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Chronic infections have posed a tremendous burden on health care systems worldwide. Approximately 60% of chronic infections are estimated to be related to biofilms, in large part due to the extraordinary antibiotic resistance of biofilm bacteria. Nanoparticle (NP)-based therapies are viable approaches to treat biofilm-associated infections due to NPs’ unique chemical and physical properties, granted by their high surface area to volume ratio. The mechanism underlying the anti-biofilm activity of various types of NPs is actively under investigation. Simply comparing biofilm disruption or reduction rates is not adequate to describe the effectiveness of NPs; many other factors need to be taken into account, such as the NP type, bacterial strain, concentration of NPs, quantification methods, and the biofilm culture environment. This review focuses on recent research on the creation, characterization, and evaluation of NPs for the prevention or treatment of biofilm infections.

Abstract Background Adequate anticoagulation is prerequisite for effective hemodialysis to prevent clotting in the extracorporeal circuit. We aimed providing first data on the efficacy and safety of the low-molecular-weight heparin certoparin in this setting. Methods Multicenter, open-label, 8-week trial. Patients received a single dose of 3,000 IU certoparin i.v. with additional titration steps of 600 IU and/or continuous infusion if necessary. Results 120 patients were screened, 109 enrolled (median age 71; range 26–90 years) and 106 available for efficacy analyses. The percentage of unsatisfactory dialysis results at 8 weeks due to clotting or bleeding, was 1.9% (n = 2/106; 95% confidence interval [CI] 0.23–6.65%); no major bleeding. 1.9% had moderate/severe clotting in the lines/bubble catcher and 2.8% in the dialyser at week 8. 15.7 ± 14.3% of the dialysis filters’ visual surface area was showing redness. In subgroups of patients receiving median doses of 3000 ± 0, 3000 (2400–6000) and 4200 (3000–6600) IU, plasma aXa levels at baseline, 4 and 8 weeks were 0.24 [95%CI 0.21–0.27], 0.33 [0.27–0.40] and 0.38 [0.33–0.45] aXa IU/ml at 2 h. C48h was 0.01 [0.01–0.02] aXa IU at all visits. At baseline and 4 weeks AUC0-48h was 2.66 [2.19–3.24] and 3.66 [3.00–4.45] aXa IU*h/ml. In 3.0% of dialyses (n = 83/2724) prolonged fistula compression times were documented. Eight patients (7.34%) had at least one episode of minor bleeding. 4) 85.3% of patients had any adverse event, 9.2% were serious without suspected drug relation; and in 32 patients a drug-relation was suspected. Conclusions Certoparin appears effective and safe for anticoagulation in patients undergoing maintenance hemodialysis.

Abstract Background Extracorporeal lung assist devices are increasingly used in the intensive care unit setting to improve extracorporeal gas exchange mainly in patients with acute respiratory distress syndrome. ARDS is frequently accompanied by acute kidney injury; however it is so far unknown how the combination of these two conditions affects long term survival of critically ill patients. Methods In a retrospective analysis of a tertiary care hospital we evaluated all patients undergoing interventional lung assist (iLA) treatment between January 1st 2005 and December 31st 2009. Data from all 61 patients (31 F/30 M), median age 40 (28 to 52) years were obtained by chart review. Follow up data up to one year were obtained. Results Of the 61 patients undergoing iLA membrane ventilator treatment 21 patients had acute kidney injury network (AKIN) stage 3 and were treated by extended dialysis (ED). Twenty-eight day survival of all patients was 33%. While patients without ED showed a 28 day survival of 40%, the survival of patients with ED was only 19%. Patients on ED were not different in respect to age, weight, Horowitz index and underlying disease. Conclusions AKI requiring ED therapy in patients undergoing iLA treatment increases mortality in ICU patients. Patients in whom iLA was placed as a bridge to lung transplantation and that were successfully transplanted showed the best outcome. Future studies have to clarify whether it is possible to identify patients that truly benefit from the combination of these two extracorporeal treatment methods.

Abstract We describe a novel strategy in which two inhibitors of HIV viral entry were incorporated into a single molecule. This bifunctional fusion inhibitor consists of an antibody blocking the binding of HIV to its co-receptor CCR5, and a covalently linked peptide which blocks envelope mediated virus-cell fusion. This novel bifunctional molecule is highly active on CCR5- and X4-tropic viruses in a single cycle assay and a reporter cell line with IC50 values of 0.03–0.05 nM. We demonstrated that both inhibitors contribute to the antiviral activity. In the natural host peripheral blood mononuclear cells (PBMC) the inhibition of CXCR4-tropic viruses is dependant on the co-expression of CCR5 and CXCR4 receptors. This bifunctional inhibitor may offer potential for improved pharmacokinetic parameters for a fusion inhibitor in humans and the combination of two active antiviral agents in one molecule may provide better durability in controlling the emergence of resistant viruses.

Wallenberg's syndrome, also known as lateral medullary syndrome (LMS), is a neurological condition resulting from damage to the lateral portion of the medulla oblongata. We present a case of a 64-year-old man with Wallenberg's syndrome who presented for acute rehabilitation after sustaining a cerebrovascular accident (CVA). As seen in our patient, common symptoms of LMS include difficulty swallowing, hoarseness, ipsilateral weakness, and ipsilateral loss of sensation or numbness. Although the prognosis following infarction is often good, dysfunction in swallowing is one of the key deficits that have a long-term impact on patient quality of life. We aim to emphasize the significance of the interdisciplinary approach to achieving favorable health outcomes in patients with LMS., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Herson et al.)

Complex regional pain syndrome (CRPS) is a neurological disorder characterized by persistent limb symptoms. With there being no definitive tests, diagnosis can be challenging. The Budapest criteria are the standard for diagnosis. The underlying mechanisms of CRPS involve changes in skin innervation, sensitization of the nervous system, inflammatory cytokines, and genetic and psychological factors. Treatment typically involves a multidisciplinary approach. We present a case of a 71-year-old male with CRPS involving the right upper extremity and a complex history of management including physical therapy, oxycodone, muscle relaxers, non-steroidal anti-inflammatory drugs, and multiple stellate ganglion blocks. The patient manages his pain with off-label medications, including methadone, duloxetine, and pregabalin. In the United States, the management of chronic pain may be affected by potential usage restrictions imposed by the Food and Drug Omnibus Reform Act (FDORA). Under this new act, physicians may face limitations in prescribing off-label medications for specific diagnoses. We aim to highlight the need for prioritizing patient care and individualized treatment in healthcare policy decision-making., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Herson et al.)

This case report discusses a 77-year-old female patient who presented to an outpatient clinic with urinary symptoms and recurrent UTIs. Imaging revealed a foreign body, which was later confirmed as a retained intrauterine device (IUD) that had caused a vesicouterine fistula (VUF). The patient had a medical history of cervical cancer treated with radiation therapy, during which her IUD's string could not be located, leading to the decision to proceed with radiation therapy without removing the IUD. The patient opted to manage her condition medically rather than undergo surgical removal due to concerns about worsening the vesicouterine fistula. This case highlights the potential risks and complications of retained IUDs, and the importance of careful consideration and communication among clinical teams and patients when managing these situations., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Briceno et al.)

Articular depression is a significant component of lateral tibial plateau fracture patterns. Current literature supports the use of subchondral rafting screws, either placed through a plate or not. However, articular comminution has been associated with increased articular subsidence despite an adequate screw-joint distance. We report four cases that underwent the subchondral rafting plate technique for fragmented articular central depression lateral tibial plateau fractures. Clinical and radiographic evaluations were performed at the last follow-up. The mean follow-up was 18 months. All patients healed the fracture without any significant articular subsidence or loss of reduction. This case study hints that this novel technique is a potentially safe and cost-effective strategy to be incorporated in the daily practice of the orthopedic trauma surgeon, especially in certain challenging circumstances when a salvage procedure is required due to lateral tibial plateau fracture malreduction and the unavailability of anatomically designed locking plates., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Giordano et al.)

Standard methods for case-control association studies of rare variation often treat disease outcome as a dichotomous phenotype. However, both theoretical and experimental studies have demonstrated that subjects with a family history of disease can be enriched for risk variation relative to subjects without such history. Assuming family history information is available, this observation motivates the idea of replacing the standard dichotomous outcome variable used in case-control studies with a more informative ordinal outcome variable that distinguishes controls (0), sporadic cases (1), and cases with a family history (2), with the expectation that we should observe increasing number of risk variants with increasing category of the ordinal variable. To leverage this expectation, we propose a novel rare-variant association test that incorporates family history information based on our previous GAMuT framework for rare-variant association testing of multivariate phenotypes. We use simulated data to show that, when family history information is available, our new method outperforms standard rare-variant association methods, like burden and SKAT tests, that ignore family history. We further illustrate our method using a rare-variant study of cleft lip and palate., (Copyright © 2020 by the Genetics Society of America.)

: media-1vid110.1542/5849572227001PEDS-VA_2018-2516 Video Abstract OBJECTIVES: For decades, infants with Duarte galactosemia (DG) have been identified by newborn screening (NBS), but whether they should be treated with dietary restrictions of galactose has remained unknown. To clarify, we conducted a study of dietary and developmental outcomes in 206 children with DG (case patients) and 144 controls, all of whom were 6 to 12 years old., Methods: We recruited case patients from states where they were identified by NBS; unaffected siblings served as controls. Diet in infancy was ascertained by retrospective parent surveys; developmental outcomes were assessed in 5 domains, yielding 73 outcome measures for each child. We divided subjects randomly into independent discovery ( n = 87) and validation ( n = 263) sets. We tested the discovery set to order the 73 outcome measures by ascending P values and tested the 10 outcomes with the lowest P values for possible association with DG in the validation set. We also tested these same 10 outcomes for possible association with milk exposure in infancy among case patients in the validation set., Results: None of the 73 outcomes tested in the discovery set revealed significant association with DG, and none of the 10 outcomes tested in the validation set revealed either significant association with DG or significant association with milk exposure among children with DG., Conclusions: Through our results, we demonstrated that there were no significant differences in outcomes tested between case patients and controls or among case patients as a function of milk exposure in infancy. In this study, we provide a long-needed foundation of knowledge for health care providers, families, and NBS professionals seeking to make evidence-based decisions about DG., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

There has been increasing interest in identifying genes within the human genome that influence multiple diverse phenotypes. In the presence of pleiotropy, joint testing of these phenotypes is not only biologically meaningful but also statistically more powerful than univariate analysis of each separate phenotype accounting for multiple testing. Although many cross-phenotype association tests exist, the majority of such methods assume samples composed of unrelated subjects and therefore are not applicable to family-based designs, including the valuable case-parent trio design. In this paper, we describe a robust gene-based association test of multiple phenotypes collected in a case-parent trio study. Our method is based on the kernel distance covariance (KDC) method, where we first construct a similarity matrix for multiple phenotypes and a similarity matrix for genetic variants in a gene; we then test the dependency between the two similarity matrices. The method is applicable to either common variants or rare variants in a gene, and resulting tests from the method are by design robust to confounding due to population stratification. We evaluated our method through simulation studies and observed that the method is substantially more powerful than standard univariate testing of each separate phenotype. We also applied our method to phenotypic and genotypic data collected in case-parent trios as part of the Genetics of Kidneys in Diabetes (GoKinD) study and identified a genome-wide significant gene demonstrating cross-phenotype effects that was not identified using standard univariate approaches., (© 2018 WILEY PERIODICALS, INC.)

Objective: To evaluate the effectiveness of a step-by-step oral recount by residents before the final execution of a practical exercise simulating a surgical fixation of a radial diaphyseal fracture., Material and Methods: The study included 10 residents of orthopaedics and traumatology (four second- year and six first-year residents) divided into two groups with five residents each. All participants initially gathered in a room in which a video was presented demonstrating the practical exercise to be performed. One group (Group A) was referred directly to the practical exercise room. The other group (Group B) attended an extra session before the practical exercise, in which they were invited by instructors to recount all the steps that they would perform during the practical exercise. During this session, the instructors corrected the residents if any errors in the step-by-step recount were identified, and clarified questions from them. After this session, both Groups A and B gathered in a room in which they proceeded to the practical exercise, while being video recorded and evaluated using a 20-point checklist., Results: Group A achieved a 57% accuracy, with results in this group ranging from 7 to 15 points out of a total of a possible 20 points. Group B achieved an 89% accuracy, with results in this group ranging from 15 to 20 points out of 20., Conclusion: An oral step-by-step recount by the residents before the final execution of a practical simulation exercise of surgical fixation of a diaphyseal radial fracture improved the technique and reduced the execution time of the exercise., (© 2017 Elsevier Ltd. All rights reserved.)

Decades of public health research have documented that smoking in pregnancy poses significant health risks to both mother and child. More recent studies have shown that even passive maternal exposure to secondhand smoke associates with negative birth outcomes. However, the mechanisms linking exposure to outcomes have remained obscure. As a first step toward defining the metabolic consequence of low-level nicotine exposure on fetal development, we conducted an untargeted metabolomic analysis of 81 paired samples of maternal serum and amniotic fluid collected from karyotypically normal pregnancies in the second trimester. By comparing the m/z and retention times of our mass spectral features with confirmed standards, we identified cotinine, a nicotine derivative, and used the calculated cotinine concentrations to classify our maternal serum samples into exposure groups using previously defined cut-offs. We found that cotinine levels consistent with low-level maternal exposure to nicotine associated with distinct metabolic perturbations, particularly in amniotic fluid. In fact, the metabolic effects in amniotic fluid of ostensibly low-level exposed mothers showed greater overlap with perturbations previously observed in the sera of adult smokers than did the perturbations observed in the corresponding maternal sera. Dysregulated fetal pathways included aspartate and asparagine metabolism, pyrimidine metabolism, and metabolism of other amino acids. We also observed a strong negative association between level of maternal serum cotinine and acetylated polyamines in the amniotic fluid. Combined, these results confirm that low-level maternal nicotine exposure, indicated by a maternal serum cotinine level of 2-10ng/mL, is associated with striking metabolic consequences in the fetal compartment, and that the affected pathways overlap those perturbed in the sera of adult smokers., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We present a general method for analyzing the character of singly excited states in terms of charge transfer (CT) and locally excited (LE) configurations. The analysis is formulated for configuration interaction singles (CIS) singly excited wave functions of aggregate systems. It also approximately works for the second-order approximate coupled cluster singles and doubles and the second-order algebraic-diagrammatic construction methods [CC2 and ADC(2)]. The analysis method not only generates a weight of each character for an excited state, but also allows to define the related quasi-diabatic states and corresponding coupling matrix elements. In the character analysis approach, we divide the target system into domains and use a modified Pipek-Mezey algorithm to localize the canonical MOs on each domain, respectively. The CIS wavefunction is then transformed into the localized basis, which allows us to partition the wavefunction into LE configurations within domains and CT configuration between pairs of different domains. Quasi-diabatic states are then obtained by mixing excited states subject to the condition of maximizing the weight of one single LE or CT configuration (localization in configuration space). Different aims of such a procedure are discussed, either the construction of pure LE and CT states for analysis purposes (by including a large number of excited states) or the construction of effective models for dynamics calculations (by including a restricted number of excited states). Applications are given to LE/CT mixing in π-stacked systems, charge-recombination matrix elements in a hetero-dimer, and excitonic couplings in multi-chromophoric systems.

We calculate two-dimensional (2D) vibronic spectra for a model system involving two electronic molecular states. The influence of a bath is simulated using a quantum-jump approach. We use a method introduced by Makarov and Metiu [J. Chem. Phys. 111, 10126 (1999)] which includes an explicit treatment of dephasing. In this way it is possible to characterize the influence of dissipation and dephasing on the 2D-spectra, using a wave function based method. The latter scales with the number of stochastic runs and the number of system eigenstates included in the expansion of the wave-packets to be propagated with the stochastic method and provides an efficient method for the calculation of the 2D-spectra.