Feedback control of organ size precision is mediated by BMP2-regulated apoptosis in the Drosophila eye.

Biological processes are intrinsically noisy, and yet, the result of development-like the species-specific size and shape of organs-is usually remarkably precise. This precision suggests the existence of mechanisms of feedback control that ensure that deviations from a target size are minimized. Still, we have very limited understanding of how these mechanisms operate. Here, we investigate the problem of organ size precision using the Drosophila eye. The size of the adult eye depends on the rates at which eye progenitor cells grow and differentiate. We first find that the progenitor net growth rate results from the balance between their proliferation and apoptosis, with this latter contributing to determining both final eye size and its variability. In turn, apoptosis of progenitor cells is hampered by Dpp, a BMP2/4 signaling molecule transiently produced by early differentiating retinal cells. Our genetic and computational experiments show how the status of retinal differentiation is communicated to progenitors through the differentiation-dependent production of Dpp, which, by adjusting the rate of apoptosis, exerts a feedback control over the net growth of progenitors to reduce final eye size variability.

Sustained innate interferon is an essential inducer of tertiary lymphoid structures.

Tertiary lymphoid structures (TLS) resemble follicles of secondary lymphoid organs and develop in nonlymphoid tissues during inflammation and cancer. Which cell types and signals drive the development of TLS is largely unknown. To investigate early events of TLS development in the lungs, we repeatedly instilled p(I:C) plus ovalbumin (Ova) intranasally. This induced TLS ranging from lymphocytic aggregates to organized and functional structures containing germinal centers. We found that TLS development is independent of FAP+ fibroblasts, alveolar macrophages, or CCL19 but crucially depends on type I interferon (IFN-I). Mechanistically, IFN-I initiates two synergistic pathways that culminate in the development of TLS. On the one hand, IFN-I induces lymphotoxin (LT)α in lymphoid cells, which stimulate stromal cells to produce the B-cell-attracting chemokine CXCL13 through LTßR-signaling. On the other hand, IFN-I is sensed by stromal cells that produce the T-cell-attracting chemokines CXCL9, CXCL10 as well as CCL19 and CCL21 independently of LTßR. Consequently, B-cell aggregates develop within a week, whereas follicular dendritic cells and germinal centers appear after 3 weeks. Thus, sustained production of IFN-I together with an antigen is essential for the induction of functional TLS in the lungs.

Biomechanics and morphological comparisons of the caudal region of titanosaurs from the Cretaceous of Brazil: Paleobiology and paleoecology inferences.

Biomechanical studies in sauropod dinosaurs are mainly focused on neck posture and feeding strategy. Few works investigate other aspects such as tail movement and function, especially in the clade Titanosauria, the most diverse within Neosauropoda. This study applied biomechanical concepts of neutral pose (cartilaginous neutral pose) and range of motion to verify the shape and direction of the caudal region of the advanced titanosaurs Adamantisaurus mezzalirai and Baurutitan britoi, in addition to comparing it with other titanosaurs (e.g., Arrudatitan maximus, Lirainosaurus astibiae, and Trigonosaurus pricei). As a result, the tails analyzed have a sigmoidal-convex shape, probably close to the ground (but not touching it). The sigmoidal-convex shape could increase the moment arm for the M. caudofemoralis longus, making it possible to use the tail as a fifth stabilizing member. This work expands our knowledge about sauropod dinosaurs by exposing a diversity of shapes for the tails of titanosaur sauropods and brings new possibilities for how these dinosaurs could use their tails.

Development and validation of the Ex-Care BR model: a multicentre initiative for identifying Brazilian surgical patients at risk of 30-day in-hospital mortality.

BACKGROUND: Surgical risk stratification is crucial for enhancing perioperative assistance and allocating resources efficiently. However, existing models may not capture the complexity of surgical care in Brazil. Using data from various healthcare settings nationwide, we developed a new risk model for 30-day in-hospital mortality (the Ex-Care BR model). METHODS: A retrospective cohort study was conducted in 10 hospitals from different geographic regions in Brazil. Data were analysed using multilevel logistic regression models. Model performance was assessed using the area under the receiver operating characteristic curve (AUROC), Brier score, and calibration plots. Derivation and validation cohorts were randomly assigned. RESULTS: A total of 107,372 patients were included, and 30-day in-hospital mortality was 2.1% (n=2261). The final risk model comprised four predictors related to the patient and surgery (age, ASA physical status classification, surgical urgency, and surgical size), and the random effect related to hospitals. The model showed excellent discrimination (AUROC=0.93, 95% confidence interval [CI], 0.93-0.94), calibration, and overall performance (Brier score=0.017) in the derivation cohort (n=75,094). Similar results were observed in the validation cohort (n=32,278) (AUROC=0.93, 95% CI, 0.92-0.93). CONCLUSIONS: The Ex-Care BR is the first model to consider regional and organisational peculiarities of the Brazilian surgical scene, in addition to patient and surgical factors. It is particularly useful for identifying high-risk surgical patients in situations demanding efficient allocation of limited resources. However, a thorough exploration of mortality variations among hospitals is essential for a comprehensive understanding of risk. CLINICAL TRIAL REGISTRATION: NCT05796024.

A non-parametric framework for evaluating total analytical error in in vitro diagnostic medical devices in transfusion medicine.

The performance assessment of quantitative measurements is predominantly based on evaluating Total Analytical Error (TAE). This evaluation encompasses several key objectives critical to ensuring accurate, reliable, and clinically relevant test results. Traditional parametric methods often fall short due to data normality assumptions in the performance assessment of in vitro diagnostic medical devices (IVD-MDs). This study presents a non-parametric approach to estimating and evaluating the TAE in transfusion medicine, aiming to enhance the reliability and patient safety of IVD-MDs. A protocol to estimate TAE over diverse data distributions is suggested, employing a robust statistical definition and comparative measurement procedures. Results from 200 samples indicate that non-parametric methods provided a more accurate reflection of TAE. The findings assert that non-parametric TAE estimation is vital for ensuring the 'fitness for purpose' of clinical tests in transfusion medicine, directly impacting post-transfusion outcomes and patient care. The study concludes that adopting non-parametric methods in transfusion services can significantly improve test accuracy, aligning with the highest laboratory practice standards.

Current principles for the establishment of the virological "cutoff points" in transfusion science and medicine: A short concise overview.

Establishing the virological cutoff point, during epidemics, such as the COVID-19 Pandemic, is crucially important as inadequate standardization and the false qualitative results, have enormous clinical and economic consequences when screening for SARS-CoV-2. Moreover, a cutoff point is a crucial step in ensuring a minimal risk of clinical misclassification. Therefore complying with such statutory requirements is an essential part of obligatory good laboratory and clinical practices. In this concise report, we propose a novel methodology for establishing cutoff points for all samples exhibiting detectable levels of the measured parameter, even those from the disease-free group. Based on target specificity and sensitivity levels of 100 % and 95 %, a value of 1209 A is identified as the "best cutoff". In fact, the ROC decision matrixes play a crucial role in determining optimal cutoff points. The most effective discriminators are those that meet specified accuracy criteria. The selection process is influenced by finding the right clinical sensitivity/specificity trade-off.

Spotlights on the trends in performance assessment of qualitative in vitro diagnostic medical devices in transfusion medicine.

For reliable clinical decisions in transfusion medicine, assessing the performance of qualitative tests performed in medical laboratories is critical. When false results are reported, these can lead to an adverse reaction to blood components. Good performance assessment practices are essential for this kind of scenario, and they still remain as one of the many unmet high-priority challenges in this area. This paper aims to provide an overview of the current trends in this field. A review of the IFCC-IUPC. qualitative vocabulary was carried out, and a particular focus was given to the evaluation protocols CLSI EP12-A3 and Eurachem AQA, such as the European Union Regulation for class D in vitro diagnostic medical devices. There is a consistency between the current protocols and recognized performance assessment principles, which are mandatory in transfusion service labs. We believe that a revised imprecision interval approach and models based on emerging qualitative test types may prove beneficial in the long run. It is also important to emphasize the uncertainty of proportions to mitigate the risk of misclassification.

Insights on trends in the management of metrological analysis of devices in blood and transfusion medicine services: Verification based on their fitness for purpose and suitability for their respective applications.

In the field of blood and transfusion medicine, European Directorate for the Quality of Medicines & HealthCare recommends practices for metrological devices. Monitoring and measurement resources, as well as their permitted metrological limits, must be considered in this regard. We must understand variables such as metrological domains, the International System of Units, metrological traceability, and metrological requirements and controls in the field of transfusions in order to understand these metrological devices. An approach to metrological analysis and subsequent actions was constructed using flowcharts. As part of this methodology, a metrological device was selected, along with regulatory and normative requirements. A calibration and a test were conducted to demonstrate the application of the figure based on current recommendations. Current recommendations are consistent with the suggested ROC approach. The metrological devices must be verified based on their suitability for their respective applications (fitness-for-purpose).

A targeted survey on teachers' perception of training/education for blood donation in high school students: An invited case report for enhancing and retention of dedicated donors in Portugal.

Promoting blood donation requires understanding and identifying the factors that motivate donations so that strategies for retaining and increasing loyalty can be developed. Transfusion literacy can be improved through school-based teaching and information about giving and solidarity to promote the development of future donors. For the purpose of aligning any strategies and motivational dynamics that promote adherence to informed donation and loyalty among students in the municipality of Coimbra. This study was undertaken to assess the perception of secondary school teachers regarding the students' knowledge of blood donation. A survey was conducted among teachers from seven public schools in Coimbra with regard to the 3rd and Secondary cycles. Based on the data, people give blood for a feeling of personal satisfaction and peer influence, as well as for the satisfaction of helping others. Blood donation should be made a focal point of relevance and interest in the school community, by implementing programs, projects, and dissemination actions targeting this target group. We are extremely glad and most enthusiastic to be invited to share our study through what's happening with the readers globally.

Diffusion-weighted imaging does not seem to be a predictor of consistency in pituitary adenomas.

PURPOSE: To prospectively evaluate the usefulness of T1-weighted imaging (T1WI) and diffusion-weighted imaging (DWI) sequences in predicting the consistency of macroadenomas. In addition, to determine their values ​​as prognostic factors of surgical outcomes. METHODS: Patients with pituitary macroadenoma and surgical indication were included. All patients underwent pre-surgical magnetic resonance imaging (MRI) that included the sequences T1WI before and after contrast administration and DWI with the apparent diffusion coefficient (ADC) map. Post-surgical MRI was performed at least 3 months after surgery. The consistency of the macroadenomas was evaluated at surgery, and they were grouped into soft and intermediate/hard adenomas. Mean ADC values, signal on T1WI and the ratio of tumor ADC values ​​to pons (ADCR) were compared with tumor consistency and grade of surgical resection. RESULTS: A total of 80 patients were included. A softened consistency was found at surgery in 53 patients and hardened in 27 patients. The median ADC in the soft consistency group was 0.532 × 10-3 mm2/sec (0.306 - 1.096 × 10-3 mm2/sec), and in the intermediate/hard consistency group was 0.509 × 10-3 mm2/sec (0.308 - 0.818 × 10-3 mm2/sec). There was no significant difference between the median values ​​of ADC, ADCR and signal on T1W between the soft and hard tumor groups, or between patients with and without tumor residue. CONCLUSION: Our results did not show usefulness of the DWI and T1WI for assessing the consistency of pituitary macroadenomas, nor as a predictor of the degree of surgical resection.

Cross-cultural adaptation, validation and establishment of the minimal clinically important change score of the European Portuguese core outcome measures index in patients with lumbar degenerative spine disease.

PURPOSE: The core outcome measures index (COMI) for the back is a questionnaire that evaluates five domains and has been translated into several languages and validated for different populations. We aimed to translate, cross-culturally adapt and validate it in European Portuguese for use in patients with degenerative lumbar disease. Additionally, we aimed to establish the minimal clinically important change score (MCIC). METHODS: The translation and cultural adaptation were done according to published guidelines. Patients awaiting surgery at a neurosurgical center completed the COMI, Oswestry Disability Index (ODI), EQ-5D questionnaires and a pain visual analog scale (VAS). To evaluate COMI's reproducibility, patients completed the questionnaire twice within two weeks, preoperatively, in addition to answering a transition question. The MCIC was determined by analysis of postoperative changes in total COMI score, using the anchor method, with a question ascertaining surgical outcome as perceived by the patient. RESULTS: The first set of questionnaires was answered by 108 patients and the second, by 98 patients. COMI's construct validity was confirmed by demonstrating the hypothesized correlation between each domain's score (Spearman Rho > 0.4) and the corresponding questionnaire score (ODI, EQ-5D and VAS) and through adequate correlation (Spearman > 0.6) between COMI's total score and ODI and EQ-5D total scores. Intraclass correlation coefficients between each domain and COMI's total score were > 0.8. The MCIC was calculated as 2.1. CONCLUSION: The cross-culturally adapted COMI questionnaire is a valid clinical assessment tool for European Portuguese-speaking patients with degenerative lumbar disease, with an MCIC of 2.1 points.

A lost tooth in the jungle: revisiting the sole dinosaurian record from northern Brazil.

The record of Mesozoic reptiles in the Northern region of Brazil is extremely limited, with the only definite occurrence consisting of two ziphodont teeth recovered from an oil well core in the municipality of Nova Olinda do Norte, Amazonas state, from strata of the Alter do Chão Formation (Cenomanian) of the Amazonas Basin. In this study, we aim to reevaluate MCT.R.514 using the most recent methodologies available for the identification of isolated theropod teeth. The cladistic analyses recovered MCT.R.514 as a possible metriacanthosaurid or non carcharodontosaurid allosauroid while the LDAs showed affinities between the specimen and Abelisauridae, Piatniktzysauridae, and Tyrannosauridae. MCT.R.514 was assigned as an abelisaurid due to its overall morphology that lacked metriacanthosaurid synapomorphies (i.e. spiraling mesial carina, strongly labially displaced distal carina, and well-marked mesiolingual longitudinal groove), while maintaining homoplastic features between both groups (i.e. irregular enamel texture, a lingually biconcave cross section, and a straight distal margin). This, together with a mostly Laurasian distribution of Metriacanthosauridae favors the assignment of MCT.R.514 as an abelisaurid as the most parsimonious hypothesis in this occasion. The identification of the specimen as an abelisaurid further expands the still scarce "Mid'' Cretaceous record of this clade in Brazil.

The rising human footprint in the Tibetan Plateau threatens the effectiveness of ecological restoration on vegetation growth.

Ecological restoration projects in the Tibetan Plateau aimed to reverse ecosystem degradation and safeguard the fragile alpine ecological environment. However, it is still being determined if the vegetation restoration is successful on a large scale or reaches the expected magnitude, restricting our ability to adapt practices to maximise the benefit. With multiple vegetation indices (VIs: NDVI, LAI, and GPP) from satellite observations and random forest machine-learning models, we performed an attribution study on vegetation growth trends caused by climate change and human activities. Then, we further explored the relationship between vegetation growth and ecological projects and human footprint without the influence of climate. The results showed that climatic change was a relatively strong driver of vegetation growth. The positive contributions of ecological restoration occurred only in half of the plateau due to the increased human footprint. Vegetation enhancement resulting from ecological restoration occurred in 13.1%-23.1% of the plateau. Among these values, ecological restoration counteracted the negative climate effects in 4.7%-8.3% of the plateau (about half of the negative climate effect area). In forest and grassland protection areas, the ecological restoration was more successful. The study provides a better understanding of the role of ecological projects in vegetation restoration and potential threats to its effectiveness. This is essential to improve future restoration projects.

On-Site Therapeutic Drug Monitoring of Paracetamol Analgesic in Non-Invasively Collected Saliva for Personalized Medicine.

Paracetamol or acetaminophen is the main non-opioid analgesic recommended for mild pain by the World Health Organization (WHO) analgesic ladder. However, the high levels used of paracetamol are associated with the hepatotoxicity and nephrotoxicity caused by accumulation of toxic metabolites. The sensor is produced on a polyester substrate containing a full electrochemical device with working, auxiliary, and reference electrodes in which, guiding personalized medicine solutions are not reported. Temporal paracetamol profiles in human saliva are performed with the subject taking different amounts of commercial analgesic pills. The variation of saliva paracetamol levels is demonstrated to be interference free from electroactive interfering species and human saliva constituents. In addition, the sensor displays to be useful as a disposable device for the fast detection of paracetamol in untreated raw saliva following pill intake. The maximum concentration (Cmax ) and half-life time (t1/2 ) for paracetamol are 143.27 µm and 110 min. The results demonstrate the potential of a simple strategy with electrochemical devices for noninvasive personalized therapy toward guiding drug interventions through tracking of active substance, detecting, and correcting insufficiency of absorption to meet individual needs avoiding overdoses, side effects, and intoxication.

Identification and characterization of a polyomavirus in the thornback skate (Raja clavata).

Members of the family Polyomaviridae have a circular double-stranded DNA genome that have been identified in various hosts ranging from mammals to arachnids. Here we report the identification and analysis of a complete genome sequence of a novel polyomavirus, Raja clavata polyomavirus (RcPyV1), from a cartilaginous fish, the thornback skate (Raja clavata). The genome sequence was determined using a metagenomics approach with an aim to provide baseline viral data in cartilaginous fish in different ecosystems. The RcPyV1 genome (4,195 nucleotides) had typical organization of polyomavirus, including early antigens (small T; Large T) encoded on one strand and late viral proteins (VP1; VP2) on the complementary strand. Maximum-likelihood phylogenetic analysis of the large T-antigen revealed that RcPyV1 clusters with a polyomavirus obtained from another cartilaginous fish, the guitarfish polyomavirus 1 (GfPyV1). These two share ~ 56% pairwise identity in LT and VP1 protein sequences. These analyses support the hypothesis that cartilaginous fishes have a specific lineage of polyomaviruses.

Toluidine blue O directly and photodynamically impairs the bioenergetics of liver mitochondria: a potential mechanism of hepatotoxicity.

Toluidine blue O (TBO) is a phenothiazine dye that, due to its photochemical characteristics and high affinity for biomembranes, has been revealed as a new photosensitizer (PS) option for antimicrobial photodynamic therapy (PDT). This points to a possible association with membranous organelles like mitochondrion. Therefore, here we investigated its effects on mitochondrial bioenergetic functions both in the dark and under photostimulation. Two experimental systems were utilized: (a) isolated rat liver mitochondria and (b) isolated perfused rat liver. Our data revealed that, independently of photostimulation, TBO presented affinity for mitochondria. Under photostimulation, TBO increased the protein carbonylation and lipid peroxidation levels (up to 109.40 and 119.87%, respectively) and decreased the reduced glutathione levels (59.72%) in mitochondria. TBO also uncoupled oxidative phosphorylation and photoinactivated the respiratory chain complexes I, II, and IV, as well as the FoF1-ATP synthase complex. Without photostimulation, TBO caused uncoupling of oxidative phosphorylation and loss of inner mitochondrial membrane integrity and inhibited very strongly succinate oxidase activity. TBO's uncoupling effect was clearly seen in intact livers where it stimulated oxygen consumption at concentrations of 20 and 40 µM. Additionally, TBO (40 µM) reduced cellular ATP levels (52.46%) and ATP/ADP (45.98%) and ATP/AMP (74.17%) ratios. Consequently, TBO inhibited gluconeogenesis and ureagenesis whereas it stimulated glycogenolysis and glycolysis. In conclusion, we have revealed for the first time that the efficiency of TBO as a PS may be linked to its ability to photodynamically inhibit oxidative phosphorylation. In contrast, TBO is harmful to mitochondrial energy metabolism even without photostimulation, which may lead to adverse effects when used in PDT.

Minimally invasive fusion surgery for patients with degenerative spondylolisthesis and severe lumbar spinal stenosis: a comparative study between MIDLIF and TLIF.

PURPOSE: This study aims to compare midline lumbar interbody fusion (MIDLIF) and minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) for treatment of patients with severe stenosis and lumbar degenerative spondylolisthesis (DS), focusing on dural tears rates, other complications, clinical and radiological outcomes. METHODS: This cohort study included patients with severe lumbar spinal stenosis (Shizas C or D) and lumbar DS who underwent MIDLIF or MIS-TLIF. Propensity score matching was done and the groups were compared regarding surgery time, length of stay, perioperative complications, clinical results and radiological outcomes, at 1 year of follow-up. RESULTS: The study included initially 80 patients, and 72 patients after matching, 36 in each group. Six patients had dural tears, four in the MIDLIF group and two in the MIS-TLIF group (p = 0.67). General complication rates and reoperations were not significantly different between the groups. Good or excellent clinical was achieved in 75% of the MIDLIF patients and 72% of the MIS-TLIF patients (p = 0.91). Radiological parameters showed small but statistically significant (p < 0.01) improvements after surgery, particularly in segmental lordosis and lumbar lordosis (2.0° and 1.7°), while pelvic tilt and global tilt decreased (1.6° and 2.6°). These findings were similar for both groups. CONCLUSION: Our study confirms that MIDLIF is a safe and reliable minimally invasive alternative for lumbar interbody fusion in DS, even in patients with severe stenosis and previous spine surgery. It seems to offer similar results to MIS-TLIF regarding clinical results, radiological outcomes and complications.

Systematic Review Procedures for the World Health Organization (WHO) Evidence Syntheses on Benefits and Harms of Structured and Standardized Education/Advice, Structured Exercise Programs, Transcutaneous Electrical Nerve Stimulation (TENS), and Needling Therapies for the Management of Chronic Low Back Pain in Adults.

As commissioned by the WHO, we updated and expanded the scope of four systematic reviews to inform its (in development) clinical practice guideline for the management of CPLBP in adults, including older adults. Methodological details and results of each review are described in the respective articles in this series. In the last article of this series, we discuss methodological considerations, clinical implications and recommendations for future research.

Systematic Review to Inform a World Health Organization (WHO) Clinical Practice Guideline: Benefits and Harms of Structured Exercise Programs for Chronic Primary Low Back Pain in Adults.

PURPOSE: Evaluate benefits and harms of structured exercise programs for chronic primary low back pain (CPLBP) in adults to inform a World Health Organization (WHO) standard clinical guideline. METHODS: We searched for randomized controlled trials (RCTs) in electronic databases (inception to 17 May 2022). Eligible RCTs targeted structured exercise programs compared to placebo/sham, usual care, or no intervention (including comparison interventions where the attributable effect of exercise could be isolated). We extracted outcomes, appraised risk of bias, conducted meta-analyses where appropriate, and assessed certainty of evidence using GRADE. RESULTS: We screened 2503 records (after initial screening through Cochrane RCT Classifier and Cochrane Crowd) and 398 full text RCTs. Thirteen RCTs rated with overall low or unclear risk of bias were synthesized. Assessing individual exercise types (predominantly very low certainty evidence), pain reduction was associated with aerobic exercise and Pilates vs. no intervention, and motor control exercise vs. sham. Improved function was associated with mixed exercise vs. usual care, and Pilates vs. no intervention. Temporary increased minor pain was associated with mixed exercise vs. no intervention, and yoga vs. usual care. Little to no difference was found for other comparisons and outcomes. When pooling exercise types, exercise vs. no intervention probably reduces pain in adults (8 RCTs, SMD = - 0.33, 95% CI - 0.58 to - 0.08) and functional limitations in adults and older adults (8 RCTs, SMD = - 0.31, 95% CI - 0.57 to - 0.05) (moderate certainty evidence). CONCLUSIONS: With moderate certainty, structured exercise programs probably reduce pain and functional limitations in adults and older people with CPLBP.

Improving Rehabilitation Research to Optimize Care and Outcomes for People with Chronic Primary Low Back Pain: Methodological and Reporting Recommendations from a WHO Systematic Review Series.

Chronic primary low back pain (CPLBP) is a prevalent and disabling condition that often requires rehabilitation interventions to improve function and alleviate pain. This paper aims to advance future research, including systematic reviews and randomized controlled trials (RCTs), on CPLBP management. We provide methodological and reporting recommendations derived from our conducted systematic reviews, offering practical guidance for conducting robust research on the effectiveness of rehabilitation interventions for CPLBP. Our systematic reviews contributed to the development of a WHO clinical guideline for CPLBP. Based on our experience, we have identified methodological issues and recommendations, which are compiled in a comprehensive table and discussed systematically within established frameworks for reporting and critically appraising RCTs. In conclusion, embracing the complexity of CPLBP involves recognizing its multifactorial nature and diverse contexts and planning for varying treatment responses. By embracing this complexity and emphasizing methodological rigor, research in the field can be improved, potentially leading to better care and outcomes for individuals with CPLBP.