleeding in the Out-of-Hospital Setting: A Systematic Review.

OBJECTIVE: Trauma, with resultant bleeding, is a significant cause of morbidity and mortality throughout the world; however, the best possible method of bleeding control by immediate responders is unknown. We performed a systematic review of the effectiveness of treatment modalities for severe, life-threatening external bleeding in the out-of-hospital first aid setting. Methods: We followed the Cochrane Handbook for Systematic Reviews of Interventions methodology and report results according to PRISMA guidelines. We included randomized controlled trials, non-randomized comparative studies and case series investigating adults and children with severe, life-threatening external bleeding who were treated with therapies potentially suitable for first aid providers. We assessed the certainty of the evidence and risk of bias. Outcomes were prioritized by first aid specialists based on importance for patients and decision-makers and included mortality due to bleeding, all-cause mortality, cessation of bleeding, time to cessation of bleeding, a decrease in bleeding, and complications/adverse effects. Results were reported in Evidence Profiles. Results: Of the 1,051 full-text articles screened, 107 were included for analysis including 22,798 patients. The primary methods of bleeding control were tourniquets (n = 49), hemostatic dressings (n = 34), hemostatic devices (n = 14), pressure dressings/bandages/devices (n = 8), pressure points (n = 4), including 2 studies that reported multiple hemorrhage control methods. Overall, certainty of evidence was very low and often relied on indirect evidence and poorly controlled studies. Tourniquets were associated with a decrease in mortality when compared with direct manual pressure. Hemostatic dressings resulted in a shorter time to hemostasis than direct manual pressure using standard dressings. Direct manual compression resulted in a shorter time to hemostasis than pressure dressings/devices. Conclusion: Overall, data regarding the control of life-threatening bleeding is of very low certainty, making it difficult to draw robust conclusions for treatment by immediate responders. While more robust data is needed on first aid treatments of life-threatening bleeding, this systematic review aggregates the most comprehensive to date to help guide recommendations. Key words: bleeding; hemorrhage; tourniquet; hemostatic dressing; direct pressure.

Ventilation Techniques and Risk for Transmission of Coronavirus Disease, Including COVID-19: A Living Systematic Review of Multiple Streams of Evidence.

BACKGROUND: Mechanical ventilation is used to treat respiratory failure in coronavirus disease 2019 (COVID-19). PURPOSE: To review multiple streams of evidence regarding the benefits and harms of ventilation techniques for coronavirus infections, including that causing COVID-19. DATA SOURCES: 21 standard, World Health Organization-specific and COVID-19-specific databases, without language restrictions, until 1 May 2020. STUDY SELECTION: Studies of any design and language comparing different oxygenation approaches in patients with coronavirus infections, including severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS), or with hypoxemic respiratory failure. Animal, mechanistic, laboratory, and preclinical evidence was gathered regarding aerosol dispersion of coronavirus. Studies evaluating risk for virus transmission to health care workers from aerosol-generating procedures (AGPs) were included. DATA EXTRACTION: Independent and duplicate screening, data abstraction, and risk-of-bias assessment (GRADE for certainty of evidence and AMSTAR 2 for included systematic reviews). DATA SYNTHESIS: 123 studies were eligible (45 on COVID-19, 70 on SARS, 8 on MERS), but only 5 studies (1 on COVID-19, 3 on SARS, 1 on MERS) adjusted for important confounders. A study in hospitalized patients with COVID-19 reported slightly higher mortality with noninvasive ventilation (NIV) than with invasive mechanical ventilation (IMV), but 2 opposing studies, 1 in patients with MERS and 1 in patients with SARS, suggest a reduction in mortality with NIV (very-low-certainty evidence). Two studies in patients with SARS report a reduction in mortality with NIV compared with no mechanical ventilation (low-certainty evidence). Two systematic reviews suggest a large reduction in mortality with NIV compared with conventional oxygen therapy. Other included studies suggest increased odds of transmission from AGPs. LIMITATION: Direct studies in COVID-19 are limited and poorly reported. CONCLUSION: Indirect and low-certainty evidence suggests that use of NIV, similar to IMV, probably reduces mortality but may increase the risk for transmission of COVID-19 to health care workers. PRIMARY FUNDING SOURCE: World Health Organization. (PROSPERO: CRD42020178187).

Cancer treatment in pregnant women.

In general, strategies for the treatment of cancer in pregnancy should not differ significantly from the treatment regimens in non-pregnant women. However, this is difficult due to either the effects of anticancer drugs on the developing foetus or the possibility of long-term complications after the exposure to drugs and radiation. The decision about the introduction and continuation of treatment in the event of pregnancy should be preceded by a detailed analysis of the potential benefits and risks. There are no data to suggest that pregnancy termination alters the biological behaviour of the tumour or patient prognosis in the presence of appropriate antineoplastic therapy. All patients should be given appropriate advice and informed that there are insufficient scientific data to determine any generally accepted consensus. It is very important to always respect the will of the patient, and the moral judgment of the physician should have no impact on the decisions taken by the woman. If the woman decides to undergo active treatment and maintain her pregnancy, it is necessary to carry out consultations with experts in the field appropriate to the type of cancer. This paper presents a basic review of the literature on the targeted therapies currently used in selected cancers diagnosed during pregnancy: breast cancer, cervical cancer, Hodgkin's disease, melanoma, thyroid cancer, ovarian cancer, and colorectal cancer.

The effect of liquid crystalline structures on antiseizure properties of aqueous solutions of ethoxylated alcohols.

Aqueous solutions of ethoxylated alcohols which form lyotropic liquid crystals at high concentrations (40-80%) were selected as model lubricating substances. Microscopic studies under polarized light and viscosity measurements were carried out in order to confirm the presence of liquid crystalline structures in the case of alcohol solutions with ethoxylation degrees of 3, 5, 7 and 10. Microscopic images and viscosity coefficient values characteristic of various mesophases were obtained. As expected, the viscosity of LLCs decreases considerably with an increase in shearing rate which is characteristic of liquid crystals being non-Newtonian liquids. Antiseizure properties were determined by means of a four-ball machine (T-02 Tester) and characterized by scuffing load (P(t)), seizure load (P(oz)) and limiting pressure of seizure (p(oz)). Alcohol ethoxylates forming mesophases in aqueous solutions have the strongest effect on the P(t) values which are several times higher than those measured in the presence of water. Ethoxylates with higher degrees of ethoxylation exhibit higher values of scuffing load. Those changes have been interpreted as a result of higher cloud points at which those compounds lose their amphiphilic properties. In general, the presence of mesophases in the bulk phase and particularly in the surface phase may lead to the formation of a lubricant film which separates the frictionally cooperating elements of a friction pair. The antiseizure efficiency of alcohol solutions is highest up to the load value which does not exceed the scuffing load value.

The Benefit of a Switch: Answer-Changing on Multiple-Choice Exams by First-Year Dental Students.

The aim of this study was to determine if dental students would benefit from changing their initial responses to what they have deemed to be more suitable answers during high-stakes multiple-choice examinations. Students are often advised to stay with their first answers despite evidence from other fields suggesting this is not the best course for obtaining optimal final exam scores. Data were collected for 160 first-year DMD students in fall 2013 for three operative dentistry and four biochemistry exams at Tufts University School of Dental Medicine. As students take all of their exams through ExamSoft, a test-taking software application that tracks and records all changes students make during the exam period, the subjective nature of previous studies on answer changing was eliminated. The results showed that all students changed their answers on a minimum of nine questions over the seven exams, with an average of 26.55 (SD=8.8) questions changed per student. Answers changed from an incorrect to a correct response comprised nearly 65% of total answer changes, while changes from a correct to an incorrect answer encompassed slightly above 10% of answer changes. Nearly all students (99.4%) benefitted from answer-changing with a net gain of at least two correct questions, with only one student not increasing the final score. Overall, the students greatly benefitted from changing their answer choice, suggesting that dental students could be advised to change their answers from their first choice if they identify a better option when taking multiple-choice exams.