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UNLABELLED: Infections caused by antimicrobial-resistant Escherichia coli are the leading cause of death attributed to antimicrobial resistance (AMR) worldwide, and the known AMR mechanisms involve a range of functional proteins. Here, we employed a pan-genome wide association study (GWAS) approach on over 1,000 E. coli isolates from sick dogs collected across the US and Canada and identified a strong statistical association (empirical P < 0.01) of AMR, involving a range of antibiotics to a group 1 capsular (CPS) gene cluster. This cluster included genes under relaxed selection pressure, had several loci missing, and had pseudogenes for other key loci. Furthermore, this cluster is widespread in E. coli and Klebsiella clinical isolates across multiple host species. Earlier studies demonstrated that the octameric CPS polysaccharide export protein Wza can transmit macrolide antibiotics into the E. coli periplasm. We suggest that the CPS in question, and its highly divergent Wza, functions as an antibiotic trap, preventing antimicrobial penetration. We also highlight the high diversity of lineages circulating in dogs across all regions studied, the overlap with human lineages, and regional prevalence of resistance to multiple antimicrobial classes. IMPORTANCE: Much of the human genomic epidemiology data available for E. coli mechanism discovery studies has been heavily biased toward shiga-toxin producing strains from humans and livestock. E. coli occupies many niches and produces a wide variety of other significant pathotypes, including some implicated in chronic disease. We hypothesized that since dogs tend to share similar strains with their owners and are treated with similar antibiotics, their pathogenic isolates will harbor unexplored AMR mechanisms of importance to humans as well as animals. By comparing over 1,000 genomes with in vitro antimicrobial susceptibility data from sick dogs across the US and Canada, we identified a strong multidrug resistance association with an operon that appears to have once conferred a type 1 capsule production system.

UNLABELLED: Cryptic conjugative plasmids lack antibiotic-resistance genes (ARGs). These plasmids can capture ARGs from the vast pool of the environmental metagenome, but the mechanism to recruit ARGs remains to be elucidated. To investigate the recruitment of ARGs by a cryptic plasmid, we sequenced and conducted mating experiments with Escherichia coli SW4848 (collected from a lake) that has a cryptic IncX (IncX4) plasmid and an IncF (IncFII/IncFIIB) plasmid with five genes that confer resistance to aminoglycosides (strA and strB), sulfonamides (sul2), tetracycline [tet(A)], and trimethoprim (dfrA5). In a conjugation experiment, a novel hybrid Tn21/Tn1721 transposon of 22,570 bp (designated Tn7714) carrying the five ARG mobilized spontaneously from the IncF plasmid to the cryptic IncX plasmid. The IncF plasmid was found to be conjugative when it was electroporated into E. coli DH10B (without the IncX plasmid). Two parallel conjugations with the IncF and the new IncX (carrying the novel Tn7714 transposon) plasmids in two separate E. coli DH10B as donors and E. coli J53 as the recipient revealed that the conjugation rate of the new IncX plasmid (with the novel Tn7714 transposon and five ARGs) is more than two orders of magnitude larger than the IncF plasmid. For the first time, this study shows experimental evidence that cryptic environmental plasmids can capture and transfer transposons with ARGs to other bacteria, creating novel multidrug-resistant conjugative plasmids with higher dispersion potential. IMPORTANCE: Cryptic conjugative plasmids are extrachromosomal DNA molecules without antibiotic-resistance genes (ARGs). Environmental bacteria carrying cryptic plasmids with a high conjugation rate threaten public health because they can capture clinically relevant ARGs and rapidly spread them to pathogenic bacteria. However, the mechanism to recruit ARG by cryptic conjugative plasmids in environmental bacteria has not been observed experimentally. Here, we document the first translocation of a transposon with multiple clinically relevant ARGs to a cryptic environmental conjugative plasmid. The new multidrug-resistant conjugative plasmid has a conjugation rate that is two orders of magnitude higher than the original plasmid that carries the ARG (i.e., the new plasmid from the environment can spread ARG more than two orders of magnitude faster). Our work illustrates the importance of studying the mobilization of ARGs in environmental bacteria. It sheds light on how cryptic conjugative plasmids recruit ARGs, a phenomenon at the root of the antibiotic crisis.

ImportanceUrinary tract infection (UTI) is the second most common infection leading to hospitalization and is often associated with gram-negative multidrug-resistant organisms (MDROs). Clinicians overuse extended-spectrum antibiotics although most patients are at low risk for MDRO infection. Safe strategies to limit overuse of empiric antibiotics are needed.ObjectiveTo evaluate whether computerized provider order entry (CPOE) prompts providing patient- and pathogen-specific MDRO risk estimates could reduce use of empiric extended-spectrum antibiotics for treatment of UTI.Design, setting, and participantsCluster-randomized trial in 59 US community hospitals comparing the effect of a CPOE stewardship bundle (education, feedback, and real-time and risk-based CPOE prompts; 29 hospitals) vs routine stewardship (n = 30 hospitals) on antibiotic selection during the first 3 hospital days (empiric period) in noncritically ill adults (≥18 years) hospitalized with UTI with an 18-month baseline (April 1, 2017-September 30, 2018) and 15-month intervention period (April 1, 2019-June 30, 2020).InterventionsCPOE prompts recommending empiric standard-spectrum antibiotics in patients ordered to receive extended-spectrum antibiotics who have low estimated absolute risk (

ImportancePneumonia is the most common infection requiring hospitalization and is a major reason for overuse of extended-spectrum antibiotics. Despite low risk of multidrug-resistant organism (MDRO) infection, clinical uncertainty often drives initial antibiotic selection. Strategies to limit empiric antibiotic overuse for patients with pneumonia are needed.ObjectiveTo evaluate whether computerized provider order entry (CPOE) prompts providing patient- and pathogen-specific MDRO infection risk estimates could reduce empiric extended-spectrum antibiotics for non-critically ill patients admitted with pneumonia.Design, setting, and participantsCluster-randomized trial in 59 US community hospitals comparing the effect of a CPOE stewardship bundle (education, feedback, and real-time MDRO risk-based CPOE prompts; n = 29 hospitals) vs routine stewardship (n = 30 hospitals) on antibiotic selection during the first 3 hospital days (empiric period) in non-critically ill adults (≥18 years) hospitalized with pneumonia. There was an 18-month baseline period from April 1, 2017, to September 30, 2018, and a 15-month intervention period from April 1, 2019, to June 30, 2020.InterventionCPOE prompts recommending standard-spectrum antibiotics in patients ordered to receive extended-spectrum antibiotics during the empiric period who have low estimated absolute risk (

Intraspecific genomic diversity brings the potential for an unreported and diverse reservoir of cryptic antibiotic resistance genes in pathogens, as cryptic resistance can occur without major mutations and horizontal transmission. Here, we predicted the differences in the types of antibiotics and genes that induce cryptic and latent resistance between micro-diverse Escherichia coli strains. For example, we hypothesize that known resistance genes will be the culprit of latent resistance within clinical strains. We used a modified functional metagenomics method to induce expression in eight E. coli strains. We found a total of 66 individual genes conferring phenotypic resistance to 11 out of 16 antibiotics. A total of 14 known antibiotic resistance genes comprised 21% of total identified genes, whereas the majority (52 genes) were unclassified cryptic resistance genes. Between the eight strains, 1.2% of core orthologous genes were positive (conferred resistance in at least one strain). Sixty-four percent of positive orthologous genes conferred resistance to only one strain, demonstrating high intraspecific variability of latent resistance genes. Cryptic resistance genes comprised most resistance genes among laboratory and clinical strains as well as natural, semisynthetic, and synthetic antibiotics. Known antibiotic resistance genes primarily conferred resistance to multiple antibiotics from varying origins and within multiple strains. Hence, it is uncommon for E. coli to develop cross-cryptic resistance to antibiotics from multiple origins or within multiple strains. We have uncovered prospective and previously unknown resistance genes as well as antibiotics that have the potential to trigger latent antibiotic resistance in E. coli strains from varying origins.IMPORTANCEIntraspecific genomic diversity may be a driving force in the emergence of adaptive antibiotic resistance. Adaptive antibiotic resistance enables sensitive bacterial cells to acquire temporary antibiotic resistance, creating an optimal window for the development of permanent mutational resistance. In this study, we investigate cryptic resistance, an adaptive resistance mechanism, and unveil novel (cryptic) antibiotic resistance genes that confer resistance when amplified within eight E. coli strains derived from clinical and laboratory origins. We identify the potential of cryptic resistance genes to confer cross-resistance to antibiotics from varying origins and within multiple strains. We discern antibiotic characteristics that promote latent resistance in multiple strains, considering intraspecific diversity. This study may help detect novel resistance genes and functional genes that could become responsible for cryptic resistance among diverse strains and antibiotics, thus also identifying potential novel antibiotic targets and mechanisms.

BACKGROUND: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure. METHODS: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individuals regional difference and global difference, were used to test for regional differences that diverge from the global difference. RESULTS: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness. CONCLUSIONS: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.

The World Health Organization has a goal of universal drug susceptibility testing for patients with tuberculosis. However, molecular diagnostics to date have focused largely on first-line drugs and predicting susceptibilities in a binary manner (classifying strains as either susceptible or resistant). Here, we used a multivariable linear mixed model alongside whole genome sequencing and a quantitative microtiter plate assay to relate genomic mutations to minimum inhibitory concentration (MIC) in 15,211 Mycobacterium tuberculosis clinical isolates from 23 countries across five continents. We identified 492 unique MIC-elevating variants across 13 drugs, as well as 91 mutations likely linked to hypersensitivity. Our results advance genetics-based diagnostics for tuberculosis and serve as a curated training/testing dataset for development of drug resistance prediction algorithms.

Methicillin-resistant Staphylococcus aureus (MRSA) is an important zoonotic pathogen associated with a wide range of infections in humans and animals. Thus, the emergence of MRSA clones poses an important threat to human and animal health. This study is aimed at elucidating the genomics insights of a strong biofilm-producing and multidrug-resistant (MDR) S. aureus MTR_BAU_H1 strain through whole-genome sequencing (WGS). The S. aureus MTR_BAU_H1 strain was isolated from food handlers hand swabs in Bangladesh and phenotypically assessed for antimicrobial susceptibility and biofilm production assays. The isolate was further undergone to high throughput WGS and analysed using different bioinformatics tools to elucidate the genetic diversity, molecular epidemiology, sequence type (ST), antimicrobial resistance, and virulence gene distribution. Phenotypic analyses revealed that the S. aureus MTR_BAU_H1 strain is a strong biofilm-former and carries both antimicrobial resistance (e.g., methicillin resistance; mecA, beta-lactam resistance; blaZ and tetracycline resistance; tetC) and virulence (e.g., sea, tsst, and PVL) genes. The genome of the S. aureus MTR_BAU_H1 belonged to ST1930 that possessed three plasmid replicons (e.g., rep16, rep7c, and rep19), seven prophages, and two clustered regularly interspaced short palindromic repeat (CRISPR) arrays of varying sizes. Phylogenetic analysis showed a close evolutionary relationship between the MTR_BAU_H1 genome and other MRSA clones of diverse hosts and demographics. The MTR_BAU_H1 genome harbours 42 antimicrobial resistance genes (ARGs), 128 virulence genes, and 273 SEED subsystems coding for the metabolism of amino acids, carbohydrates, proteins, cofactors, vitamins, minerals, and lipids. This is the first-ever WGS-based study of a strong biofilm-producing and MDR S. aureus strain isolated from human hand swabs in Bangladesh that unveils new information on the resistomes (ARGs and correlated mechanisms) and virulence potentials that might be linked to staphylococcal pathogenesis in both humans and animals.

Background/Objectives: Efforts have been made toward primary or secondary stroke or transient ischemic attack (TIA) prevention. However, little attention has been paid to recurrent stroke or TIA. This study investigated risk factors for multiple or single recurrent stroke or TIA. Methods: Data from 3646 patients with ischemic stroke or TIA were obtained from the Korea University Ansan Hospital Stroke Center between March 2014 and December 2021, using the prospective institutional database of the Korea University Stroke Registry. The associations between clinical features and recurrent stroke or TIA were assessed using bivariable and multivariable Cox models. Results: Recurrent stroke or TIA was associated with male sex (adjusted hazard ratio (HR) 1.95, 95% confidence interval (CI) 1.42–2.80), hypertension (HR 1.49, 95% CI 1.00–2.23), diabetes mellitus (HR 1.54, 95% CI 1.13–2.13), an etiologic subtype of transient ischemic attack (HR 1.88, 95% CI 1.09–3.16), white matter changes (HR 1.62, 95% CI 1.05–2.38), and cerebral microbleeds (HR 1.79, 95% CI 1.26–2.59). Multiple recurrent stroke or TIA was associated with male sex (HR 3.86, 95% CI 1.94–11.55), diabetes mellitus (HR 2.40, 95% CI 1.31–4.53), and anemia (HR 4,58, 95% CI 2.31–10.44). Conclusions: Given the risk factor profiles for recurrent stroke or TIA, risks differed among patient subgroups and were based on multiple or single recurrences. It may exert an effect as a prognostic indicator in the high risk of recurrences. [ABSTRACT FROM AUTHOR]

Objective: To compare the risk of intrapartum cesarean delivery (CD) between patients with twin and singleton pregnancies undergoing a trial of labor and identify risk factors for intrapartum CD in twin pregnancies. Methods: The present study was a retrospective cohort study of patients with a twin or singleton pregnancy who underwent a trial of labor at ≥340/7 weeks in a single center (2015–2022). The primary outcome was the rate of intrapartum CD. In twin pregnancies, this outcome was limited to CD of both twins. The association of plurality with intrapartum CD was estimated using multivariable Poisson regression. Results: A total of 20 754 patients met the study criteria, 669 of whom had a twin pregnancy. Patients with twins had a greater risk of intrapartum CD (of both twins) than those with singleton pregnancies (22.1% vs 15.9%, respectively; aRR 1.38 [95% CI: 1.15–1.66]), primarily due to a greater risk of failure to progress. In addition, 4.1% of the twin pregnancies had a CD for the second twin, resulting in an overall CD rate in twin pregnancies of 26.2%. Variables associated with intrapartum CD in twin pregnancies included nulliparity (aOR 3.50, 95% CI: 2.34–5.25), birthweight discordance >20% (aOR 2.47, 95% CI: 1.27–4.78), and labor induction (aOR 1.64, 95% CI: 1.07–2.53). The rate of intrapartum CD was highest when all three risk factors were present (67% [95% CI: 41%–87%]). Conclusion: Twin pregnancies are associated with a greater risk of intrapartum CD than singleton pregnancies. Information on the individualized risk of intrapartum CD may be valuable when counseling patients with twins regarding mode of delivery. Synopsis: Twin pregnancies are associated with a greater risk of intrapartum cesarean delivery, primarily due to a greater risk of failure of labor to progress. [ABSTRACT FROM AUTHOR]

Homicide involving multiple victims is relatively rare in England and Wales. When it does occur, mental illness is assumed to have played a significant role. However, reliable evidence to support this is often lacking. We aimed to describe the prevalence of multiple homicide and its subgroups: serial murder, mass murder and familicide and the presence of mental disorder. Data were obtained from the Home Office, HM Court Service, the Police National Computer and NHS Trusts. In England and Wales 470 killed multiple victims between 1997 and 2018. Most did not have evidence of mental health symptoms at the time of offence (85%) or a recorded history of mental disorder (69%). Mental disorder was also not found in most serial homicides (90%), mass murders (94%), or familicides (70%). A tenth of all multiple homicide perpetrators had been under the care of mental health services a year before the incident. This finding challenges commonly held views about mental disorders and the stigma that is perpetuated when multiple-victim homicides occur. Low prevalence and low levels of contact with mental health services make preventing multiple homicide difficult. Reducing violence across society by adopting a multi-agency public health approach is recommended. [ABSTRACT FROM AUTHOR]

Patients before and after lung transplantation often have osteoporosis with existing and recent symptomatic insufficiency fractures, which reduce the quality of life and increase general morbidity and mortality. Due to the reduced bone quality with a significantly increased fracture risk, even low-energy trauma results in the risk of acquiring multiple and complex fractures. The rarefied bone substance can be very challenging for subsequent osteosynthetic treatment. Antiosteoporotic medication is always necessary, and osteoanabolic therapy should be discussed in such cases. In the following, we report about the successful osteosynthetic treatment of an immunosuppressed patient with multiple fractures after a fall from low height. To support fracture healing with antiosteoporotic drug therapy, the patient was switched from antiresorptive to osteoanabolic medication, which resulted in complete fracture consolidation over the course of 6 months. There were also no new insufficiency fractures during this period; however, no improvement in bone density was achieved. [ABSTRACT FROM AUTHOR]

There is a lack of data on the role of characteristics of injured vessels on the outcomes of patients with blunt cerebrovascular injuries (BCVIs). The aim of this study was to assess the effect of the number (single vs multiple) of injured vessels on outcomes. This is a retrospective study at two American College of Surgeons Level I trauma centers (2017-2021). Adult (>16 years) trauma patients with BCVIs are included. Injuries were graded by the Denver Scale based on the initial computed tomography angiography (CTA). Early repeat CTA was performed 7 to 10 days after diagnosis. Patients were stratified by the number (single vs multiple) of the involved vessels. Outcomes included progression of BCVIs on repeat CTA, stroke, and in-hospital mortality attributable to BCVIs. Multivariable regression analyses were performed to identify the association between the number of injured vessels and outcomes. A total of 491 patients with 591 injured vessels (285 carotid and 306 vertebral arteries) were identified. Sixty percent were male, the mean age was 44 years, and the median Injury Severity Score was 18 (interquartile range, 11-25). Overall, 18% had multiple-vessel injuries, 16% had bilateral vessel injuries, and 3% had multiple injuries on the same side. The overall rates of progression to higher-grade injuries, stroke, and mortality were 23%, 7.7%, and 8.8%, respectively. On uni- and multivariable analyses, multiple BCVIs were associated with progression to higher-grade injuries on repeat imaging, stroke, and mortality compared with single-vessel injuries. BCVIs with multiple injured vessels are more likely to progress to higher grades on repeat CTA, with multiple injuries independently associated with worse clinical outcomes, compared with those with single injuries. These findings highlight the importance of incorporating the number of injured vessels in clinical decision-making and in defining protocols for repeat imaging. [ABSTRACT FROM AUTHOR]

Introduction Gall stones are currently classified based mainly on their composition. Though some studies have suggested differences in patients with multiple and solitary gallstones, there is sparse data regarding this, leaving a lacuna for research work which could help expand our understanding of the disease. Aim & Objectives Evaluation of difference in presentation, surgical implications and complications between patients of solitary and multiple gall stone disease. Methods 100 patients admitted with and undergoing surgery for cholelithiasis and its complications at Muzaffarnagar Medical College & Hospital, Muzaffarnagar (UP, India) were divided into two groups- those with single gall stones, and those with multiple gall stones. Results In our study, 63 cases had multiple gallstones, while 37 had a single gallstone. No significant difference was found between the two groups with respect to the studied symptoms. However, a significantly higher percentage of patients with multiple stones suffered from acute cholecystitis (p value 0.014), and choledocholithiasis (p value 0.015), as compared to those with single stones. Mucocele was found to be significantly more common in single stone patients (p-value = 0.001). The comparison of the duration of cholecystectomy, prevalence of dense adhesions, and rate of lap to open conversions revealed no statistically significant difference between the two groups. Conclusion While differential rates of some complications were observed between patients with single and multiple gall stones, the symptom profile was similar and no significant difference between the two groups regarding operative difficulties could be illustrated. [ABSTRACT FROM AUTHOR]

The versatility of cytochrome P450 reductase (CPR) in transferring electrons to P450s from other closely related species has been extensively exploited, e.g., by using An. gambiae CPR (AgCPR), as a homologous surrogate, to validate the role of An. funestus P450s in insecticide resistance. However, genomic variation between the AgCPR and An. funestus CPR (AfCPR) suggests that the full metabolism spectrum of An. funestus P450s might be missed when using AgCPR. To test this hypothesis, we expressed AgCPR and AfCPR side-by-side with CYP6P9a and CYP6P9b and functionally validated their role in the detoxification of insecticides from five different classes. Major variations were observed within the FAD- and NADP-binding domains of AgCPR and AfCPR, e.g., the coordinates of the second FAD stacking residue AfCPR-Y456 differ from that of AgCPR-His456. While no significant differences were observed in the cytochrome c reductase activities, when co-expressed with their endogenous AfCPR, the P450s significantly metabolized higher amounts of permethrin and deltamethrin, with CYP6P9b-AfCPR membrane metabolizing α-cypermethrin as well. Only the CYP6P9a-AfCPR membrane significantly metabolized DDT (producing dicofol), bendiocarb, clothianidin, and chlorfenapyr (bioactivation into tralopyril). This demonstrates the broad substrate specificity of An. funestus CYP6P9a/-b, capturing their role in conferring cross-resistance towards unrelated insecticide classes, which can complicate resistance management. [ABSTRACT FROM AUTHOR]

The paper develops a multiple matching attenuation method based on extended filtering in the curvelet domain, which combines the traditional Wiener filtering method with the matching attenuation method in curvelet domain. Firstly, the method uses the predicted multiple data to generate the Hilbert transform records, time derivative records and time derivative records of Hilbert transform. Then, the above records are transformed into the curvelet domain and multiple matching attenuation based on least squares extended filtering is performed. Finally, the attenuation results are transformed back into the time-space domain. Tests on the model data and field data show that the method proposed in the paper effectively suppress the multiples while preserving the primaries well. Furthermore, it has higher accuracy in eliminating multiple reflections, which is more suitable for the multiple attenuation tasks in the areas with complex structures compared to the time-space domain extended filtering method and the conventional curvelet transform method. [ABSTRACT FROM AUTHOR]

The diagnosis and treatment of gliomas have traditionally been both a research hotspot and a challenge in clinical medicine. Intracranial multiple gliomas are rare, and their diagnosis and treatment are often more difficult than those of solitary gliomas. In this article, we report our experience with the diagnosis and treatment of a case of intracranial multiple glioblastomas that closely resembled metastatic tumors in terms of neuroimaging and anatomy. This case may provide a useful reference and insight into the clinical management of this type of disease.

ObjectivesMultidrug-resistant TB (MDR-TB) is a severe burden and public health threat worldwide. This study aimed to develop a radiomics model based on the tree-in-bud (TIB) sign and nodules and validate its predictive performance for MDR-TB.MethodsWe retrospectively recruited 454 patients with proven active TB from two hospitals and classified them into three training and testing cohorts: TIB (n = 295, 102), nodules (n = 302, 97), and their combination (n = 261, 81). Radiomics features relating to TIB and nodules were separately extracted. The maximal information coefficient and recursive feature elimination were used to select informative features per the two signs. Two radiomics models were constructed to predict MDR-TB using a random forest classifier. Then, a combined model was built incorporating radiomics features based on these two signs. The capability of the models in the combined training and testing cohorts was validated with ROC curves.ResultsSixteen features were extracted from TIB and 15 from nodules. The AUCs of the combined model were slightly higher than those of the TIB model in the combined training cohort (0.911 versus 0.877, p > 0.05) and testing cohort (0.820 versus 0.786, p  0.05) and testing cohort (0.820 versus 0.855, p > 0.05).ConclusionsThe CT-based radiomics models hold promise for use as a non-invasive tool in the prediction of MDR-TB.Clinical relevance statementOur study revealed that complementary information regarding MDR-TB can be provided by radiomics based on the TIB sign and nodules. The proposed radiomics models may be new markers to predict MDR in active TB patients.Key points• This is the first study to build, validate, and apply radiomics based on tree-in-bud sign and nodules for the prediction of MDR-TB. • The radiomics model showed a favorable performance for the identification of MDR-TB. • The combined model holds potential to be used as a diagnostic tool in routine clinical practice.

Miller-Dieker syndrome (MDS) is a rare disease characterized by type I lissencephaly, craniofacial dysmorphisms, intellectual disability, seizures, and death in early childhood. We report a case of a premature infant with MDS with an anomalous right coronary artery from the pulmonary artery who developed sudden bowel ischemia. This case prompts the reconsideration of cardiovascular involvement in patients with MDS. In addition, this review highlights key clinical features and reviews the critical manifestations of MDS that persist into childhood. [Pediatr Ann. 2023;52(8):e283-e291.].

Intussusception is a condition in which the proximal segment of the bowel telescopes into the distal segment. 90% of the cases, especially in infants and toddlers, do not have any lead point and are due to lymphoid hypertrophy, following a viral infection. The presence of polyps in the form of lead point in children is rare. In fact, multiple polyps presenting as multiple sites intussusception are much rarer. We report a case of multiple intussusceptions in a 11-year-old female who presented with complaints of pain abdomen and blood-mixed stool. On imaging examination, she was found to having multiple polyps serving as a possible lead point, and was managed with hydroreduction. Imaging in case of multiple intussusception typically reveals concentric rings of bowel within the bowel giving a “target sign” on axial scans and a “pseudo-kidney sign” on coronal/sagittal CT scans. Our case report shows that, multiple intussusception due to multiple polyps can be a possibility for acute pain abdomen in children.

Prediction models help to target patients at risk of multidrug-resistant organism (MDRO) colonization or infection and could serve as tools informing clinical practices to prevent MDRO transmission and inappropriate empiric antibiotic therapy. However, there is limited evidence to identify which among the available models are of low risk of bias and suitable for clinical application. To identify, describe, appraise, and summarise the performance of all prognostic and diagnostic models developed or validated for predicting MDRO colonization or infection. Six electronic literature databases and clinical registration databases were searched until April 2022. Development and validation studies of any multivariable prognostic and diagnostic models to predict MDRO colonization or infection in adults. Adults (≥ 18 years old) without MDRO colonization or infection (in prognostic models) or with unknown or suspected MDRO colonization or infection (in diagnostic models). The Prediction Model Risk of Bias Assessment Tool was used to assess the risk of bias. Evidence certainty was assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach. Meta-analyses were conducted to summarize the discrimination and calibration of the models' external validations conducted in at least two non-overlapping datasets. We included 162 models (108 studies) developed for diagnosing (n = 135) and predicting (n = 27) MDRO colonization or infection. Models exhibited a high-risk of bias, especially in statistical analysis. High-frequency predictors were age, recent invasive procedures, antibiotic usage, and prior hospitalization. Less than 25% of the models underwent external validations, with only seven by independent teams. Meta-analyses for one diagnostic and two prognostic models only produced very low to low certainty of evidence. The review comprehensively described the models for identifying patients at risk of MDRO colonization or infection. We cannot recommend which models are ready for application because of the high-risk of bias, limited validations, and low certainty of evidence from meta-analyses, indicating a clear need to improve the conducting and reporting of model development and external validation studies to facilitate clinical application. [ABSTRACT FROM AUTHOR]

Many patients suffer from osteoarthritis (OA) in multiple joints, possibly resulting in multiple joint arthroplasties (MJAs). Primarily, we determined the cumulative incidence (C in) of MJA in hip and knee joints up to 10 years. Secondly, we calculated the mean time between the first and subsequent joint arthroplasty, and evaluated the different MJA trajectories. Lastly, we compared patient characteristics and outcomes (functionality and pain) after surgery between MJA patients and single hip arthroplasty or knee arthroplasty (HA and KA) patients. Primary index (first) HA or KA for OA were extracted from the Dutch Arthroplasty Register. The 1, 2, 5, and 10-year C in (including competing risk death) of MJA, mean time intervals, and MJA-trajectories were calculated and stratified for primary index HA or KA. Sex, preoperative age, and body mass index were compared using ordinal logistic regression. Outcomes, measured preoperatively, 3, 6, and 12 months postoperatively (function: Hip Disability or Knee Injury and OA Outcome Score; Pain: Numerical Rating Scale), were compared using linear regression. A total of 140,406 HA-patients and 140,268 KA-patients were included. One, 2, 5, and 10-year C in for a second arthroplasty were respectively 8.9% [95% confidence interval (CI): 8.7 to 9.0], 14.3% [95% CI: 14.1 to 14.5], 24.0% [95% CI: 23.7 to 24.2], and 32.7% [95% CI: 32.2 to 33.1] after index HA, and 9.5% [95% CI: 9.4 to 9.7], 16.0% [95% CI: 15.9 to 16.2], 26.4% [95% CI: 26.1 to 26.6], and 35.8% [95% CI: 35.4 to 36.3] after index KA. The 10-year C in for > 2 arthroplasties were small in both the index HA and KA groups. Time-intervals from first to second, third, and fourth arthroplasty were 26 [95% CI: 26.1 to 26.7], 47 [95% CI: 46.4 to 48.4], and 58 [95% CI: 55.4 to 61.1] months after index HA, and 26 [95% CI: 25.9 to 26.3], 52 [95% CI: 50.8 to 52.7], and 61 [95% CI: 58.3 to 63.4] months after index KA. There were 83% of the second arthroplasties placed in the contralateral cognate joint (ie, knee or hip). Differences in postoperative functionality and pain between MJAs and single HAs and KAs were small. The 10-year C in showed that about one-third of patients received a second arthroplasty after approximately 2 years, with the majority in the contralateral cognate joint. Few patients received > 2 arthroplasties within 10 years. Being a women, having a higher body mass index, and being younger increased the odds of MJA. Postoperative outcomes were slightly negatively affected by MJA. [ABSTRACT FROM AUTHOR]

Background: Basal cell carcinoma (BCC) cases exhibit variations in tumour number, location, and growth patterns. While some patients develop only one BCC, approximately one-third of patients later develop one or more additional lesions. Aims: The aim of the study was to identify risk factors for further BCC lesions in patients with different phenotypic presentations. Materials and Methods: We retrospectively evaluated 1052 histopathologically diagnosed tumours of 861 patients, who were divided into four phenotypic presentation groups according to tumour number at initial diagnosis and during follow-up. Age, sex, tumour characteristics, surgical margins, re-excision and residual tumour rates were compared. Univariate and multivariate logistic regression analyses were performed to determine risk factors for multiple tumour development. Results: There were 723 patients in the single presentation phenotype 1 (SPP1) group, 19 in the SPP-more group, 114 in the multiple presentation phenotype (MPP)-cluster initial group, and five patients in the MPP-cluster later group. Male sex was more common in the MPP-cluster later group (P = 0.028). The mean age was lower in the SPP1 and SPP-more groups (P = 0.002). Ear involvement was more common in the MPP-cluster later group (P < 0.05). Superficial and basosquamous subtypes were more common in the SPP-more and MPP-cluster later groups (P < 0.05). Re-excision and residual tumour rates were lowest in the SPP1 group (P < 0.05). Age over 69 years, male sex, and periorbital or upper extremity location were significant risk factors for multiple tumour development (P < 0.05). Limitations: The limitations of our study include the inability to evaluate environmental risk factors, phenotypic and ethnic characteristics, and the short follow-up period for newly added patients. Conclusions: Predicting different phenotypic presentations by taking the age, gender, and tumour characteristics (localization, histopathological subtype) of the patients into account may allow new tumours to be detected at an early stage.

Objective Design Setting Population Methods Main Outcome Measures Results Conclusions To identify current practices in the management of selective fetal growth restriction (sFGR) in monochorionic diamniotic (MCDA) twin pregnancies.Cross‐sectional survey.International.Clinicians involved in the management of MCDA twin pregnancies with sFGR.A structured, self‐administered survey.Clinical practices and attitudes to diagnostic criteria and management strategies.Overall, 62.8% (113/180) of clinicians completed the survey; of which, 66.4% (75/113) of the respondents reported that they would use an estimated fetal weight (EFW) of <10th centile for the smaller twin and an inter‐twin EFW discordance of >25% for the diagnosis of sFGR. For early‐onset type I sFGR, 79.8% (75/94) of respondents expressed that expectant management would be their routine practice. On the other hand, for early‐onset type II and type III sFGR, 19.3% (17/88) and 35.7% (30/84) of respondents would manage these pregnancies expectantly, whereas 71.6% (63/88) and 57.1% (48/84) would refer these pregnancies to a fetal intervention centre or would offer fetal intervention for type II and type III cases, respectively. Moreover, 39.0% (16/41) of the respondents would consider fetoscopic laser surgery (FLS) for early‐onset type I sFGR, whereas 41.5% (17/41) would offer either FLS or selective feticide, and 12.2% (5/41) would exclusively offer selective feticide. For early‐onset type II and type III sFGR cases, 25.9% (21/81) and 31.4% (22/70) would exclusively offer FLS, respectively, whereas 33.3% (27/81) and 32.9% (23/70) would exclusively offer selective feticide.There is significant variation in clinician practices and attitudes towards the management of early‐onset sFGR in MCDA twin pregnancies, especially for type II and type III cases, highlighting the need for high‐level evidence to guide management. [ABSTRACT FROM AUTHOR]

Keyhole surgery has been widely used to clip various intracranial aneurysms. Here, the feasibility of microsurgical clipping of multiple intracranial aneurysms via the keyhole approach was further investigated. The clinical data of 80 patients with multiple intracranial aneurysms treated with keyhole surgery were retrospectively analyzed. The patients included 25 males and 55 females, with an average age of 57.5 years. There were 13 patients with unruptured aneurysms, 67 patients with ruptured aneurysms (small aneurysms accounted for 52.2% of ruptured aneurysms), and a total of 198 aneurysms. A 4 cm incision and a bone hole of approximately 2.5 cm were used per craniotomy standards. Forty-eight cases were treated via the supraorbital keyhole approach, 45 cases via the pterional keyhole approach, and 3 cases via the interhemispheric keyhole approach. A bilateral and unilateral keyhole approach was applied in 18 and 62 cases, respectively. A total of 170 ipsilateral and 7 contralateral aneurysms were clipped. The complete clipping rate was 98.9%. During the follow-up period of 6–12 months after surgery, the Glasgow outcome scale score was 5 points in 74 cases, 4 points in 5 cases, and 3 points in 1 case. The prognosis was associated with the preoperative Hunt–Hess classification but not with the number of operative sides, the operation opportunity, or the number of clipped aneurysms. Early keyhole surgical clipping of multiple intracranial aneurysms is an effective treatment. Among ruptured aneurysms, small aneurysms are common and need attention and timely treatment. [ABSTRACT FROM AUTHOR]

The species included in the ESKAPE group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and the genus Enterobacter) have a high capacity to develop antimicrobial resistance (AMR), a health problem that is already among the leading causes of death and could kill 10 million people a year by 2050. The generation of new potentially therapeutic molecules has been insufficient to combat the AMR "crisis", and the World Health Organization (WHO) has stated that it will seek to promote the development of rapid diagnostic strategies. The physicochemical properties of metallic nanoparticles (MNPs) have made it possible to design biosensors capable of identifying low concentrations of ESKAPE bacteria in the short term; other systems identify antimicrobial susceptibility, and some have been designed with dual activity in situ (bacterial detection and antimicrobial activity), which suggests that, in the near future, multifunctional biosensors could exist based on MNPs capable of quickly identifying bacterial pathogens in clinical niches might become commercially available. This review focuses on the use of MNP-based systems for the rapid and accurate identification of clinically important bacterial pathogens, exhibiting the necessity for exhaustive research to achieve these objectives. This review focuses on the use of metal nanoparticle-based systems for the rapid and accurate identification of clinically important bacterial pathogens. [ABSTRACT FROM AUTHOR]

It is indisputable that some type of coordinate measurement system (CMS) is generally used to assess the quality of dimensional and geometric characteris- tics. Considering the required accuracy, flexibility, and speed of measurement, a CMM with a scanning sensor may offer the best performance. These measurement systems are very complex, and many factors affect the reliability of the measurement results. A Metrologist's choice represents the greatest variability in the measurement strategy. Previous research has shown that the measurement results can be changed up to 100 % by choosing a different measurement strategy when evaluating the form error. This paper conducts a detailed study of the impact of the measurement strategy on the cylindricity error when measuring eleven workpieces with the same nominal characteristics, but different real characteristics described by roughness and the reference value of cylindricity. To examine the influence and importance of certain factors and their levels, design of experiment (DoE) and unsupervised machine learning techniques of PCA (Principal Component Analysis) and Multiple Correspondence Analysis (MCA), were used. The results suggest that depending on the real ge- ometry of the workpiece, different factors with different percentages influence the output characteristic. The objective was to choose a uniform measurement strategy when measuring cylindricity on the CMM, while the prior information about the actual geometry of the workpiece is lacking. [ABSTRACT FROM AUTHOR]

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Purpose: To present our initial experience in the management of multiple ureteral polyps with robotic or laparoscopic ileal ureter replacement (IUR). Methods: Eight consecutive patients diagnosed with multiple ureteral polyps underwent robotic or laparoscopic IUR between July 2019 and November 2022. Unilateral IUR was performed in 5 patients with polyps in the left (n = 3) or right (n = 2) side, and 3 patients with bilateral multiple polyps underwent bilateral IUR. Demographic characteristics, perioperative data and follow-up outcomes were prospectively collected. Results: A cohort of 5 male and 3 female patients (11 ureters) with a mean age of 32.8 ± 11.3 years were included. Among these patients, 5 presented with recurrent flank pain, 1 had hematuria, and 2 were asymptomatic. Four patients experienced prior failed surgical interventions. The mean length of diseased ureter was 11.9 ± 4.7 cm, with more than 10 cm in eight sides. All procedures were performed successfully. The mean operation time was 319 ± 87.6 min with 3 patients who simultaneously underwent intraoperative ureteroscopy. The mean length of ileal graft was 23.8 ± 5.8 cm. During the mean follow-up of 20.4 ± 12.8 months, one major complication, specifically incision infection, and four minor complications, including urinary infection (n = 3) and metabolic acidosis (n = 1), were observed. All patients presented symptom-free, with improved/stabilized hydronephrosis and no signs of restenosis. Conclusion: Robotic or laparoscopic IUR is a feasible, safe, and effective surgical option for patients with long ureteral defects caused by multiple polyps. [ABSTRACT FROM AUTHOR]

Background: Inflammatory myofibroblastic tumors (IMTs) are uncommon neoplasms most prevalent in individuals under 40 years old and predominantly in the lungs. Despite their rarity, multiple anaplastic lymphoma kinase (ALK)-positive IMTs, especially those of various sizes, have not been widely reported. This report describes a case of multiple ALK-positive IMTs in the lungs, aiming to further our understanding of their behavior and management. Case presentation: Herein, we present the case of a 64-year-old woman who presented with an abnormal shadow on chest examination. Chest computed tomography revealed a main tumor in the right middle lobe and multiple irregularly shaped small nodules in both lungs. Thus, thoracoscopic wedge resection of the left lower lobe was performed for diagnosis. Pathological findings indicated smooth muscle proliferation without malignancy. IMT was diagnosed following thoracoscopic right middle lobectomy. Twenty months postoperatively, one residual nodule shrank, but another grew. Conclusions: This is the first report of multiple ALK-positive IMTs in both lungs, highlighting the need for definitive diagnosis and treatment of IMTs based on surgical resection. Although caution is required in patients with lymph node metastases or distant metastases, careful follow-up is acceptable unless there is a tendency for nodules to increase in size on imaging. [ABSTRACT FROM AUTHOR]

Background: Basal cell carcinoma (BCC) cases exhibit variations in tumour number, location, and growth patterns. While some patients develop only one BCC, approximately one-third of patients later develop one or more additional lesions. Aims: The aim of the study was to identify risk factors for further BCC lesions in patients with different phenotypic presentations. Materials and Methods: We retrospectively evaluated 1052 histopathologically diagnosed tumours of 861 patients, who were divided into four phenotypic presentation groups according to tumour number at initial diagnosis and during follow-up. Age, sex, tumour characteristics, surgical margins, re-excision and residual tumour rates were compared. Univariate and multivariate logistic regression analyses were performed to determine risk factors for multiple tumour development. Results: There were 723 patients in the single presentation phenotype 1 (SPP1) group, 19 in the SPP-more group, 114 in the multiple presentation phenotype (MPP)-cluster initial group, and five patients in the MPP-cluster later group. Male sex was more common in the MPP-cluster later group (P = 0.028). The mean age was lower in the SPP1 and SPP-more groups (P = 0.002). Ear involvement was more common in the MPP-cluster later group (P < 0.05). Superficial and basosquamous subtypes were more common in the SPP-more and MPP-cluster later groups (P < 0.05). Re-excision and residual tumour rates were lowest in the SPP1 group (P < 0.05). Age over 69 years, male sex, and periorbital or upper extremity location were significant risk factors for multiple tumour development (P < 0.05). Limitations: The limitations of our study include the inability to evaluate environmental risk factors, phenotypic and ethnic characteristics, and the short follow-up period for newly added patients. Conclusions: Predicting different phenotypic presentations by taking the age, gender, and tumour characteristics (localization, histopathological subtype) of the patients into account may allow new tumours to be detected at an early stage. [ABSTRACT FROM AUTHOR]

Objective: By presenting a case study on multiple instances of Bowen's disease and the consistent use of narrow‐band ultraviolet B (NB‐UVB) phototherapy over a three‐year period, our aim is to enhance the comprehension of domestic clinicians regarding the disease. Additionally, we seek to review existing literature, encouraging dermatologists to consider clinical secondary primary lesion diagnoses. Method: Our approach involves analyzing a diagnosed case of multiple Bowen's disease, examining clinical manifestations, histopathology, imaging results, and treatment methods related to NB‐UVB phototherapy. We aim to facilitate discussion and understanding through a comprehensive literature analysis. Results: An elderly male with a 30‐year history of psoriasis vulgaris initiated continuous NB‐UVB therapy three years ago. A year later, he developed red patches and plaques with distinct borders and scaly surfaces on his face, trunk, lower extremities, and scrotum. Histopathological examination confirmed Bowen's disease. Treatment involved liquid nitrogen cryotherapy, with no recurrence observed during the one‐year follow‐up. Conclusion: This case highlights that Bowen's disease, typically solitary, can manifest as multiple instances, especially in individuals with a history of psoriasis vulgaris. While NB‐UVB stands as the primary treatment for psoriasis vulgaris, caution is warranted due to the potential risk of skin tumor induction with prolonged high‐dose usage. Clinicians should be vigilant in monitoring and assessing the long‐term implications of such therapies. [ABSTRACT FROM AUTHOR]

BACKGROUND: Antibacterial resistance is a growing concern worldwide, including in Mozambique. Diarrhea is an important cause of mortality in Mozambique, yet few local studies have reported on the resistance of bacterial pathogens in this context. Therefore, this study aims to characterize antibiotic susceptibility patterns of Salmonella, Shigella and Campylobacter spp. among patients with diarrhea, including those who are HIV-infected and-uninfected. METHODS: We conducted antibiotic susceptibility testing on 157 stool isolates recovered from 129 patients aged between 0 and 80 years with diarrhea, including HIV infected (n = 68) and-uninfected individuals (n = 61), assisted at two health centers in Maputo city. The isolates comprised of 99 Salmonella, 45 Shigella and 13 Campylobacter strains. The Kirby-Bauer disk diffusion method was used on Mueller-Hinton II agar for Salmonella and Shigella spp., while Mueller-Hinton II agar with 5% defibrinated sheep blood was used for Campylobacter spp. We tested six antibiotics listed on the national essential medicines list, including ciprofloxacin, erythromycin, azithromycin, trimethoprim-sulfamethoxazole, gentamicin, and tetracycline. RESULTS: All isolates were resistant to at least one antibiotic. A high percentage of Salmonella spp. isolates were found to be resistant to trimethoprim-sulfamethoxazole (89.9%, n = 89), erythromycin (88.9%, n = 88) and tetracycline (76.8%, n = 76). In addition, 86.6% (n = 39) and 68.9% (n = 31) of Shigella isolates were resistant to trimethoprim-sulfamethoxazole and tetracycline, respectively. The majority of Campylobacter isolates (92.3%, n = 12) were resistant to erythromycin, azithromycin and tetracycline. Multidrug resistance (MDR) was observed in 79.8% of Salmonella spp., 76.9% of Campylobacter spp., and 57.8% of Shigella spp. Drug susceptibility profiles for Salmonella spp. and Campylobacter were similar in both HIV-1 infected and uninfected patients. However, Shigella spp. isolates obtained from patients without HIV infection were significantly more likely to be resistant to erythromycin, azithromycin or to exhibit multidrug resistance than those obtained from patients with HIV-1 infection (p

While the goal of universal drug susceptibility testing has been a key component of the WHO End TB Strategy, in practice, this remains inaccessible to many. Rapid molecular tests for tuberculosis (TB) and antituberculosis drug resistance could significantly improve access to testing. In this study, we evaluated the accuracy of the Akonni Biosystems XDR-TB (extensively drug-resistant TB) TruArray and lateral-flow-cell (XDR-LFC) assay (Akonni Biosystems, Inc., Frederick, MD, USA), a novel assay that detects mutations in seven genes associated with resistance to antituberculosis drugs: katG, the inhA promoter, and the ahpC promoter for isoniazid; rpoB for rifampin; gyrA for fluoroquinolones; rrs and the eis promoter for kanamycin; and rrs for capreomycin and amikacin. We evaluated assay performance using direct sputum samples from 566 participants recruited in a prospective cohort in Moldova over 2 years. The sensitivity and specificity against the phenotypic reference were both 100% for isoniazid, 99.2% and 97.9% for rifampin, 84.8% and 99.1% for fluoroquinolones, 87.0% and 84.1% for kanamycin, 54.3% and 100% for capreomycin, and 79.2% and 100% for amikacin, respectively. Whole-genome sequencing data for a subsample of 272 isolates showed 95 to 99% concordance with the XDR-LFC-reported suspected mutations. The XDR-LFC assay demonstrated a high level of accuracy for multiple drugs and met the WHO's minimum target product profile criteria for isoniazid and rifampin, while the sensitivity for fluoroquinolones and amikacin fell below target thresholds, likely due to the absence of a gyrB target in the assay. With optimization, the XDR-LFC shows promise as a novel near-patient technology to rapidly diagnose drug-resistant tuberculosis.

BackgroundAntimicrobial resistance (AMR) poses a critical threat to public health and disproportionately affects the health and well-being of persons in low-income and middle-income countries. Our aim was to identify synthetic antimicrobials termed conjugated oligoelectrolytes (COEs) that effectively treated AMR infections and whose structures could be readily modified to address current and anticipated patient needs.MethodsFifteen chemical variants were synthesized that contain specific alterations to the COE modular structure, and each variant was evaluated for broad-spectrum antibacterial activity and for in vitro cytotoxicity in cultured mammalian cells. Antibiotic efficacy was analyzed in murine models of sepsis; in vivo toxicity was evaluated via a blinded study of mouse clinical signs as an outcome of drug treatment.FindingsWe identified a compound, COE2-2hexyl, that displayed broad-spectrum antibacterial activity. This compound cured mice infected with clinical bacterial isolates derived from patients with refractory bacteremia and did not evoke bacterial resistance. COE2-2hexyl has specific effects on multiple membrane-associated functions (e.g., septation, motility, ATP synthesis, respiration, membrane permeability to small molecules) that may act together to negate bacterial cell viability and the evolution of drug-resistance. Disruption of these bacterial properties may occur through alteration of critical protein-protein or protein-lipid membrane interfaces-a mechanism of action distinct from many membrane disrupting antimicrobials or detergents that destabilize membranes to induce bacterial cell lysis.InterpretationThe ease of molecular design, synthesis and modular nature of COEs offer many advantages over conventional antimicrobials, making synthesis simple, scalable and affordable. These COE features enable the construction of a spectrum of compounds with the potential for development as a new versatile therapy for an imminent global health crisis.FundingU.S. Army Research Office, National Institute of Allergy and Infectious Diseases, and National Heart, Lung, and Blood Institute.

BackgroundLiveborn infants with non-mosaic trisomy 22 are rarely described in the medical literature. Reported lifespan of these patients ranges from minutes to 3 years, with the absence of cardiac anomalies associated with longer-term survival. The landscape for offering cardiac surgery to patients with rare autosomal trisomies is currently evolving, as has been demonstrated recently in trisomies 13 and 18. However, limited available data on patients with rare autosomal trisomies provides a significant challenge in perinatal counseling, especially when there are options for surgical intervention.Case presentationIn this case report, we describe an infant born at term with prenatally diagnosed apparently non-mosaic trisomy 22 and multiple cardiac anomalies, including a double outlet right ventricle, hypoplastic aortic valve and severe aortic arch hypoplasia, who underwent cardiac surgery. The decisions made by her family lending to her progress and survival to this day were made with a focus on the shared decision making model and support in the prenatal and perinatal period. We also review the published data on survival and quality of life after cardiac surgery in infants with rare trisomies.ConclusionsThis patient is the only known case of apparently non-mosaic trisomy 22 in the literature who has undergone cardiac surgery with significant survival benefit. This case highlights the impact of using a shared decision making model when there is prognostic uncertainty.

Antimicrobial resistance in urinary tract infections (UTIs) is a major public health concern. This study aims to characterize the phenotypic and genetic basis of multidrug resistance (MDR) among expanded-spectrum cephalosporin-resistant (ESCR) uropathogenic Escherichia coli (UPEC) causing UTIs in California patient populations. Between February and October 2019, 577 ESCR UPEC isolates were collected from patients at 6 clinical laboratory sites across California. Lineage and antibiotic resistance genes were determined by analysis of whole-genome sequence data. The lineages ST131, ST1193, ST648, and ST69 were predominant, representing 46%, 5.5%, 4.5%, and 4.5% of the collection, respectively. Overall, 527 (91%) isolates had an expanded-spectrum β-lactamase (ESBL) phenotype, with blaCTX-M-15, blaCTX-M-27, blaCTX-M-55, and blaCTX-M-14 being the most prevalent ESBL genes. In the 50 non-ESBL phenotype isolates, 40 (62%) contained blaCMY-2, which was the predominant plasmid-mediated AmpC (pAmpC) gene. Narrow-spectrum β-lactamases, blaTEM-1B and blaOXA-1, were also found in 44.9% and 32.1% of isolates, respectively. Among ESCR UPEC isolates, isolates with an ESBL phenotype had a 1.7-times-greater likelihood of being MDR than non-ESBL phenotype isolates (P < 0.001). The cooccurrence of blaCTX-M-15, blaOXA-1, and aac(6')-Ib-cr within ESCR UPEC isolates was strongly correlated. Cooccurrence of blaCTX-M-15, blaOXA-1, and aac(6')-Ib-cr was associated with an increased risk of nonsusceptibility to piperacillin-tazobactam, cefepime, fluoroquinolones, and amikacin as well as MDR. Multivariate regression revealed the presence of blaCTX-M-55, blaTEM-1B, and the ST131 genotype as predictors of MDR. IMPORTANCE The rising incidence of resistance to expanded-spectrum cephalosporins among Escherichia coli strains, the most common cause of UTIs, is threatening our ability to successfully empirically treat these infections. ESCR E. coli strains are often MDR; therefore, UTI caused by these organisms often leads to treatment failure, increased length of hospital stay, and severe complications (D. G. Mark, Y.-Y. Hung, Z. Salim, N. J. Tarlton, et al., Ann Emerg Med 78:357-369, 2021, https://doi.org/10.1016/j.annemergmed.2021.01.003). Here, we performed an in-depth analysis of genetic factors of ESCR E. coli associated with coresistance and MDR. Such knowledge is critical to advance UTI diagnosis, treatment, and antibiotic stewardship.

BackgroundSleep disturbance is common, impairing, and may affect symptomatology in developmental neuropsychiatric disorders. Here, we take a genetics-first approach to study the complex role of sleep in psychopathology. Specifically, we examine severity of sleep disturbance in individuals with a reciprocal copy number variant (CNV) at the 22q11.2 locus and determine sleep's effect on psychiatric symptoms. CNVs (deletion or duplication) at this locus confer some of the greatest known risks of neuropsychiatric disorders; recent studies suggest the 22q11.2 deletion negatively impacts sleep, but sleep disruption associated with 22q11.2 duplication has not been investigated.MethodsWe compared subjective sleep disturbance and its relationship to psychiatric symptoms cross-sectionally and longitudinally over 1 year in 107 22q11.2 deletion (22qDel) carriers (14.56±8.0 years; 50% male), 42 22q11.2 duplication (22qDup) carriers (16.26±13.1 years; 54.8% male), and 88 age- and sex-matched controls (14.65±7.4 years; 47.1% male). Linear mixed models were used to compare sleep disturbance, assessed via the Structured Interview for Psychosis-Risk Syndromes (SIPS), across groups. Next, CNV carriers were categorized as good or poor sleepers to investigate sleep effects on multiple neurobehavioral traits: psychosis-risk symptoms (SIPS), autism-related behaviors (Repetitive Behavior Scale (RBS) and Social Responsiveness Scale (SRS)), real-world executive function (Behavior Rating Inventory of Executive Function (BRIEF)), and emotional/behavioral problems (Child Behavior Checklist (CBCL)). Linear mixed models tested the effect of sleep category and a group-by-sleep interaction on each measure, cross-sectionally and longitudinally.Results22qDel and 22qDup carriers both reported poorer sleep than controls, but did not differ from each other. Cross-sectionally and longitudinally, poor sleepers scored higher on positive symptoms, anxious/depressed, somatic complaints, thought problems, and aggressive behavior, as well as RBS and SRS total scores. There were significant group-by-sleep interactions for positive symptoms and the majority of CBCL subdomains, in which the difference between good and poor sleepers was larger in 22qDel compared to 22qDup.ConclusionsOur findings indicate that CNVs at the 22q11.2 locus impact sleep which, in turn, influences psychopathology. Sleep disturbances can differentially impact psychopathology, depending on 22q11.2 gene dosage. Our findings serve as a starting point for exploring a genetic basis for sleep disturbance in developmental neuropsychiatric disorders.

BackgroundKDM6A is a demethylase encoded by a gene with female-biased expression due to escape from X inactivation. Its main role is to facilitate gene expression through removal of the repressive H3K27me3 mark, with evidence of some additional histone demethylase-independent functions. KDM6A mutations have been implicated in congenital disorders such as Kabuki Syndrome, as well as in sex differences in cancer.MethodsKdm6a was knocked out using CRISPR/Cas9 gene editing in F1 male and female mouse embryonic stem cells (ES) derived from reciprocal crosses between C57BL6 x Mus castaneus. Diploid and allelic RNA-seq analyses were done to compare gene expression between wild-type and Kdm6a knockout (KO) clones. The effects of Kdm6a KO on sex-biased gene expression were investigated by comparing gene expression between male and female ES cells. Changes in H3K27me3 enrichment and chromatin accessibility at promoter regions of genes with expression changes were characterized by ChIP-seq and ATAC-seq followed by diploid and allelic analyses.ResultsWe report that Kdm6a KO in male and female embryonic stem (ES) cells derived from F1 hybrid mice cause extensive gene dysregulation, disruption of sex biases, and specific parental allele effects. Among the dysregulated genes are candidate genes that may explain abnormal developmental features of Kabuki syndrome caused by KDM6A mutations in human. Strikingly, Kdm6a knockouts result in a decrease in sex-biased expression and in preferential downregulation of the maternal alleles of a number of genes. Most promoters of dysregulated genes show concordant epigenetic changes including gain of H3K27me3 and loss of chromatin accessibility, but there was less concordance when considering allelic changes.ConclusionsOur study reveals new sex-related roles of KDM6A in the regulation of developmental genes, the maintenance of sex-biased gene expression, and the differential expression of parental alleles.

Purpose: Cancer, the second leading cause of mortality worldwide, represents a global health challenge, primarily due to drug resistance. Vinorelbine is a chemotherapeutic agent that disrupts cancer cell growth by targeting microtubules and inducing apoptosis. However, drug resistance remains a formidable obstacle. This resistance is caused by various factors including genetic mutations, drug efflux mechanisms, and DNA repair systems. Resolution of this challenge requires an innovative approach. This study investigated the potential of small interfering RNA (siRNA) to target and downregulate a vinorelbine-resistant MCF-7/ADR breast cancer cell line. Methods: Cells were cultured in Dulbecco's modified Eagle's medium (DMEM) 10% fetal bovine serum/penicillin/streptomycin. An siRNA targeting ABCB1 was designed and synthesized, and the cells were transfected with siRNA at final concentrations of 10, 20, and 30 nM. The3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to assess cell viability. ABCB1 mRNA expression levels were determined by real-time polymerase chain reaction (PCR). Results: MCF-7 cells exhibited a higher sensitivity to vinorelbine than MCF-7/ADR cells. MCF-7/ADR cells exhibited resistance to vinorelbine at concentrations, 12.50 and 25.00 μM. Treatment with siRNA significantly reduced ABCB1 expression by 2.93-fold (P =0.0001). Similarly, co-treatment with siRNA and vinorelbine produced a substantial 2.89-fold decrease in ABCB1 gene expression in MCF-7 cells compared to that in MCF-7/ADR cells (P =0.0001). Conclusion: The results of the present study indicate that the concurrent use of siRNA and vinorelbine holds substantial promise as a therapeutic approach to overcome ABCB1-mediated multidrug resistance (MDR) in breast cancer. It is necessary to conduct comprehensive clinical trials to determine the true effectiveness of this combination therapy. [ABSTRACT FROM AUTHOR]

BACKGROUND: Synovial chondromatosis is a non-malignant synovial disorder characterized by the presence of cartilage formation within the synovial membrane, leading to the emergence of multiple cartilaginous nodules that may be either attached or unattached. The presence of this anatomical feature is frequently observed in articulations such as the knee, hip, elbow, and ankle. CASE REPORT: In this study, we present a case of synovial chondromatosis in the knee joint of a healthy male in his early 60s. Notably, the patient exhibited the simultaneous presence of 87 large loose bodies. The occurrence of a substantial quantity of unattached entities of notable dimensions within the joint is highly uncommon. CONCLUSIONS: The patient had several synovial chondromas, a rare disease. Synovial chondromatosis is a benign disorder; however, growing synovium can cause pyogenic cartilage nodules. Most loose bodies in joints can abrade and degenerate articular cartilage, causing long-term discomfort. Thus, an early-stage procedure to remove loose bodies and carefully excise synovial tissue is necessary to treat this condition. [ABSTRACT FROM AUTHOR]

The enhancement of energy systems in industrial zones is attracting the attention of researchers from all over the world. At the same time, optimization and advancement in heat recovery systems are now generating major interest in the energy sector. In this context, the present study suggests a new multiple heat recovery system should be applied to an industrial thermal peeling press machine. The new system consists of multiple sources of energy: the heat excess in the chimney, the exhaust gas of the chimney, and the exhaust gas of the boiler. To proceed with testing the potential of the suggested system, a hydraulic thermal peel press machine in the wood industry undergoes different tests to achieve the best configuration that will enable this machine to reach its operational temperature when heating. Five test configurations are proposed, designed, and applied experimentally on this machine. Many parameters were effective during the experimental tests, such as water flow rate, ambient air temperature, and initial water temperature. It was found that the application of the multiple heat recovery system increases the rate of heating from around 7 °C/min to around 13 °C/min. In terms of energy and economy, the "chimney + boiler only" configuration proved to be the best system to apply during the fall and winter seasons. [ABSTRACT FROM AUTHOR]

Simple Summary: Females with PTEN Hamartoma Tumor Syndrome (PHTS) have very high hereditary breast cancer risks up to 76%. The aim of this European cohort study was to the describe the lifestyle in PHTS patients and to assess associations between physical activity, alcohol consumption, tobacco smoking, BMI and breast cancer in female adult PHTS patients. It was observed that of 125 patients who completed the questionnaire, 81% were ≥2 times/week physically active, 86% consumed on average <1 glass of alcohol/day, 78% never smoked and most patients were overweight or obese (72%). In total, 39 developed breast cancer (31%). No indications were found that associations between lifestyle and breast cancer in PHTS patients are different from the general population. These findings suggest that awareness about lifestyle among PHTS patients is important, as a healthier lifestyle could potentially decrease their breast cancer risk in a similar way as for the general population. Females with PTEN Hamartoma Tumor Syndrome (PHTS) have breast cancer risks up to 76%. This study assessed associations between breast cancer and lifestyle in European female adult PHTS patients. Data were collected via patient questionnaires (July 2020–March 2023) and genetic diagnoses from medical files. Associations between lifestyle and breast cancer were calculated using logistic regression corrected for age. Index patients with breast cancer before PHTS diagnosis (breast cancer index) were excluded for ascertainment bias correction. In total, 125 patients were included who completed the questionnaire at a mean age of 44 years (SD = 13). This included 21 breast cancer indexes (17%) and 39 females who developed breast cancer at 43 years (SD = 9). Breast cancer patients performed about 1.1 times less often 0–1 times/week physical activity than ≥2 times (ORtotal-adj = 0.9 (95%CI 0.3–2.6); consumed daily about 1.2–1.8 times more often ≥1 than 0–1 glasses of alcohol (ORtotal-adj = 1.2 (95%CI 0.4–4.0); ORnon-breastcancer-index-adj = 1.8 (95%CI 0.4–6.9); were about 1.04–1.3 times more often smokers than non-smokers (ORtotal-adj = 1.04 (95%CI 0.4–2.8); ORnon-breastcancer-index-adj = 1.3 (95%CI 0.4–4.2)); and overweight or obesity (72%) was about 1.02–1.3 times less common (ORtotal-adj = 0.98 (95%CI 0.4–2.6); ORnon-breastcancer-index-adj = 0.8 (95%CI 0.3–2.7)). Similar associations between lifestyle and breast cancer are suggested for PHTS and the general population. Despite not being statistically significant, results are clinically relevant and suggest that awareness of the effects of lifestyle on patients' breast cancer risk is important. [ABSTRACT FROM AUTHOR]

Introduction: Multiple synchronous spinal extradural arachnoid cysts are extremely rare in children and can lead to cord compression and disability. Multiple spinal extradural arachnoid cysts (SEDACs) in children with immature and growing spine need to be studied separately from multiple SEDACs in adults with mature and fully grown spine because of multiple surgical limitations in children (blood loss, surgery duration, long-term spinal stability after long segment exposure, etc.). Material and methods: We planned a non-systematic literature review of similar cases described in literature to analyse the pattern of presentation, management, and outcome of this surgically curable disease. Results: A total of 28 cases of paediatric multiple SEDACs in the age range of 5 months to 17 years and mean age of 11.54 years were analysed. Exposure was achieved by laminectomy in 9, laminoplastic laminotomy in 13, laminectomy in first surgery followed by laminoplasty in second surgery (re-exploration) in 1, hemilaminectomy in 2, and technique "not reported" in 3 children. Complete/near-complete recovery was seen in 27 (96.42%) children. Postoperative spine deformity was reported in 7 (25%) children and was progressive in 2 children during serial follow-up. Conclusions: Symptomatic multiple synchronous SEDACs in children is a rare surgically curable condition. Sincere attempt to find out a dural defect in all cysts is a very important step in multiple SEDAC surgery. Total cyst wall excision with closure of all dural defects is the gold standard treatment for symptomatic cases. Laminoplasty is preferred for excision of multiple SEDACs in children to prevent postoperative spine deformity during long-term follow-up. Long serial follow-up for postoperative spine deformity is necessary. [ABSTRACT FROM AUTHOR]

Background Risk factors for ciprofloxacin or MDR in primary care urine specimens are not well defined. Objectives We created a primary care-specific antibiogram for Escherichia coli isolates from cases with complicated and uncomplicated urinary tract infection (UTI) and evaluated risk factors for ciprofloxacin, trimethoprim/sulfamethoxazole and MDR among Enterobacterales. Methods We conducted a cross-sectional study to determine resistance and risk factors by collecting urine cultures from all patients (≥18 years) presenting with provider-suspected UTI at two primary care, safety-net clinics in Houston, TX, USA between November 2018 and March 2020. Results Among 1262 cultures, 308 cultures grew 339 uropathogens. Patients with Enterobacterales (n  = 199) were mostly female (93.5%) with a mean age of 48.5 years. E. coli was the predominant uropathogen isolated (n  = 187/339; 55%) and had elevated trimethoprim/sulfamethoxazole (43.6%) and ciprofloxacin (29.5%) resistance, low nitrofurantoin (1.8%) resistance, and no fosfomycin resistance. Among E. coli , 10.6% were ESBL positive and 24.9% had MDR. Birth outside the U.S.A. prior (2 year) trimethoprim/sulfamethoxazole resistance, and diabetes mellitus were associated with trimethoprim/sulfamethoxazole resistance. Prior (60 day) fluoroquinolone use, prior ciprofloxacin resistance and both diabetes mellitus and hypertension were strongly associated with ciprofloxacin resistance. Prior fluoroquinolone use and a history of resistance to any studied antibiotic were associated with MDR, while pregnancy was protective. Conclusions We found elevated resistance to UTI-relevant antimicrobials and novel factors associated with resistance; these data can be incorporated into clinical decision tools to improve organism and drug concordance. [ABSTRACT FROM AUTHOR]

Objectives To characterize the genetic environments of ESBL gene bla VEB-1 in mcr -positive Aeromonas strains from raw meat in China. Methods Whole genomes of Aeromonas strains were sequenced using the Illumina or Nanopore platforms. Genetic environments of bla VEB-1 were analysed using the BLAST program. Results The bla VEB-1 gene was detected in five Aeromonas strains carrying the mcr-7 -like gene. WGS revealed that all bla VEB-1 genes were located on Aeromonas chromosome, and were carried by two novel different genomic islands named Aeromonas veronii genomic islands AveGI1 and AveGI2, as well as one transposon named Tn 7690. AveGI1 is a new member of the Salmonella genomic island 1 family, incorporated into the 3′-end of mnmE (trmE). AveGI2 is a novel genomic island that has a size of 23 180 bp and is incorporated into the 3′-end of syd. The MDR regions of AveGI1 and AveGI2 are two different class 1 integrons containing 10 and five resistance genes, respectively. Tn 7690 is a Tn 1722 derivative containing In4-type integron and Tn 5393 , which harbours 10 resistance genes and integrates into different positions on the chromosomes of three strains with the capacity for mobility. Conclusions We report chromosomally located novel MDR genomic islands and transposon that carry bla VEB-1 in mcr -positive Aeromonas strains. These genetic elements may mediate the spread of bla VEB-1 in Aeromonas , and may also evolve by capturing new antimicrobial resistance genes or other mobile genetic elements. [ABSTRACT FROM AUTHOR]

Objectives Haemophilus parainfluenzae is an opportunistic pathogen causing respiratory tract infection and sexually transmitted diseases. The emergence of multidrug resistance in this species is particularly worrisome, especially since the recent description of CTX-M-15 ESBL-producing isolates in Spain. The aim of this study was to characterize a CTX-M-15-producing H. parainfluenzae clinical isolate, HP01, obtained from a urethral swab. Methods MICs were determined with gradient strips for this isolate. Hydrolysis assays were performed with the β LACTA test. Genomic DNA from HP01 was subjected to Illumina and Oxford Nanopore sequencing to investigate the genetic environment of bla CTX-M-15. Phylogenetic analysis was performed with available H. parainfluenzae genomes from the NCBI database, including CTX-M-15 producers. Results HP01, an XDR isolate, was resistant to penicillin, third-generation cephalosporins, fluoroquinolones, macrolides, cyclines and co-trimoxazole and susceptible only to carbapenems and rifampicin. HP01 carried bla TEM-1, bla CTX-M-15, tet (M), catS and mef (E) /mel and harboured amino acid substitutions in PBP3, PBP5, GyrA, ParC and FolA implicated in resistance. Genomic analysis revealed that bla CTX-M-15 was carried by a Tn 3 -like transposon inserted into a novel integrative and conjugative element (ICE), ICE Hpa SLS, present on the chromosome and belonging to the ICE Hin1056 family described in Haemophilus influenzae. The tet (M)-MEGA element was also detected on the chromosome. No plasmid was found. The phylogenetic analysis showed that four H. parainfluenzae producing CTX-M-15 clustered in the same clade. Conclusions Here we report the description of an XDR H. parainfluenzae producing bla CTX-M-15 isolated from a urethral swab. The bla CTX-M-15 gene was inserted into an ICE structure similar to those recently described in CTX-M-15 producers in Spain. The emergence of XDR H. parainfluenzae producing bla CTX-M-15 is a matter of great concern. Careful surveillance is required to prevent its spread. [ABSTRACT FROM AUTHOR]