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Abstract The armed conflict in Tigray, which spanned from November 2020 to November 2022, along with the accompanying siege, led to the near-total collapse of Tigray’s healthcare system. Type 1 Diabetes Mellitus, the most common chronic condition in children, requires significant lifestyle adjustments, including daily insulin injections, regular glucose monitoring, and dietary modifications; all of which are severely impacted by war and siege. This study compared Type 1 diabetes care for children at the Ayder Comprehensive Specialized Hospital, Tigray, during the conflict and siege period with that of the pre-war period. We conducted a retrospective cross-sectional survey, analyzing data from September 2019 to August 2020 (pre-war period) and comparing it with data from September 2021 to August 2022 (war and siege period). Descriptive statistics, including frequencies and percentages, were employed, and Pearson’s or Spearman’s correlation analyses were used to evaluate correlations where appropriate. We identified 143 pediatric patients admitted (56 during the pre-war period and 87 during the war and siege period), with a mean age of 109 months in both periods. During the war and siege, a higher proportion of diabetes admissions were due to diabetic ketoacidosis (DKA) (90%) compared to the pre-war period (75%). In the pre-war period, the most common trigger for DKA was infections (35%), while in the war and siege period, it shifted to malnutrition (47%), infections (46%), lack of access to healthcare facilities (31%), and running out of medicines (24%). Complications such as death, renal failure, cerebral edema, and shock were more prevalent during the war and siege periods. The case fatality rate was significantly higher during the war and siege (9%) compared to the pre-war period (0%), correlating strongly with the severity of DKA, the degree of hypokalemia, the presence of complications, and admission during the war and siege. Our study showed the negative impact of war and siege on diabetes care in children demonstrating a high rate of DKA admissions with increased severity, complications, malnutrition, and case fatality rates. People with diabetes especially type 1 deserve great attention during such a crisis as the lack of insulin could lead to severe complications including death.

Abstract Non-syndromic permanent tooth agenesis affects a significant proportion of the population, especially if third molars are considered. Although tooth agenesis has been linked to a smaller craniofacial size, reduced facial convexity and a shorter skeletal face, the occlusal characteristics of individuals with tooth agenesis remain largely unexplored. Therefore, this study investigated potential associations between tooth agenesis and metric occlusal traits in 806 individuals (491 with 4.1 missing teeth per subject, including third molars, and 315 without any tooth agenesis). Dentoskeletal morphology was defined through anatomical landmarks on pre-treatment cephalometric radiographs. Multivariate regression models, adjusted for sex and age, showed that tooth agenesis was significantly associated with a reduced overjet, an increased interincisal angle, and shorter upper and lower dental arch lengths, but not with overbite. Moreover, apart from reduced tooth length and dentoalveolar effects, as the number of missing teeth increased the upper front teeth were progressively retruded according to the craniofacial complex and to the face. Thus, tooth agenesis has a substantial influence on dental and occlusal characteristics, as well as on the sagittal position and inclination of anterior teeth. These findings emphasize the necessity for personalized, multidisciplinary approaches in individuals with multiple agenesis to successfully meet treatment goals.

The long-term persistence of biochar in soil is often predicted by extrapolating mineralization data from short-term laboratory incubations. Single first-order, double first-order, triple first-order and power models have been employed for this purpose, all of which have an inherent assumption that biochar is biodegradable. However, recent insights challenge this assumption by suggesting that a large fraction of biochar is inert. If so, it would make sense to reflect this in the models used, by incorporating an inert carbon (C) pool. We hypothesized that such inert pool models would fit better to incubation data than existing models and give more reliable long-term predictions. We evaluated this by fitting the models to data from a recently compiled extensive dataset of biochar incubations. The inclusion of an inert pool enhanced the model fits over first-order models in most cases. However, inert pool models overestimated biochar persistence compared to the measured outcomes. By contrast, the double first-order model, which has been the most widely used to date, underestimated biochar persistence even in the short term. The power model in general outperformed all other models and gave the most reliable predictions, although it was sensitive to increasing or fluctuating mineralization rates in the datasets.

Water quality is deteriorating in the world's freshwater bodies, and Lake Tana in Ethiopia is becoming unpleasant to biodiversity. The objective of this study is to retrieve non-optical water quality data, specifically total nitrogen (TN) and total phosphorus (TP) concentrations, in Lake Tana using Machine Learning (ML) techniques applied to Landsat 8 OLI imagery. The ML methods employed include Artificial Neural Networks (ANN), Support Vector Regression (SVR), Random Forest Regression (RF), XGBoost Regression (XGB), AdaBoost Regression (AB), and Gradient Boosting Regression (GB). The XGB algorithm provided the best result for TN retrieval, with determination coefficient (R2), mean absolute error (MARE), relative mean square error (RMSE) and Nash Sutcliff (NS) values of 0.80, 0.043, 0.52, and 0.81 mg/L, respectively. The RF algorithm was most effective for TP retrieval, with R2 of 0.73, MARE of 0.076, RMSE of 0.17 mg/L, and NS index of 0.74. These methods accurately predicted TN and TP spatial concentrations, identifying hotspots along river inlets and northeasters. The temporal patterns of TN, TP, and their ratios were also accurately represented by combining in-situ, RS and ML-based models. Our findings suggest that this approach can significantly improve the accuracy of water quality retrieval in large inland lakes and lead to the development of potential water quality digital services.

Abstract Cyanobacterial phycocyanin and phycoerythrin are gaining commercial interest due to their nutrition and healthcare values. This research analyzed the biomass accumulation and pigment production of two strains of Leptolyngbya under different combinations of light colors and intensities. The results showed that while Leptolyngbya sp.4 B1 (B1) produced all phycobiliproteins, Leptolyngbya sp.5 F2 (F2) only had phycocyanin and allophycocyanin. Both the color of the light and its light intensity affect the biomass accumulation and phycoerythrin concentration in strain B1. Although white light at medium intensity (50 μmol m-2 s-1) causes greater biomass accumulation (1.66 ± 0.13 gDW L-1), low-intensity (25 μmol m-2 s-1) green light induces lower biomass accumulation with twice the pigment content (87.70 ± 2.46 mg gDW -1), culminating in 71% greater productivity. In contrast, for the F2 strain, light intensity positively influenced biomass and pigment accumulation, being observed 2.25 ± 0.10 gDW L-1 under white light at 100 μmol m-2 s-1 and higher phycocyanin concentration (138.38 ± 3.46 mg gDW -1) under red light at 100 μmol m-2 s-1. These findings provide insights into optimizing the growth conditions by altering the intensity and wavelength of light for future production of phycocyanin and phycoerythrin from local cyanobacteria.

Abstract Objective Functional endoscopic sinus surgery is a commonly performed otolaryngologic procedure that often uses the microdebrider device for tissue removal. Given the ubiquitous nature of the instrument, we sought to better define the patterns of device failure using the postmarket surveillance openFDA database. Methods The openFDA database was queried for all microdebrider‐related adverse events from January 1, 2000 to November 1, 2020. Descriptive information on the nature of device failure and any associated patient injury was compiled. Reports not directly related to device failure were excluded from the analysis. Results A total of 641 events were included in the analysis. The most common device failure was overheating (n = 348, 54.3%), followed by material separation (n = 173, 27%), and inconsistent device activation (n = 52, 8.1%). Of the reported events, the vast majority did not result in patient harm (n = 579, 90.3%). On review of the remaining cases, only 24 events (3.7%) resulted in true harm to the patient, defined as a temporary or permanent injury or >30 min of additional anesthesia time. Of these cases, the need to reschedule surgical cases (n = 5, 0.8%), retained foreign body (n = 5, 0.8%), and thermal tissue injury (n = 3,0.5%) were the most common. Five patients suffered an injury due to surgeon error unrelated to device malfunction (n = 5, 0.8%). Conclusions Microdebrider device failures are extremely rare. When they do occur, less than 10% result in patient harm. In cases of patient harm related to microdebrider failure, preoperative testing of the device before use could prevent many of the reported malfunctions.

The climate change mitigation benefits of biochar systems arise largely from carbon storage in biochar. However, while biochar is increasingly recognized as a carbon dioxide removal technology, there are on-going scientific discussions on how to estimate the persistence of biochar carbon when biochar is used in soils. Estimates vary from decades to millennia, building on different modelling approaches and evidence. Here, we revisited the persistence estimates derived from extrapolation of biochar incubation experiments, with the aims of making incubation data available, modelling choices transparent, and results reproducible. An extensive dataset of biochar incubations, including 129 biochar decomposition time series, was compiled and is made available alongside code for its analysis. Biochar persistence correlations were sensitive to data selection procedures and to the curve fitting modelling step, while soil temperature adjustments methods had less impact. Biochar H/C ratio remained the main predictor of biochar persistence, in line with previous research, regardless of the extrapolation assumptions (multi-pool exponential functions or power function) used in curve fitting. The relation between H/C and percentage of biochar carbon remaining after 100 years (BC100) was better explained by a power model than a linear model, with R2 values between 0.5 and 0.9. Using multi-pool exponential functions, estimated BC100 varied between 90 % and 60 % for H/C from 0 to 0.7. However, using power functions, BC100 was constrained between 90 % and 80 % for the same H/C range. Additional information about the biochar, the pyrolysis conditions or the environmental incubation conditions did not significantly increase explained variance. Notably, the dataset lacks observations at H/C ratios below 0.2, of biochar made from manure and biosolids, biochar from processes other than slow pyrolysis, field studies, and incubation temperatures below 10 °C, which should guide future experimental work. The detailed analysis performed in this study does not cast doubts on the longevity of biochar carbon storage; rather, it confirms previous knowledge by critically examining the modelling, elucidating the assumptions and limitations, and making the analysis fully reproducible. There is a need for further interdisciplinary work on integration of various theories and approaches to biochar persistence, ultimately leading to the formulation of policy-relevant conclusions.

Introduction: The prevalence of fatigue in patients with diabetes mellitus (DM) can be as high as 50 %. Physical, mental, and psychosocial components of fatigue negatively impact quality of life (QOL), morbidity and mortality. Several tools have been developed to address fatigue, but none specifically for measuring fatigue in DM. The aim of this study was to assess the impact of diabetes and neuropathy on fatigue using the Norfolk QOL-Fatigue (QOL-F) survey. Methods: 605 adult participants from [Anonymous] were recruited (400 subjects with type 1 or type 2 DM and 205 subjects without diabetes (controls)). All subjects completed the Norfolk QOL-F. Demographics, weight, BMI, and duration of diabetes were obtained. The Norfolk QOL-F, a 35-item validated questionnaire, assesses five domains: subjective fatigue, physical and cognitive fatigue, reduced activities, impaired activities of daily living, and depression. Results: Subjects with DM reported significantly higher fatigue total scores (52.63vs33.89, p

Acute illness-related stress can result in severe hypercortisolism and bilateral adrenal enlargement in certain patients. We report a case of stress-induced hypercortisolism and bilateral adrenal enlargement in a patient admitted for acute respiratory distress and cardiogenic shock. Bilateral adrenal enlargement and hypercortisolism found during hospitalization for acute illness resolved 3 weeks later following the resolution of acute illness. Acute illness can be a precipitating factor for stress-induced hypercortisolism and bilateral adrenal enlargement. We hypothesize that increased adrenocorticotrophic hormone mediated by corticotrophin-releasing hormone from physical stress resulted in significant adrenal hyperplasia and hypercortisolism. This mechanism is downregulated once acute illness resolves.

Electrical synapses are neuronal gap junction (GJ) channels associated with a macromolecular complex called the electrical synapse density (ESD), which regulates development and dynamically modifies electrical transmission. However, the proteomic makeup and molecular mechanisms utilized by the ESD that direct electrical synapse formation are not well understood. Using the Mauthner cell of zebrafish as a model, we previously found that the intracellular scaffolding protein ZO1b is a member of the ESD, localizing postsynaptically, where it is required for GJ channel localization, electrical communication, neural network function, and behavior. Here, we show that the complexity of the ESD is further diversified by the genomic structure of the ZO1b gene locus. The ZO1b gene is alternatively initiated at three transcriptional start sites resulting in isoforms with unique N-termini that we call ZO1b-Alpha, -Beta, and -Gamma. We demonstrate that ZO1b-Beta and ZO1b-Gamma are broadly expressed throughout the nervous system and localize to electrical synapses. By contrast, ZO1b-Alpha is expressed mainly non-neuronally and is not found at synapses. We generate mutants in all individual isoforms, as well as double mutant combinations in cis on individual chromosomes, and find that ZO1b-Beta is necessary and sufficient for robust GJ channel localization. ZO1b-Gamma, despite its localization to the synapse, plays an auxiliary role in channel localization. This study expands the notion of molecular complexity at the ESD, revealing that an individual genomic locus can contribute distinct isoforms to the macromolecular complex at electrical synapses. Further, independent scaffold isoforms have differential contributions to developmental assembly of the interneuronal GJ channels. We propose that ESD molecular complexity arises both from the diversity of unique genes and from distinct isoforms encoded by single genes. Overall, ESD proteomic diversity is expected to have critical impacts on the development, structure, function, and plasticity of electrical transmission.

Abstract Larvae of Leucothyreus spp. have been reported causing damage to several crops in Brazil. From May 2012 to April 2013, adults and immatures of Leucothyreus alvarengai Frey (Coleoptera: Melolonthidae: Rutelinae) samples were obtained from sugarcane (Saccharum officinarum L.) (Poaceae) fields in the municipalities of Naviraí and Nova Andradina, Mato Grosso do Sul, Brazil. Adults were collected with the aid of light traps, whereas immatures were sampled by opening two trench sizes (30 x 30 x 30 cm and 80 x 50 x 40 cm) in the soil, beside the plants. The collected larvae were reared in laboratory conditions, fed by sugarcane seedlings. The biological cycle of L. alvarengai was completed in 230 days, displaying three larval instars with mean size of the cephalic capsule of 1.68, 2.46, and 3.00 mm for the first, second, and third instar, respectively. Adults were collected in greater numbers in December 2012, and first-instar larvae were observed as of January 2013. Conversely, pupae were observed in the field from July 2012 to January 2013. This is the first record of larvae and adults of L. alvarengai in sugarcane fields in Mato Grosso do Sul state, contributing with the knowledge about its biology and temporal distribution in the field.

Abstract Objective Evaluation of serum neurofilament light chain (sNfL), measured using high‐throughput assays on widely accessible platforms in large, real‐world MS populations, is a critical step for sNfL to be utilized in clinical practice. Methods Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) is a network of healthcare institutions in the United States and Europe collecting standardized clinical/imaging data and biospecimens during routine clinic visits. sNfL was measured in 6974 MS and 201 healthy control (HC) participants, using a high‐throughput, scalable immunoassay. Results Elevated sNfL levels for age (sNfL‐E) were found in 1238 MS participants (17.8%). Factors associated with sNfL‐E included male sex, younger age, progressive disease subtype, diabetes mellitus, impaired renal function, and active smoking. Higher body mass index (BMI) was associated with lower odds of elevated sNfL. Active treatment with disease‐modifying therapy was associated with lower odds of sNfL‐E. MS participants with sNfL‐E exhibited worse neurological function (patient‐reported disability, walking speed, manual dexterity, and cognitive processing speed), lower brain parenchymal fraction, and higher T2 lesion volume. Longitudinal analyses revealed accelerated short‐term rates of whole brain atrophy in sNfL‐E participants and higher odds of new T2 lesion development, although both MS participants with or without sNfL‐E exhibited faster rates of whole brain atrophy compared to HC. Findings were consistent in analyses examining age‐normative sNfL Z‐scores as a continuous variable. Interpretation Elevated sNfL is associated with clinical disability, inflammatory disease activity, and whole brain atrophy in MS, but interpretation needs to account for comorbidities including impaired renal function, diabetes, and smoking.

IntroductionAntimicrobial resistance is a pressing global concern that has led to the search for new antibacterial agents with novel targets or non-traditional approaches. Recently, organogold compounds have emerged as a promising class of antibacterial agents. In this study, we present and characterize a (C^S)-cyclometallated Au(III) dithiocarbamate complex as a potential drug candidate.Methods and resultsThe Au(III) complex was found to be stable in the presence of effective biological reductants, and showed potent antibacterial and antibiofilm activity against a wide range of multidrug-resistant strains, particularly gram-positive strains, and gram-negative strains when used in combination with a permeabilizing antibiotic. No resistant mutants were detected after exposing bacterial cultures to strong selective pressure, indicating that the complex may have a low propensity for resistance development. Mechanistic studies indicate that the Au(III) complex exerts its antibacterial activity through a multimodal mechanism of action. Ultrastructural membrane damage and rapid bacterial uptake suggest direct interactions with the bacterial membrane, while transcriptomic analysis identified altered pathways related to energy metabolism and membrane stability including enzymes of the TCA cycle and fatty acid biosynthesis. Enzymatic studies further revealed a strong reversible inhibition of the bacterial thioredoxin reductase. Importantly, the Au(III) complex demonstrated low cytotoxicity at therapeutic concentrations in mammalian cell lines, and showed no acute in vivo toxicity in mice at the doses tested, with no signs of organ toxicity.DiscussionOverall, these findings highlight the potential of the Au(III)-dithiocarbamate scaffold as a basis for developing novel antimicrobial agents, given its potent antibacterial activity, synergy, redox stability, inability to produce resistant mutants, low toxicity to mammalian cells both in vitro and in vivo, and non-conventional mechanism of action.

We present a catalog of hard X-ray serendipitous sources detected in the first 80 months of observations by the Nuclear Spectroscopic Telescope Array (NuSTAR). The NuSTAR serendipitous survey 80 month (NSS80) catalog has an unprecedented ∼62 Ms of effective exposure time over 894 unique fields (a factor of 3 increase over the 40 month catalog, NSS40), with an areal coverage of ∼36 deg ^2 , larger than all NuSTAR extragalactic surveys. NSS80 provides 1274 hard X-ray sources in the 3−24 keV band (822 new detections compared to the previous NSS40). Approximately 76% of the NuSTAR sources have lower-energy (

Cyclic five-membered disulfides (1,2-dithiolanes) have been reported either as nonspecific redox motifs, or as highly specific cellular probes for thioredoxin reductase (TrxR). Here the authors show that 1,2-dithiolane probes are nonspecifically reduced by a range of thiol reductants and are not sensitive to TrxR modulation, thus they are unsuitable as cellular probes for TrxR.

Abstract The main objective of this study is to propose different probabilistic models for adjusting the trend component, since it significantly influences the quality of the spatio-temporal interpolation of rainfalls. We used the monthly total precipitation data of the São Francisco River Basin (SFRB) for the period of 31 years, 1989–2019. The SFRB occupies 8% of the whole Brazilian territory, mostly located in the Northeast Brazilian region. For the trend component, we propose the fitted GAMLSS models by comparing different probability distribution families, which in most cases include the characteristics of these data. The results indicate the existence of a spatio-temporal pattern of the residues obtained from the adjustment of the trend with zero adjusted Gamma distribution for the accumulated monthly precipitation. The adjustment revealed a spatial dependence of up to 873 km between the pluviometric stations and temporal autocorrelation of approximately 1.6 months. The methodology used in this study enabled us to create rainfall maps, interpolating unobserved locations in differences years. The projection of these maps to the SFRB is considered extremely important for planning and implementing activities related to water resources across the river basin.

Abstract Objective To assess the independent contributions of clinical measures (relapses, Expanded Disability Status Scale [EDSS] scores, and neuroperformance measures) and nonclinical measures (new brain magnetic resonance imaging [MRI] activity and serum neurofilament light chain [sNfL] levels) for distinguishing natalizumab‐treated from placebo‐treated patients. Methods We conducted post hoc analyses using data from the AFFIRM trial of natalizumab for multiple sclerosis. We used multivariable regression analyses with predictors (EDSS progression, no relapse, new or enlarging MRI activity, brain atrophy, sNfL levels, and neuroperformance worsening) to identify measures that independently discriminated between treatment groups. Results The multivariable model that best distinguished natalizumab from placebo was no new or enlarging T2 or gadolinium‐enhancing activity on MRI (odds ratio; 95% confidence interval: 7.2; 4.7–10.9), year 2 sNfL levels

Abstract Background Extremely rare progressive diseases like Sedaghatian-type Spondylometaphyseal Dysplasia (SSMD) can be neonatally lethal and therefore go undiagnosed or are difficult to treat. Recent sequencing efforts have linked this disease to mutations in GPX4, with consequences in the resulting enzyme, glutathione peroxidase 4. This offers potential diagnostic and therapeutic avenues for those suffering from this disease, though the steps toward these treatments is often convoluted, expensive, and time-consuming. Main body The CureGPX4 organization was developed to promote awareness of GPX4-related diseases like SSMD, as well as support research that could lead to essential therapeutics for patients. We provide an overview of the 21 published SSMD cases and have compiled additional sequencing data for four previously unpublished individuals to illustrate the genetic component of SSMD, and the role of sequencing data in diagnosis. We outline in detail the steps CureGPX4 has taken to reach milestones of team creation, disease understanding, drug repurposing, and design of future studies. Conclusion The primary aim of this review is to provide a roadmap for therapy development for rare, ultra-rare, and difficult to diagnose diseases, as well as increase awareness of the genetic component of SSMD. This work will offer a better understanding of GPx4-related diseases, and help guide researchers, clinicians, and patients interested in other rare diseases find a path towards treatments.

Abstract Background Time-lapse microscopy live-cell imaging is essential for studying the evolution of bacterial communities at single-cell resolution. It allows capturing detailed information about the morphology, gene expression, and spatial characteristics of individual cells at every time instance of the imaging experiment. The image analysis of bacterial "single-cell movies" (videos) generates big data in the form of multidimensional time series of measured bacterial attributes. If properly analyzed, these datasets can help us decipher the bacterial communities' growth dynamics and identify the sources and potential functional role of intra- and inter-subpopulation heterogeneity. Recent research has highlighted the importance of investigating the role of biological "noise" in gene regulation, cell growth, cell division, etc. Single-cell analytics of complex single-cell movie datasets, capturing the interaction of multiple micro-colonies with thousands of cells, can shed light on essential phenomena for human health, such as the competition of pathogens and benign microbiome cells, the emergence of dormant cells (“persisters”), the formation of biofilms under different stress conditions, etc. However, highly accurate and automated bacterial bioimage analysis and single-cell analytics methods remain elusive, even though they are required before we can routinely exploit the plethora of data that single-cell movies generate. Results We present visualization and single-cell analytics using R (ViSCAR), a set of methods and corresponding functions, to visually explore and correlate single-cell attributes generated from the image processing of complex bacterial single-cell movies. They can be used to model and visualize the spatiotemporal evolution of attributes at different levels of the microbial community organization (i.e., cell population, colony, generation, etc.), to discover possible epigenetic information transfer across cell generations, infer mathematical and statistical models describing various stochastic phenomena (e.g., cell growth, cell division), and even identify and auto-correct errors introduced unavoidably during the bioimage analysis of a dense movie with thousands of overcrowded cells in the microscope's field of view. Conclusions ViSCAR empowers researchers to capture and characterize the stochasticity, uncover the mechanisms leading to cellular phenotypes of interest, and decipher a large heterogeneous microbial communities' dynamic behavior. ViSCAR source code is available from GitLab at https://gitlab.com/ManolakosLab/viscar .

Cellular models of organs have been used to investigate mechanisms of disease. Here the authors generate a human alpha synuclein-induced brain-chip model that recapitulates blood-brain barrier dysfunction, as a potential testing platform for novel therapeutics in Parkinson’s disease.

Summary: Introduction: Periprosthetic joint infection (PJI) is a devastating complication occurring in 1–2% of primary and up to 10% of revised total hip and knee arthroplasties (THA and TKA) impairing patient's quality of life. Occult infections are underdiagnosed, sub-treated and sub-clinically experienced by patients. This study aimed to correlate patients' clinical outcomes with early antibiotic treatment based on use or non-use of a sonication technique on explanted prostheses. Methods: 33 patients with revised THA or TKA were retrospectively evaluated. Clinical outcomes were assessed via Oxford hip or knee scores, and correlated with administration or not of antibiotic treatment based on sonication results. Results: According to laboratory findings the patients were divided in the following three groups: 1. Septic loosening (conventional cultures and/or sonication positive), 2. Aseptic loosening (conventional cultures and sonication negative) and 3. Occult loosening (conventional cultures negative, sonication not performed). The average Oxford score was poor (27.9/60) for the septic, excellent (43.8/60) for the aseptic and intermediate (37.7/60) for the occult group. Additionally, conventional cultures were negative, but sonication-positive, in 6 individuals with patient-related risk factors (male gender, BMI > 30 kg/m2, diabetes, hypertension, steroids and rheumatoid arthritis). Conclusions: Sonication represents a valuable diagnostic technique to guide administration of effective antibiotic treatment for patients, especially for detection of persistent post-revision occult infections. We recommend the systematic investigation of revised prostheses with a sonication technique, but especially in cases with risk factors for infection who it is suspected may have occult loosening.

Rafael da Silva Sá,1,2 Angela Flávia Logullo,3 Simone Elias,1 Gil Facina,1 Vanessa Monteiro Sanvido,1 Afonso Celso Pinto Nazário1 1Department of Gynaecology, Breast Surgery Team, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil; 2Universidade do Oeste Paulista (UNOESTE), Presidente Prudente, Brazil; 3Department of Pathology, Universidade Federal de São Paulo (UNIFESP), São Paulo, BrazilCorrespondence: Rafael da Silva SáDepartment of Gynaecology, Breast Surgery Team, Universidade Federal de São Paulo (UNIFESP), Rua Marselhesa, 249, São Paulo, SP, CEP 04020-060, BrazilTel +55 11 55764848Email rafasamed@hotmail.comBackground: Mammography screening has become widely spread and provided a marked increase in ductal carcinoma in situ (DCIS) diagnosis. In DCIS, the ductal epithelium proliferates without invasion through the basal cell membrane. However, histologic underestimation can happen in some cases.Objective: To analyze the rate of histologic underestimation (histopathologic results upgraded to invasive carcinoma after surgery) and the rate of positive results of sentinel lymph node biopsy (SLNB) in patients diagnosed with DCIS in a Brazilian public hospital.Methods: We reviewed medical records of all consecutive patients admitted between 2009 and 2013 whose initial diagnosis was DCIS through core needle biopsy. DCIS cases with a high risk of invasion underwent SLNB. We excluded cases with invasion or micro-invasion components in the first biopsy.Results: A total of 86 women were included, most with microcalcifications as the primary radiological lesion (73.2%), and underwent preoperative biopsy, with an invasive component in 21 (24.4%) in the final pathology report. Most had invasive carcinoma of no special type (NST): 52.3% (n = 11) and microinvasive tumors (7 cases, 33.3%). The main factors associated with histologic underestimation were nodular lesion (61.9%, p< 0.001) and an ultra-sonography-guided biopsy (71.4%, p=0.0005). The positivity rate of SLNB was 4.3%. All these patients underwent mastectomy, and the initial histologic pattern was solid DCIS.Conclusion: The “histologic underestimation” rate among patients with DCIS was not low, and less than 5% of patients who underwent SLNB had axillary positivity. This result suggests that patients who have DCIS and a high risk of invasion and undergoing mastectomy should have SLNB. As to the patients who will undergo lumpectomy, SLNB could be omitted and could be performed if patients have upgraded to invasive breast cancer.Keywords: breast cancer, ductal carcinoma in situ, underestimation rates, positive sentinel lymph node

Summary: Species differences in brain and blood–brain barrier (BBB) biology hamper the translation of findings from animal models to humans, impeding the development of therapeutics for brain diseases. Here, we present a human organotypic microphysiological system (MPS) that includes endothelial-like cells, pericytes, glia, and cortical neurons and maintains BBB permeability at in vivo relevant levels. This human Brain-Chip engineered to recapitulate critical aspects of the complex interactions that mediate neuroinflammation and demonstrates significant improvements in clinical mimicry compared to previously reported similar MPS. In comparison to Transwell culture, the transcriptomic profiling of the Brain-Chip displayed significantly advanced similarity to the human adult cortex and enrichment in key neurobiological pathways. Exposure to TNF-α recreated the anticipated inflammatory environment shown by glia activation, increased release of proinflammatory cytokines, and compromised barrier permeability. We report the development of a robust brain MPS for mechanistic understanding of cell-cell interactions and BBB function during neuroinflammation.

Approximately five million students in US public schools have a home language other than English and are actively learning English (National Center for Education Statistics, 2020), indicating that a large number of students could be considered emergent bilingual (EB). Although measuring student skills in English may be informative, it does not provide a complete understanding of student skill and language development because the student's native language is not considered. Curriculum-based measurement (CBM) is often used in schools to measure student academic skills because of its utility in understanding student performance, educational decision-making, and progress monitoring. However, there is limited understanding of the extent of the empirical literature focused on CBMs in languages other than English. Results of this scoping review of the available empirical literature on CBM in other languages with linguistically diverse student populations highlight the need to further understand and expand this area of research given the rise of the emergent bilingual student population and dual-language program in US public schools.

Water quality degradation of freshwater bodies is a concern worldwide, particularly in Africa, where data are scarce and standard water quality monitoring is expensive. This study explored the use of remote sensing imagery and machine learning (ML) algorithms as an alternative to standard field measuring for monitoring water quality in large and remote areas constrained by logistics and finance. Six machine learning (ML) algorithms integrated with Landsat 8 imagery were evaluated for their accuracy in predicting three optically active water quality indicators observed monthly in the period from August 2016 to April 2022: turbidity (TUR), total dissolved solids (TDS) and Chlorophyll a (Chl-a). The six ML algorithms studied were the artificial neural network (ANN), support vector machine regression (SVM), random forest regression (RF), XGBoost regression (XGB), AdaBoost regression (AB), and gradient boosting regression (GB) algorithms. XGB performed best at predicting Chl-a, with an R2 of 0.78, Nash–Sutcliffe efficiency (NSE) of 0.78, mean absolute relative error (MARE) of 0.082 and root mean squared error (RMSE) of 9.79 µg/L. RF performed best at predicting TDS (with an R2 of 0.79, NSE of 0.80, MARE of 0.082, and RMSE of 12.30 mg/L) and TUR (with an R2 of 0.80, NSE of 0.81, and MARE of 0.072 and RMSE of 7.82 NTU). The main challenges were data size, sampling frequency, and sampling resolution. To overcome the data limitation, we used a K-fold cross validation technique that could obtain the most out of the limited data to build a robust model. Furthermore, we also employed stratified sampling techniques to improve the ML modeling for turbidity. Thus, this study shows the possibility of monitoring water quality in large freshwater bodies with limited observed data using remote sensing integrated with ML algorithms, potentially enhancing decision making.

The global identification of enzyme substrates is still challenging. Here, the authors develop a method based on proteome-wide thermal shift assays to discover enzyme substrates directly from cell lysates, identifying known and novel oxidoreductase, kinase and poly-(ADP-ribose) polymerase substrates.

Background & Aims: The limited availability of organoid systems that mimic the molecular signatures and architecture of human intestinal epithelium has been an impediment to allowing them to be harnessed for the development of therapeutics as well as physiological insights. We developed a microphysiological Organ-on-Chip (Emulate, Inc, Boston, MA) platform designed to mimic properties of human intestinal epithelium leading to insights into barrier integrity. Methods: We combined the human biopsy-derived leucine-rich repeat-containing G-protein–coupled receptor 5–positive organoids and Organ-on-Chip technologies to establish a micro-engineered human Colon Intestine-Chip (Emulate, Inc, Boston, MA). We characterized the proximity of the model to human tissue and organoids maintained in suspension by RNA sequencing analysis, and their differentiation to intestinal epithelial cells on the Colon Intestine-Chip under variable conditions. Furthermore, organoids from different donors were evaluated to understand variability in the system. Our system was applied to understanding the epithelial barrier and characterizing mechanisms driving the cytokine-induced barrier disruption. Results: Our data highlight the importance of the endothelium and the in vivo tissue-relevant dynamic microenvironment in the Colon Intestine-Chip in the establishment of a tight monolayer of differentiated, polarized, organoid-derived intestinal epithelial cells. We confirmed the effect of interferon-γ on the colonic barrier and identified reorganization of apical junctional complexes, and induction of apoptosis in the intestinal epithelial cells as mediating mechanisms. We show that in the human Colon Intestine-Chip exposure to interleukin 22 induces disruption of the barrier, unlike its described protective role in experimental colitis in mice. Conclusions: We developed a human Colon Intestine-Chip platform and showed its value in the characterization of the mechanism of action of interleukin 22 in the human epithelial barrier. This system can be used to elucidate, in a time- and challenge-dependent manner, the mechanism driving the development of leaky gut in human beings and to identify associated biomarkers.

Astrocytes are instrumental in maintaining central nervous system (CNS) homeostasis and responding to injury. A major limitation of studying neurodegenerative diseases like multiple sclerosis (MS) is lack of human pathological specimens obtained during the acute stages, thereby relegating research to post-mortem specimens obtained years after the initiation of pathology. Rodent reactive astrocytes have been shown to be cytotoxic to neurons and oligodendrocytes but may differ from human cells, especially in diseases with genetic susceptibility. Herein, we purified human CD49f+ astrocytes from induced pluripotent stem cells derived from individual patient and control peripheral leukocytes. We compared TNF and IL1α stimulated human reactive astrocytes from seven persons with MS and six non-MS controls and show their transcriptomes are remarkably similar to those described in rodents. The functional effect of astrocyte conditioned media (ACM) was examined in a human oligodendrocyte precursor cell (OPC) line differentiation assay. ACM was not cytotoxic to the OPCs but robustly inhibited the myelin basic protein (MBP) reporter. No differences were seen between MS and control stimulated astrocytes at either the transcript level or in ACM mediated OPC suppression assays. We next used RNAseq to interrogate differentially expressed genes in the OPC lines that had suppressed differentiation from the human ACM. Remarkably, not only was OPC differentiation and myelin gene expression suppressed, but we observed induction of several immune pathways in OPCs exposed to the ACM. These data support the notion that reactive astrocytes can inhibit OPC differentiation thereby limiting their remyelination capacity, and that OPCs take on an immune profile in the context of inflammatory cues.

Abstract Background The estrogen receptor (ER)-positive breast cancer represents over 80% of all breast cancer cases. Even though adjuvant hormone therapy with tamoxifen (TMX) is saving lives of patients with ER-positive breast cancer, the acquired resistance to TMX anti-estrogen therapy is the main hurdle for successful TMX therapy. Here we address the mechanism for TMX resistance and explore the ways to eradicate TMX-resistant breast cancer in both in vitro and ex vivo experiments. Experimental design To identify compounds able to overcome TMX resistance, we used short-term and long-term viability assays in cancer cells in vitro and in patient samples in 3D ex vivo, analysis of gene expression profiles and cell line pharmacology database, shRNA screen, CRISPR-Cas9 genome editing, real-time PCR, immunofluorescent analysis, western blot, measurement of oxidative stress using flow cytometry, and thioredoxin reductase 1 enzymatic activity. Results Here, for the first time, we provide an ample evidence that a high level of the detoxifying enzyme SULT1A1 confers resistance to TMX therapy in both in vitro and ex vivo models and correlates with TMX resistance in metastatic samples in relapsed patients. Based on the data from different approaches, we identified three anticancer compounds, RITA (Reactivation of p53 and Induction of Tumor cell Apoptosis), aminoflavone (AF), and oncrasin-1 (ONC-1), whose tumor cell inhibition activity is dependent on SULT1A1. We discovered thioredoxin reductase 1 (TrxR1, encoded by TXNRD1) as a target of bio-activated RITA, AF, and ONC-1. SULT1A1 depletion prevented the inhibition of TrxR1, induction of oxidative stress, DNA damage signaling, and apoptosis triggered by the compounds. Notably, RITA efficiently suppressed TMX-unresponsive patient-derived breast cancer cells ex vivo. Conclusion We have identified a mechanism of resistance to TMX via hyperactivated SULT1A1, which renders selective vulnerability to anticancer compounds RITA, AF, and ONC-1, and provide a rationale for a new combination therapy to overcome TMX resistance in breast cancer patients. Our novel findings may provide a strategy to circumvent TMX resistance and suggest that this approach could be developed further for the benefit of relapsed breast cancer patients.

Objective: To determine whether the pulmonary embolism (PE) categories of massive, submassive, PE with no right ventricle dysfunction (NRVD), and subsegmental only (SSO) adequately predict clinical outcome. Methods: Patients treated for acute PE (March 1, 2013, through July 31, 2019) were followed forward prospectively to compare venous thromboembolism (VTE) recurrence, all-cause mortality, major bleeding, and clinically relevant nonmajor bleeding (CRNMB) across 4 PE categories. Results: Of 2703 patients with VTE, 1188 (44%) had PE, of which 1021 (85.9%) completed at least 3 months of therapy or had clinical outcomes precluding further treatment (27 with massive, 217 submassive, 557 NRVD, and 220 SSO PE). One patient with massive, 8 with submassive, 23 with NRVD, and 5 with SSO PE had recurrent VTE (3.90, 5.33, 5.36, and 3.66 per 100 person-years, respectively; P=.84). There were 3 deaths in massive, 27 in submassive, 140 in NRVD, and 34 in SSO PE groups (11.59, 17.37, 31.74, and 24.74 per 100 person-years, respectively; P=.02); when adjusted for cancer, the relationship was no longer significant (P=.27). One patient with massive, 5 with submassive, 22 with NRVD, and 5 with SSO PE had major bleeding (3.90, 3.31, 5.24, and 3.75 per 100 person-years, respectively; P=.66). Similar cumulative rates for CRNMB were observed (P=.87). Three-month rates of VTE recurrence, death, major bleeding, and CRNMB did not differ by PE category. Conclusion: In the setting of anticoagulation therapy with maximal standardization and evidence-based practice, there is no evidence of a difference between PE categories and outcomes. Trial Registration: clinicaltrials.gov Identifier: NCT03504007

Environmental hazards (wildfires, floods, oil spills) are often modeled as “continuous objects” which evolve in space and time taking irregular shapes. Tracking their boundaries and accurately predicting their spatiotemporal spreading patterns is of paramount importance to combat their often catastrophic consequences. Wireless Sensor Networks (WSN) have been very instrumental for this purpose. However, current WSN-based methods require a prohibitively large density of deployed sensors to achieve a reasonable boundary reconstruction accuracy because they are based on the explicit identification of nodes close to the boundary. We present a novel approach that can track and predict the global boundary using only a relatively small number of distributed local front estimates. Our approach first filters and fuses the available sparse set of local front estimates (e.g. vectors of local orientation, direction and speed) and then uses the resulting information to reconstruct a smooth curve prediction of the evolving object's boundary at a future time. Moreover, since the uncertainty of the local front parameters is modeled, it can provide a heatmap representation of the evolving object, indicating the probability for each point in the area of interest to be reached at a future time by the spreading hazard. These predictive modeling capabilities when combined enable effective decision support for crisis management. We demonstrate that different types of continuous objects can be tracked with accuracy, even when only a relatively small number of noisy local front estimates is available. Our approach is practical since it can be applied in many situations where global boundary prediction updates are important to obtain by new sparsely distributed noisy local front estimates as soon as they reach a control center while the hazard is still progressing.

Background: Alanine aminotransferase (ALT) is the most commonly used serum biomarker for chronic liver diseases (CLDs) but may not accurately reflect hepatic disorders and easily underestimates hepatic fibrosis. The previously revised upper limit of normal (ULN) of ALT (19 U/L for women and 30 U/L for men) increases its sensitivity but yields higher numbers of false-positives. Moreover, CLDs patients with ALT lower than the revised ULN may nonetheless have progression of disease. Therefore there is a need of novel biomarkers to complement the use of ALT. Here we have evaluated measurements of serum dithiothreitol-oxidizing capacity (DOC) in cohorts of chronic hepatitis B patients with different stages of disease as an exploratory pilot study for this purpose. Methods: Serum samples obtained from healthy persons and from chronic hepatitis B patients with normal ALT values were used for sensitivity evaluation. The hepatitis B patients encompassed end-stage liver diseases (ELD), chronic hepatitis B (CHB), CHB with persistently normal ALT (CHB-P) and inactive carriers (ICs). Sensitivity was also evaluated with samples from patients with other diseases. The study period was March 2018 to December 2020. Findings: DOC was found to be a robust biomarker that may become complementary to ALT measurements, especially in patients displaying low ALT levels. ROC analyses indicated that the AUC values of DOC reached 0.983 and 0.956 in ELD and CHB patients exhibiting normal ALT levels, respectively. Importantly, the AUC values of DOC reached 0.852 and 0.844 in CHB-P patients and ICs, respectively. Such AUC values permit screening and continued monitoring, corresponding to over 30% and 50% sensitivity with 99% and 95% specificity for CHB-P and ICs, respectively. DOC was also significantly correlated with indicators for fibrosis, assessing both APRI (Pearson r = 0.4905, P < 0.0001) and FIB-4 (Pearson r = 0.4421, P < 0.0001). Surprisingly, the AUC values of DOC in the hepatitis B patients with ALT levels lower than the revised ULN were not compromised. In examined non-liver diseases, DOC was low and normal, including in patients with acute myocardial infection displaying increased ALT levels. Interpretations: The results suggest that DOC can be promising as a complementary biomarker used in addition to ALT for monitoring of disease in chronic hepatitis B patients, especially when ALT levels are normal. DOC should be further evaluated for possible clinical use as biomarker also in other CLDs. Funding: This study was funded by the National Natural Science Foundation of China (Grant numbers: 31771971 and 32001013).

Summary: The circulating metabolome provides unique insights into multiple sclerosis (MS) pathophysiology, but existing studies are relatively small or characterized limited metabolites. We test for differences in the metabolome between people with MS (PwMS; n = 637 samples) and healthy controls (HC; n = 317 samples) and assess the association between metabolomic profiles and disability in PwMS. We then assess whether metabolic differences correlate with changes in cellular gene expression using publicly available scRNA-seq data and whether identified metabolites affect human immune cell function. In PwMS, we identify striking abnormalities in aromatic amino acid (AAA) metabolites (p = 2.77E−18) that are also strongly associated with disability (p = 1.01E−4). Analysis of scRNA-seq data demonstrates altered AAA metabolism in CSF and blood-derived monocyte cell populations in PwMS. Treatment with AAA-derived metabolites in vitro alters monocytic endocytosis and pro-inflammatory cytokine production. We identify shifts in AAA metabolism resulting in the reduced production of immunomodulatory metabolites and increased production of metabotoxins in PwMS.

Radial grooving is a machining process usually applied to generate grooves for thread relief, O-ring positioning, or even cutting-off operations. Due to the high machining forces and difficult chip removal, radial grooving is considered a critical process, and cutting fluids are usually applied for cooling, lubricating, and assistance on the chip removal. Compressed air (AIR) and minimum quantity lubrication (MQL) are lubri-cooling methods studied as environmentally-friendly alternatives to conventional flood (WET) applications of cutting fluids. Although already applied for years in several machining processes, the research associated with using alternative lubri-cooling techniques in radial grooving is incipient. This work presents a comparative analysis of these methods (WET, MQL, and AIR) and their radial grooving effects. In each case, a factorial design of experiments was used to evaluate the influence of lubri-cooling conditions, cutting speed, and feed rate over feed force, cutting force, and surface roughness. Results indicate that both AIR and MQL may be suitable substitutes for traditional WET lubrication when active force components and surface finish are considered. Besides, smaller cutting forces were obtained with AIR machining for radial grooving, followed by MQL and WET machining.

The aim of this systematic review is to distinguish the clinical features of immunocompetent children with non-typhoid Salmonella spondylodiscitis and summarize the diagnosis, diagnostic tools, and treatment methods to guide clinicians. The review was conducted according to the preferred PRISMA guidelines. We conducted a literature search in the PubMed, Embase, and Cochrane Library databases. Article screening, data extraction, and study evaluation were performed by two independent reviewers. A total of 20 articles, published between 1977 and 2020, were selected, which included 21 patients with average age of 12.76 years (range, 2–18) without comorbidities; in total, 19% of the patients had positive blood cultures for non-typhoid Salmonella, and 80.9% underwent either CT-guided or open biopsy, which were positive for NTS. All infections were monomicrobial, and 11 different serotypes of non-typhoid Salmonella were identified. Analyzing the reviewed cases, 52.4% of the patients presented with fever, 90.5% had localized pain, and only 19% had gastroenteritis. The most common level of discitis was the lumbar region, especially the L4/L5 level. Primarily, third-generation cephalosporin was administered, and antibiotic treatment was given for an average of 9.6 weeks. Non-typhoid Salmonella spondylodiscitis is a rare clinical entity in healthy and immunocompetent children. The identification of the responsible organism is essential to guide antibiotic therapy and define the treatment duration. A significant limiting factor in this systematic review was the lack of published research articles and case series due to the rarity of the disease.

Maher Abdessater,1 Sandra Elias,2 Johnny Boustany,3 Raghid El Khoury31Urology Department, Centre Hospitalier Régional René DUBOS, Pontoise, 95300, France; 2Anesthesia Department, Institut Gustave Roussy, Villejuif, 94550, France; 3Urology Department, Notre Dame Des Secours University Medical Center, Byblos, LebanonObjective: To describe our new laparoscopic approach in ureterolysis using the ERBEJET® 2 device to hydrodissect the ureters in idiopathic retroperitoneal fibrosis.Methods: Bilateral laparoscopic ureterolysis was done after medical therapy failure (steroids) in a 47 year old patient with retroperitoneal fibrosis. Ureteral stents were placed before surgery. Only five trocars were used for both sides, Toldt’s fascia was opened and the dissection was performed till the psoas muscle. The ureters were completely freed from the fibrotic tissue using the ERBEJET 2 device (pure hydrodissection). An omental wrap was passed behind the colonic flexure at the right and placed around the ureter. At the left, we closed Toldt’s fascia by running sutures back to the freed ureter.Results: The operating time was 198 mins. The blood loss was 50 cc. The hospital stay was 3 days. The double J stents were removed at 4 weeks postoperatively. After 2 years, the patient is free of symptoms with normal creatinine level and no urinary tract obstructions.Conclusions: Hydrodissection of the ureter in retroperitoneal fibrosis is a new application in the upper urinary tract laparoscopic approach that has not been described in literature before. It seems to offer excellent midterm outcomes. The use of ERBEJET 2 device seems to simplify the procedure and make it feasible and safe (less trauma to the ureter and more conservation of its blood supply). We believe that comparative studies are needed to assess the role of hydrodissection in ureterolysis for retroperitoneal fibrosis.Keywords: hydrodissection, laparoscopic ureterolysis, retroperitoneal fibrosis, new technique

Wildfires are natural hazards with severe consequences worryingly worsening for many climate-change affected regions of our planet. Unfortunately, technologies that can provide real-time fire-line information, such as satellites, in-field sensors, and social media texts, exhibit low spatial/temporal resolution or cannot be deployed cost-effectively in widespread geographical areas. We present the design, development, and implementation of a novel software service, called CITISENS, which by exploiting commodity smartphone sensors allows ordinary citizens to easily georeference a fire-line in real-time and report its coordinates as they are photographing a wildfire. The location/orientation sensors and the camera are used to compute the view-ray of the smartphone, and a digital elevation model is employed to estimate the ray's intersection with the topography. We have tested the georeferencing accuracy obtained and it is to be on par with, or even better, than that of existing satellite wildfire hotspot services. When combined with FLogA, a flexible wildfire spread simulator we have also developed, CITISENS offers the following unique advantages: real-time prediction of burn probabilities, dynamic assimilation of citizen-reported hotspots into ongoing simulations for improved predictive accuracy, and decision support to issue citizen alarms based on the estimated time-dependent risk at their location due to an approaching wildfire.

Background: In people with multiple sclerosis (MS), optic neuritis (ON) results in inner retinal layer thinning, and reduced density of the retinal microvasculature.Objective: To compare inter-eye differences (IEDs) in macular optical coherence tomography (OCT) and OCT angiography (OCTA) measures in MS patients with a history of unilateral ON (MS ON) vs. MS patients with no history of ON (MS non-ON), and to assess how these measures correlate with visual function outcomes after ON.Methods: In this cross-sectional study, people with MS underwent OCT and OCTA. Superficial vascular plexus (SVP) density of each eye was quantified using a deep neural network. IEDs were calculated with respect to the ON eye in MS ON patients, and with respect to the right eye in MS non-ON patients. Statistical analyses used mixed-effect regression models accounting for intra-subject correlations.Results: We included 43 MS ON patients (with 92 discrete OCT/OCTA visits) and 14 MS non-ON patients (with 24 OCT/OCTA visits). Across the cohorts, mean IED in SVP density was −2.69% (SD 3.23) in MS ON patients, as compared to 0.17% (SD 2.39) in MS non-ON patients (p = 0.002). When the MS ON patients were further stratified according to time from ON and compared to MS non-ON patients with multiple cross-sectional analyses, we identified that IED in SVP density was significantly increased in MS ON patients at 1–3 years (p = < 0.001) and >3 years post-ON (p < 0.001), but not at

One of the most common dental anomalies in humans is the congenital absence of teeth, referred to as tooth agenesis. The association of tooth agenesis to craniofacial morphology has been previously investigated but remains unclear. We investigated this association by applying geometric morphometric methods in a large sample of modern humans. In line with previous studies, we report here that a reduced teeth number is linked to a less convex profile, as well as to a shorter face. The effects were similar for males and females; they increased as the severity of the tooth agenesis increased and remained unaltered by the inclusion of third molars and of allometry in the analysis. Furthermore, in cases with tooth agenesis only in the maxilla, there was no detectable effect in mandibular shape, whereas maxillary shape was affected independently of the location of missing teeth. The robustness of the present sample along with the shape analysis and the statistical approach applied, allowed for thorough testing of various contributing factors regarding the presence but also the magnitude of effects. The present findings suggest a relationship between number of teeth and overall craniofacial development and have evolutionary implications.