Circadian autophagy drives iTRF-mediated longevity.

Time-restricted feeding (TRF) has recently gained interest as a potential anti-ageing treatment for organisms from Drosophila to humans1-5. TRF restricts food intake to specific hours of the day. Because TRF controls the timing of feeding, rather than nutrient or caloric content, TRF has been hypothesized to depend on circadian-regulated functions; the underlying molecular mechanisms of its effects remain unclear. Here, to exploit the genetic tools and well-characterized ageing markers of Drosophila, we developed an intermittent TRF (iTRF) dietary regimen that robustly extended fly lifespan and delayed the onset of ageing markers in the muscles and gut. We found that iTRF enhanced circadian-regulated transcription and that iTRF-mediated lifespan extension required both circadian regulation and autophagy, a conserved longevity pathway. Night-specific induction of autophagy was both necessary and sufficient to extend lifespan on an ad libitum diet and also prevented further iTRF-mediated lifespan extension. By contrast, day-specific induction of autophagy did not extend lifespan. Thus, these results identify circadian-regulated autophagy as a critical contributor to iTRF-mediated health benefits in Drosophila. Because both circadian regulation and autophagy are highly conserved processes in human ageing, this work highlights the possibility that behavioural or pharmaceutical interventions that stimulate circadian-regulated autophagy might provide people with similar health benefits, such as delayed ageing and lifespan extension.

Wettability-based ultrasensitive detection of amphiphiles through directed concentration at disordered regions in self-assembled monolayers.

Various forms of ecological monitoring and disease diagnosis rely upon the detection of amphiphiles, including lipids, lipopolysaccharides, and lipoproteins, at ultralow concentrations in small droplets. Although assays based on droplets' wettability provide promising options in some cases, their reliance on the measurements of surface and bulk properties of whole droplets (e.g., contact angles, surface tensions) makes it difficult to monitor trace amounts of these amphiphiles within small-volume samples. Here, we report a design principle in which self-assembled monolayer-functionalized microstructured surfaces coated with silicone oil create locally disordered regions within a droplet's contact lines to effectively concentrate amphiphiles within the areas that dominate the droplet static friction. Remarkably, such surfaces enable the ultrasensitive, naked-eye detection of amphiphiles through changes in the droplets' sliding angles, even when the concentration is four to five orders of magnitude below their critical micelle concentration. We develop a thermodynamic model to explain the partitioning of amphiphiles at the contact line by their cooperative association within the disordered, loosely packed regions of the self-assembled monolayer. Based on this local analyte concentrating effect, we showcase laboratory-on-a-chip surfaces with positionally dependent pinning forces capable of both detecting industrially and biologically relevant amphiphiles (e.g., bacterial endotoxins), as well as sorting aqueous droplets into discrete groups based on their amphiphile concentrations. Furthermore, we demonstrate that the sliding behavior of amphiphile-laden aqueous droplets provides insight into the amphiphile's effective length, thereby allowing these surfaces to discriminate between analytes with highly disparate molecular sizes.

Nanotechnology and malaria: Evaluation of efficacy and toxicity of green nanoparticles.

Malaria is a global health problem that causes 1.5-2.7 million deaths worldwide each year. Resistance to antimalarial drugs in malaria parasites and to insecticides in vectors is one of the most serious issues in the fight against the disease. Moreover, the lack of an effective vaccine against malaria is still a major concern. Recent developments in nanotechnology have resulted in new prospects for the fight against malaria, especially by obtaining metal nanoparticles (NPs) that are less toxic, highly biocompatible, environmentally friendly, and less expensive. Numerous studies have been conducted on the synthesis of green NPs using plants and microorganisms (bacteria, fungi, algae, actinomycetes, and viruses). To our knowledge, there is no literature review that compares toxicities and antimalarial effects of some existing metallic nanoparticles revealing their advantages and disadvantages. The purpose of this review is to assess the metal NPs obtained through various green synthesis processes, to display the worth of future malaria research, and to determine future strategies. The literature review revealed that there are very limited studies on green NPs covering all stages of malaria parasites. Additionally, green metal nanoparticles have yet to be studied for their possible toxic effects on infected as well as healthy erythrocytes. Moreover, the toxicities of green metal NPs obtained from various sources differed according to concentration, size, shape, synthesis method, and surface charge, indicating the necessity of optimizing the methods used in future studies. This work has investigated the effectiveness of green metal nanoparticles synthesized from different sources against malaria, as well as their advantages and disadvantages. It was concluded that studies on the toxic properties of green nanoparticles would be very important for future stages.

Light Driven Ultrafast Bioinspired Molecular Motors: Steering and Accelerating Photoisomerization Dynamics of Retinal.

Photoisomerization of retinal protonated Schiff base in microbial and animal rhodopsins are strikingly ultrafast and highly specific. Both protein environments provide conditions for fine-tuning the photochemistry of their chromophores. Here, by combining time-resolved action absorption spectroscopy and high-level electronic structure theory, we show that similar control can be gained in a synthetically engineered retinal chromophore. By locking the dimethylated retinal Schiff base at the C11═C12 double bond in its trans configuration (L-RSB), the excited-state decay is rendered from a slow picosecond to an ultrafast subpicosecond regime in the gas phase. Steric hindrance and pretwisting of L-RSB are found to be important for a significant reduction in the excited-state energy barriers, where isomerization of the locked chromophore proceeds along C9═C10 rather than the preferred C11═C12 isomerization path. Remarkably, the accelerated excited-state dynamics also becomes steered. We show that L-RSB is capable of unidirectional 360° rotation from all-trans to 9-cis and from 9-cis to all-trans in only two distinct steps induced by consecutive absorption of two 600 nm photons. This opens a way for the rational design of red-light-driven ultrafast molecular rotary motors based on locked retinal chromophores.

Should Arthroscopic Bone Marrow Stimulation Be Used in the Management of Secondary Osteochondral Lesions of the Talus? A Systematic Review.

BACKGROUND: Osteochondral lesions of the talus are common, particularly after trauma. Arthroscopic bone marrow stimulation has emerged as the first-choice surgical treatment for small primary lesions less than 100 mm2. Individual studies on the topic are small and heterogeneous, and they have differed in their main findings; for this reason, systematically reviewing the available evidence seems important. QUESTIONS/PURPOSES: In this systematic review, we asked: (1) What patient-reported outcomes and pain scores have been observed after arthroscopic bone marrow stimulation for secondary osteochondral lesions of the talus? (2) What complications were reported? (3) What demographic and clinical factors were reported to be associated with better patient-reported outcome scores? METHODS: We performed a systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using Embase, EmCare, PubMed, CINAHL, and Scopus (databases last searched June 23, 2021). A two-stage title/abstract and full-text screening process was performed independently by two reviewers. Randomized control trials, cohort studies, and observational studies published in English that evaluated the outcome of arthroscopic bone marrow stimulation for secondary osteochondral lesions of the talus were included. Case reports, review articles, commentaries, abstracts, and letters to the editor were excluded. A total of 12 articles (10 case series and two retrospective comparative studies) involving 446 patients were included. Of these, 111 patients with a mean age of 33 years (range 20 to 49) received arthroscopic bone marrow stimulation for a secondary osteochondral lesion of the talus. The Methodological Index for Non-randomized Studies (MINORS) criteria were used to assess the methodologic quality of included studies. The MINORS is a numerical score ranging from 0 to 16 for studies with no comparison group and 0 to 24 for comparative studies, with higher quality studies receiving higher scores. Of the 10 noncomparative case series, the highest score was 10 of 16, with a median (range) score of 7.5 (4 to 10), while the two comparative studies scored 22 of 24 and 19 of 24, respectively. RESULTS: Studies varied widely in terms of patient-reported outcome measures such as the American Orthopaedic Foot and Ankle Society score (AOFAS), with inconsistent reporting across studies regarding whether or how much patients improved; there was variation in some effect sizes with regard to improvement seeming close to or below the minimum clinically important difference (MCID). Although no perioperative complications were reported in any included studies, 34% (26 of 77, in seven studies that reported on this endpoint) of patients who underwent a revision procedure. One study found a negative association between lesion size and AOFAS and VAS score. No other studies reported on factors associated with patient-reported outcome scores, and most studies were far too small to explore relationships of this sort. CONCLUSION: We found that arthroscopic bone marrow stimulation for secondary osteochondral lesions of the talus yielded inconsistent and often small improvements in patient-reported outcomes, with approximately one in three patients undergoing a revision procedure. Reported outcomes likely represent a best-case scenario, inflated by low-level study designs and major sources of bias that are known to make treatment effects seem larger than they are. Therefore, the use of arthroscopic bone marrow stimulation in such patients cannot be recommended, unless we are able to refine selection criteria to effectively identify patients who show a substantial clinical benefit. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Gastrocnemius release is an effective management option for Achilles tendinopathy: a systematic review.

PURPOSE: This systematic review aims to summarise the outcomes of gastrocnemius release in the management of Achilles Tendinopathy. METHODS: A systematic review was performed according to PRISMA guidelines. A computer-based search was performed in PubMed, Embase, Cinahl, Scopus and ISI Web of Science. Two independent reviewers performed both title/abstract and full-text screening according to a-priori selection criteria. English-language original research studies reporting outcomes for gastrocnemius recession in patients with Achilles tendinopathy were included. Study quality and risk of bias were assessed using the MINORS criteria. RESULTS: Of the 229 articles identified following database searching, nine studies describing 145 cases of gastrocnemius recession were included in the review. Clinically important differences were reported across a range of validated patient reported outcome scores including VISA-A, FFI, FAAM and VAS pain score. Outcomes appear to be superior in patients with noninsertional Achilles tendinopathy, however further research is required to confirm this. Studies also reported an increase in ankle dorsiflexion range of motion and a good rate of return to sport/work. The overall complication rate was 10/123 (8.1%), with sural nerve injury being the most common complication, occurring in 5/123 (4.1%) of cases. CONCLUSION: The results of this review suggest gastrocnemius release to be an effective treatment option in the management of patients with Achilles tendinopathy, who have gastrocnemius contracture and have previously failed to respond adequately to non-operative treatment. LEVEL OF EVIDENCE: Level IV.

Development and internal validation of clinical prediction models for outcomes of complicated intra-abdominal infection.

BACKGROUND: Complicated intra-abdominal infections (cIAIs) are associated with significant morbidity and mortality. The aim of this study was to describe the clinical characteristics of patients with cIAI in a multicentre study and to develop clinical prediction models (CPMs) to help identify patients at risk of mortality or relapse. METHODS: A multicentre observational study was conducted from August 2016 to February 2017 in the UK. Adult patients diagnosed with cIAI were included. Multivariable logistic regression was performed to develop CPMs for mortality and cIAI relapse. The c-statistic was used to test model discrimination. Model calibration was tested using calibration slopes and calibration in the large (CITL). The CPMs were then presented as point scoring systems and validated further. RESULTS: Overall, 417 patients from 31 surgical centres were included in the analysis. At 90 days after diagnosis, 17.3 per cent had a cIAI relapse and the mortality rate was 11.3 per cent. Predictors in the mortality model were age, cIAI aetiology, presence of a perforated viscus and source control procedure. Predictors of cIAI relapse included the presence of collections, outcome of initial management, and duration of antibiotic treatment. The c-statistic adjusted for model optimism was 0.79 (95 per cent c.i. 0.75 to 0.87) and 0.74 (0.73 to 0.85) for mortality and cIAI relapse CPMs. Adjusted calibration slopes were 0.88 (95 per cent c.i. 0.76 to 0.90) for the mortality model and 0.91 (0.88 to 0.94) for the relapse model; CITL was -0.19 (95 per cent c.i. -0.39 to -0.12) and - 0.01 (- 0.17 to -0.03) respectively. CONCLUSION: Relapse of infection and death after complicated intra-abdominal infections are common. Clinical prediction models were developed to identify patients at increased risk of relapse or death after treatment, these now require external validation.

Controlling Light-Induced Proton Transfer from the GFP Chromophore.

The front cover artwork is provided by the groups of Assoc. Prof. Anastasia V. Bochenkova (Lomonosov Moscow State University) and Prof. Lars H. Andersen (Aarhus University). The image shows the quantum nature of wavelength-dependent excited-state proton transfer in gas-phase H-bonded complexes of the GFP chromophore with an anionic proton acceptor. Read the full text of the Article at 10.1002/cphc.202100068.

Controlling Light-Induced Proton Transfer from the GFP Chromophore.

Green Fluorescent Protein (GFP) is known to undergo excited-state proton transfer (ESPT). Formation of a short H-bond favors ultrafast ESPT in GFP-like proteins, such as the GFP S65T/H148D mutant, but the detailed mechanism and its quantum nature remain to be resolved. Here we study in vacuo, light-induced proton transfer from the GFP chromophore in hydrogen-bonded complexes with two anionic proton acceptors, I- and deprotonated trichloroacetic acid (TCA- ). We address the role of the strong H-bond and the quantum mechanical proton-density distribution in the excited state, which determines the proton-transfer probability. Our study shows that chemical modifications to the molecular network drastically change the proton-transfer probability and it can become strongly wavelength dependent. The proton-transfer branching ratio is found to be 60 % for the TCA complex and 10 % for the iodide complex, being highly dependent on the photon energy in the latter case. Using high-level ab initio calculations, we show that light-induced proton transfer takes place in S1 , revealing intrinsic photoacid properties of the isolated GFP chromophore in strongly bound H-bonded complexes. ESPT is found to be very sensitive to the topography of the highly anharmonic potential in S1 , depending on the quantum-density distribution upon vibrational excitation. We also show that the S1 potential-energy surface, and hence excited-state proton transfer, can be controlled by altering the chromophore microenvironment.

Platelet Transfusion After Traumatic Intracranial Hemorrhage in Patients on Antiplatelet Agents.

BACKGROUND: With an aging population, the number of patients on antiplatelet medications and traumatic brain injury (TBI) is increasing. Our study aimed to evaluate the role of platelet transfusion on outcomes after traumatic intracranial bleeding (IB) in these patients. METHODS: We analyzed our prospectively maintained TBI database from 2014 to 2016. We included all isolated TBI patients with an IB, who were on preinjury antiplatelet agents and excluded patients taking anticoagulants. Outcome measures included the progression of IB, neurosurgical intervention, and mortality. Regression analysis was performed. RESULTS: A total of 343 patients met the inclusion criteria. Mean age was 58 ± 11 y, 58% were men, and median injury severity score was 15 (10-24). Distribution of antiplatelet agents was as follows: aspirin (60%) and clopidogrel (35%). Overall, 74% patients received platelet transfusion after admission with a median number of two platelet units. After controlling for confounders, patients who received one unit of pooled platelets had no difference in progression of IB (odds ratio [OR]: 0.98, [0.6-1.9], P = 0.41), need for neurosurgical intervention (OR: 1.09, [0.7-2.5], P = 0.53), and mortality (OR: 0.84, [0.6-1.8], P = 0.51). However, patients who received two units of pooled platelets had lower rate of progression of IB (OR: 0.69, [0.4-0.8], P = 0.02), the need for neurosurgical intervention (OR: 0.81, [0.3-0.9], P = 0.03), and mortality (OR: 0.84, [0.5-0.9], P = 0.04). Both groups were compared with those who did not receive platelet transfusion. CONCLUSIONS: The use of two units of platelet may decrease the risk of IB progression, neurosurgical intervention, and mortality in patients on preinjury antiplatelet agents and TBI. Further studies should focus on developing protocols for platelet transfusion to improve outcomes in these patients. LEVEL OF EVIDENCE: Level III prognostic.

A mixed-method feasibility study of a novel transitional regime of incremental haemodialysis: study design and protocol.

BACKGROUND: Incremental haemodialysis/haemodiafiltration (HD) may help reduce early mortality rates in patients starting HD. This mixed-method feasibility study aims to test the acceptability, tolerance and safety of a novel incremental HD regime, and to study its impact on parameters of patient wellbeing. METHOD: We aim to enrol 20 patients who will commence HD twice-weekly with progressive increases in duration and frequency, achieving conventional treatment times over 15 weeks (incremental group). Participants will be followed-up for 6 months and will undergo regular tests including urine collections, bio-impedance analyses and quality-of-life questionnaires. Semi-structured interviews will be conducted to explore patients' prior expectations from HD, their motivations for participation and experiences of receiving incremental HD. For comparison of safety and indicators of dialysis adequacy, a cohort of 40 matched patients who previously received conventional HD will be constructed from local dialysis records (historical controls). RESULTS: Data will be recorded on the numbers screened and proportions consented and completing the study (primary outcome). Incremental and conventional groups will be compared in terms of differences in blood pressure control, interdialytic weight changes, indicators of dialysis adequacy and differences in adverse and serious adverse events. In analyses restricted to incremental group, measurements of RRF, fluid load and quality-of-life during follow-up will be compared with baseline values. From patient interviews, a narrative description of key themes along with anonymised quotes will be presented. CONCLUSION: Results from this study will address a significant knowledge gap in the prescription HD therapy and inform the development novel future therapy regimens.

Age, Gender and Diabetes as Risk Factors for Early Mortality in Dialysis Patients: A Systematic Review.

Objective: To study the impact of age, gender, and presence of diabetes (any type) on the risk of early deaths (180-day mortality) in patients starting long-term hemodialysis (HD) therapy.Design: Systematic review of the literature.Setting: Out-patient (non-hospitalized), community-based HD therapy world-wide.Participants: Patients with advanced chronic kidney disease (CKD) starting long-term HD treatment for end-stage renal disease (ESRD).Methods: Medline and EMBASE were searched for studies published between 1/1/1985 and 12/31/2017. Observational studies involving adult subjects commencing HD were included. Data extracted included population characteristics and settings. In addition, patient or treatment related factors studied with reference to their relationship with the risk of early mortality were documented. The Quality in Prognosis Studies tool was used to assess risk of bias in individual studies. Findings were summarized, and a narrative account was drawn.Results: Included were 26 studies (combined population 1,098,769; representing 287,085 person-years of observation for early mortality). There were 17 cohort and 9 case-control studies. Risk of bias was low in 13 and high in a further 13 studies. Patients who died in the early period were older than those who survived. Mortality rates increased with advancing age. Female gender was associated with slightly increased early mortality rates in larger and higher quality studies. The available data showed conflicting results in relation to the association of diabetes and risk of early mortality.Conclusions: This systematic review evaluated the impact of key demographic and co-morbid factors on risk of early mortality in patients starting maintenance HD. The information could help in delivering more tailored prognostic information and planning of future interventions.

Distributed Consensus Tracking Control of Chaotic Multi-Agent Supply Chain Network: A New Fault-Tolerant, Finite-Time, and Chatter-Free Approach.

Over the last years, distributed consensus tracking control has received a lot of attention due to its benefits, such as low operational costs, high resilience, flexible scalability, and so on. However, control methods that do not consider faults in actuators and control agents are impractical in most systems. There is no research in the literature investigating the consensus tracking of supply chain networks subject to disturbances and faults in control input. Motivated by this, the current research studies the fault-tolerant, finite-time, and smooth consensus tracking problems for chaotic multi-agent supply chain networks subject to disturbances, uncertainties, and faults in actuators. The chaotic attractors of a supply chain network are shown, and its corresponding multi-agent system is presented. A new control technique is then proposed, which is suitable for distributed consensus tracking of nonlinear uncertain systems. In the proposed scheme, the effects of faults in control actuators and robustness against unknown time-varying disturbances are taken into account. The proposed technique also uses a finite-time super-twisting algorithm that avoids chattering in the system's response and control input. Lastly, the multi-agent system is considered in the presence of disturbances and actuator faults, and the proposed scheme's excellent performance is displayed through numerical simulations.

Resuscitation of the Helicobacter pylori Coccoid Forms by Resuscitation Promoter Factor Obtained from Micrococcus Luteus.

Helicobacter pylori is a gram negative, spiral-shaped, and microaerophilic bacteria which can cause life-threatening diseases. It is known that more than 55% of the human population in the world is already infected by this bacterium. The traditional treatment of H. pylori infection consists of a combination of two or more antibiotics. However, H. pylori has evolved to turning its shape from spiral to coccoid form in the presence of antibiotics and this decreases the therapeutic efficacies of conventional antibiotic applications. Resuscitation promoter factor (RPF) is a protein secreted by Micrococcus luteus have significant resuscitation effects on some bacteria especially in the group of viable but non-culturable (VBNC) pathogens. However, there is no study in the literature investigating the resuscitation effects of RPF derived from M. luteus on H. pylori in order to change its form from coccoid to spiral. The purpose of this study is to investigate the resuscitation effect of RPF-containing metabolites isolated from M. luteus on the morphological transformation of H. pylori coccoid forms to spiral forms in order to increase their susceptibilities to antibiotic treatments. Rpf-containing metabolites were primarily obtained from M. luteus culture supernatants. H. pylori was exposed to five different conditions such as prolonged culture, incubation at + 4 °C, incubation at + 22 °C, cultivation in PBS and treatment with kanamycin in order to induce transformations of bacteria to coccoid forms. Induced H.pylori coccoids were characterized by inverted microscope, UV spectrophotometer, SEM imaging, and flow-cytometer. As a result, it was found that the most suitable condition for inducing coccoid forms was cultivation of bacteria with kanamycin. Followingly, different concentrations of RPF-containing metabolites were applied on H. pylori coccoids induced by kanamycin. For the first time in this study, it was determined that the Rpf-containing metabolites obtained from M. luteus demonstrated very high resuscitation effect on kanamycin-induced H. pylori coccoid forms. This new approach for resuscitation of H. pylori coccoids is thought to play an important role in increasing the treatment effectiveness of the conventional antibiotics against the infection.

Can incremental haemodialysis reduce early mortality rates in patients starting maintenance haemodialysis?

PURPOSE OF REVIEW: Early mortality rates after the start of maintenance haemodialysis therapy are high. Compared with three-times weekly haemodialysis, incremental haemodialysis is associated with better preservation of residual renal function (RRF) and at least equivalent mid-term to long-term survival. However, there is paucity of data in relation to its use as a means of helping patients through the transitional period, when they first become dialysis dependent. RECENT FINDINGS: Studies of incremental haemodialysis have overlooked early mortality as an outcome measure. This is primarily due to their retrospective design which makes it difficult to link early deaths to the frequency of haemodialysis. New data confirm previous observations associating incremental haemodialysis with favourable outcomes. They also raise the possibility that in selected groups and for short periods, the pursuit of set clearance targets during the early days of dialysis may not necessarily bring additional short-term gains. SUMMARY: We argue that, while simpler ways of estimating RRF are being explored, future trials must consider implementing incremental haemodialysis focusing on practical aspects of care in the transitional period; safety monitoring in such regimes should be undertaken using conventional methods. Such an approach is likely to benefit a larger subset of haemodialysis population.

Superior antibacterial activity of ZnO-CuO nanocomposite synthesized by a chemical Co-precipitation approach.

Synthesis of highly efficient antibacterial agents has become highly important due to emergence of antibiotic resistance. Herein, Pristine ZnO and ZnO-CuO nanocomposite has been synthesized by simple chemical co-precipitation method and characterized by X-ray diffraction (XRD), microscopic and spectroscopic techniques. The prepared ZnO-CuO nanocomposite is composed of two dimensional nanosheets consisting of hexagonal ZnO and monoclinic CuO crystal phases present in coexistence. Moreover, a minute presence of Cu5Zn8 cubic phase has been evident in the XRD pattern of ZnO-CuO nanocomposite. Fourier Transform Infrared Spectroscopy (FTIR) spectrum of the prepared nanocomposite has revealed the presence of vibrational modes related to both Zn-O and Cu-O. Photoluminescence (PL) investigations depicted the formation of huge amounts of surface defects in ZnO-CuO nanocomposite as compared to pristine ZnO nanostructures. The prepared ZnO-CuO nanocomposite has efficiently killed Methicillin resistant Staphylococus aureus (s. aureus) bacterium by producing 24 mm of zone of inhibition (ZOI) comparing to 8 mm ZOI produced by pristine ZnO. The superior antibacterial activity of ZnO-CuO nanocomposite has been attributed to oxidative stress generated by electron transfer pathway and reactive oxygen species (ROS) generation.

Review of massive transfusion protocols in the injured, bleeding patient.

PURPOSE OF REVIEW: Massive haemorrhage is a significant cause of mortality and morbidity in a variety of clinical settings, although most research has been related to trauma patients. Military studies from recent conflicts found that higher ratios of plasma to red blood cells (RBCs) were associated with increased survival in injured soldiers, and subsequent trials in civilian populations showed similar decreased mortality. Over the last decade, massive transfusion protocols (MTPs) have become an important component in the treatment of the massively bleeding patient. This review is intended to summarize the more recent findings and trends in massive transfusion. RECENT FINDINGS: There have been several observational studies suggesting that higher ratios of plasma to RBC and platelets to RBC are associated with improved survival but there is a paucity of randomized studies relating to specific ratios, dosages, timing, and guidance. Other studies have developed and assessed scoring systems used to initiate MTPs and specific tests used to guide MTPs. Finally, the specific blood components and adjuncts that constitute a MTP are the subject of further ongoing research. SUMMARY: The absence of a universal definition of massive bleeding or massive transfusion, heterogeneity in patients suffering from massive bleeding, and the difficulty in predicting which patients will require a massive transfusion all contribute to the difficulty of studying massive transfusion. However, there is evidence that higher plasma : RBC ratios correlate with improved survival, and that adjuncts to transfusion play a key role. Furthermore, recent validations of massive haemorrhage scoring systems should allow more consistent and appropriate triggering of massive transfusions.

Meta-analysis of the effect of bariatric surgery on physical function.

BACKGROUND: Obesity leads to an impairment of physical function that limits the ability to perform basic physical activities affecting quality of life. Literature on the effect of bariatric surgery on physical function is confounding and generally of low quality. METHODS: A comprehensive search was undertaken using MEDLINE, Scopus (including Embase), CENTRAL, PubMed, SPORTDiscus, Scirus and OpenGrey for published research and non-published studies to 31 March 2017. Studies employing objective measurement and self-reporting of physical function before and after bariatric surgery were included. The magnitude of experimental effect was calculated in terms of the standardized mean difference (MD), and confidence intervals were set at 95 per cent to reflect a significance level of 0·05. RESULTS: Thirty studies including 1779 patients met the inclusion criteria. Physical function improved after bariatric surgery at 0-6 months (MD 0·90, 95 per cent c.i. 0·60 to 1·21; P < 0·001), more than 6 to 12 months (MD 1·06, 0·76 to 1·35; P < 0·001) and more than 12 to 36 months (MD 1·30, 1·07 to 1·52; P < 0·001). Objective assessment of physical function after bariatric surgery showed improvement at 0-6 months (MD 0·94, 0·57 to 1·32; P < 0·001), more than 6 to 12 months (MD 0·77, 0·15 to 1·40; P = 0·02) and more than 12 to 36 months (MD 1·04, 0·40 to 1·68; P = 0·001). Self-reported assessment of physical function showed similar improvements at 0-6 months (MD 0·80, 0·12 to 1·47; P = 0·02), more than 6 to 12 months (MD 1·42, 1·23 to 1·60; P < 0·001) and more than 12 to 36 months (MD 1·41, 1·20 to 1·61; P < 0·001) after a bariatric procedure. CONCLUSION: Bariatric surgery improves physical function significantly within 6 months of the procedure and this effect persists over time to 36 months after surgery, whether measured objectively or by self-reporting.

Low TGFß1 expression prevents and high expression exacerbates diabetic nephropathy in mice.

Nephropathy develops in many but not all patients with long-standing type 1 diabetes. Substantial efforts to identify genotypic differences explaining this differential susceptibility have been made, with limited success. Here, we show that the expression of the transforming growth factor ß1 gene (Tgfb1) affects the development of diabetic nephropathy in mice. To do this we genetically varied Tgfb1 expression in five steps, 10%, 60%, 100%, 150%, and 300% of normal, in mice with type 1 diabetes caused by the Akita mutation in the insulin gene (Ins2(Akita)). Although plasma glucose levels were not affected by Tgfb1 genotype, many features of diabetic nephropathy (mesangial expansion, elevated plasma creatinine and urea, decreased creatinine clearance and albuminuria) were progressively ameliorated as Tgfb1 expression decreased and were progressively exacerbated when expression was increased. The diabetic 10% hypomorphs had comparable creatinine clearance and albumin excretion to wild-type mice and no harmful changes in renal morphology. The diabetic 300% hypermorphs had ∼1/3 the creatinine clearance of wild-type mice, >20× their albumin excretion, ∼3× thicker glomerular basement membranes and severe podocyte effacement, matching human diabetic nephropathy. Switching Tgfb1 expression from low to high in the tubules of the hypomorphs increased their albumin excretion more than 10-fold but creatinine clearance remained high. Switching Tgfb1 expression from low to high in the podocytes markedly decreased creatinine clearance, but minimally increased albumin excretion. Decreasing expression of Tgfb1 could be a promising option for preventing loss of renal function in diabetes.