Staphylococcus aureus FtsZ and PBP4 bind to the conformationally dynamic N-terminal domain of GpsB.

In the Firmicutes phylum, GpsB is a membrane associated protein that coordinates peptidoglycan synthesis with cell growth and division. Although GpsB has been studied in several bacteria, the structure, function, and interactome of Staphylococcus aureus GpsB is largely uncharacterized. To address this knowledge gap, we solved the crystal structure of the N-terminal domain of S. aureus GpsB, which adopts an atypical, asymmetric dimer, and demonstrates major conformational flexibility that can be mapped to a hinge region formed by a three-residue insertion exclusive to Staphylococci. When this three-residue insertion is excised, its thermal stability increases, and the mutant no longer produces a previously reported lethal phenotype when overexpressed in Bacillus subtilis. In S. aureus, we show that these hinge mutants are less functional and speculate that the conformational flexibility imparted by the hinge region may serve as a dynamic switch to fine-tune the function of the GpsB complex and/or to promote interaction with its various partners. Furthermore, we provide the first biochemical, biophysical, and crystallographic evidence that the N-terminal domain of GpsB binds not only PBP4, but also FtsZ, through a conserved recognition motif located on their C-termini, thus coupling peptidoglycan synthesis to cell division. Taken together, the unique structure of S. aureus GpsB and its direct interaction with FtsZ/PBP4 provide deeper insight into the central role of GpsB in S. aureus cell division.

Effect of functional appliances on sleep-disordered breathing in Class II division 1 malocclusion children: Randomized controlled trial.

OBJECTIVES: A randomized controlled trial was undertaken to investigate the orthopaedic effect of functional appliances on the pharyngeal airway space and nocturnal breathing of children with skeletal class II due to mandibular retrusion. MATERIALS AND METHODS: Forty patients were randomized into a 1:1 ratio study (Twin block) group and a control (fixed appliance) group. Each group included equal numbers of boys and girls. Diagnosis with sleep-disordered breathing was not an inclusion criterion. The duration of the trial was 12 months (T0 - T12). Eligibility criteria included skeletal Class II division 1 malocclusion with mandibular retrognathism, SNA ≥82, SNB ≤78, ANB ≥4, overjet ≥6 mm, and patients in circumpubertal stage CVM2 and CVM3. The main outcomes were pharyngeal airway volume, oxygen desaturation index (ODI), and maximum expiratory pressure (MEP), while the secondary outcomes were skeletal and dental changes of the maxilla and mandible. Randomization was accomplished with random blocks of 20 patients with allocation concealed in sequentially numbered, opaque, and sealed envelopes. Blinding was only applicable for data analysis of radiographic measurements and data extracted from the pulse oximeter. RESULTS: The mean age of the patients was 10 ± 1.5 and 10 ± 1.2 at (T0) for the Twin Block and the control groups, respectively. The changes in the oropharyngeal (2.66 cc and 0.056; P = .03) and nasopharyngeal (1.3 cc and 0.84; P = .053) airway volumes for the Twin block and control groups, respectively, were significantly different for the oropharynx. There was a significant decrease in ODI by [median -3.55 (-5.05 to 0.50); P ≤ .001] and a significant increase [median 45 (0.0-110); P ≤ .001] in MEP for the Twin block group. A significant inverse correlation (r = -.589; P = .006) could be found between the total volume of the oropharynx and ODI. No serious harm was observed. CONCLUSIONS: The Twin block group showed significant change in oropharyngeal airway volume and improvement of nocturnal breathing. REGISTRATION: This trial was registered at https://www. CLINICALTRIALS: gov, registration number NCT04255511.

Mechanism of proton transfer in class A ß-lactamase catalysis and inhibition by avibactam.

Gram-negative bacteria expressing class A ß-lactamases pose a serious health threat due to their ability to inactivate all ß-lactam antibiotics. The acyl-enzyme intermediate is a central milestone in the hydrolysis reaction catalyzed by these enzymes. However, the protonation states of the catalytic residues in this complex have never been fully analyzed experimentally due to inherent difficulties. To help unravel the ambiguity surrounding class A ß-lactamase catalysis, we have used ultrahigh-resolution X-ray crystallography and the recently approved ß-lactamase inhibitor avibactam to trap the acyl-enzyme complex of class A ß-lactamase CTX-M-14 at varying pHs. A 0.83-Å-resolution CTX-M-14 complex structure at pH 7.9 revealed a neutral state for both Lys73 and Glu166. Furthermore, the avibactam hydroxylamine-O-sulfonate group conformation varied according to pH, and this conformational switch appeared to correspond to a change in the Lys73 protonation state at low pH. In conjunction with computational analyses, our structures suggest that Lys73 has a perturbed acid dissociation constant (pKa) compared with acyl-enzyme complexes with ß-lactams, hindering its function to deprotonate Glu166 and the initiation of the deacylation reaction. Further NMR analysis demonstrated Lys73 pKa to be ∼5.2 to 5.6. Together with previous ultrahigh-resolution crystal structures, these findings enable us to follow the proton transfer process of the entire acylation reaction and reveal the critical role of Lys73. They also shed light on the stability and reversibility of the avibactam carbamoyl acyl-enzyme complex, highlighting the effect of substrate functional groups in influencing the protonation states of catalytic residues and subsequently the progression of the reaction.

Case-control study to evaluate risk factors for acute hepatitis B virus infection in Egypt.

Hepatitis B virus (HBV) infection is a significant health problem in Egypt. To better define risk factors associated with HBV transmission, we conducted a case-control study among patients admitted with acute hepatitis to an infectious disease hospital in Cairo. A total of 60 cases and 120 controls were interviewed about various exposures within 6 months prior to admission. Univariate analysis revealed HBV case-patients were more likely to report providing injections to relatives or friends, injecting drug use, exposure to a household contact with hepatitis, exposure to invasive medical procedures and being in the military. Efforts should be made to implement strict infection control standards in Egypt.

Case-control study to evaluate risk factors for acute hepatitis B virus infection in Egypt

Hepatitis B virus [HBV] infection is a significant health problem in Egypt. To better define risk factors associated with HBV transmission, we conducted a case-control study among patients admitted with acute hepatitis to an infectious disease hospital in Cairo. A total of 60 cases and 120 controls were interviewed about various exposures within 6 months prior to admission. Univariate analysis revealed HBV case-patients were more likely to report providing injections to relatives or friends, injecting drug use, exposure to a household contact with hepatitis, exposure to invasive medical procedures and being in the military. Efforts should be made to implement strict infection control standards in Egypt

Injection prescribing patterns in public health care facilities in Egypt.

This study assessed the frequency of and rationale for use of injections at health care facilities in Egypt based on WHO core drug use indicators. We reviewed 1406 prescriptions in 43 randomly selected hospitals and primary health care clinics in 2 governorates in Upper and Lower Egypt in 2001. Patients received an injection at 18.1% of encounters. The most frequently prescribed parenteral drugs were anti-infectives (56.9% of injections) and analgesics (13.7%). Injections were more often prescribed in hospitals than in primary health care clinics and in rural than in urban settings. Most injections (94.7%) could have been replaced by a suitable oral preparation. Further efforts are needed to enforce the essential medicines programme in Egypt to improve rational drug prescribing.

Injection prescribing patterns in public health care facilities in Egypt

This study assessed the frequency of and rationale for use of injections at health care facilities in Egypt based on WHO core drug use indicators. We reviewed 1406 prescriptions in 43 randomly selected hospitals and primary health care clinics in 2 governorates in Upper and Lower Egypt in 2001. Patients received an injection at 18.1% of encounters. The most frequently prescribed parenteral drugs were anti-infectives [56.9% of injections] and analgesics [13.7%]. Injections were more often prescribed in hospitals than in primary health care clinics and in rural than in urban settings. Most injections [94.7%] could have been replaced by a suitable oral preparation. Further efforts are needed to enforce the essential medicines programme in Egypt to improve rational drug prescribing

Improving the classification of multiple disorders with problem decomposition.

Differential diagnosis of multiple disorders is a challenging problem in clinical medicine. According to the divide-and-conquer principle, this problem can be handled more effectively through decomposing it into a number of simpler sub-problems, each solved separately. We demonstrate the advantages of this approach using abductive network classifiers on the 6-class standard dermatology dataset. Three problem decomposition scenarios are investigated, including class decomposition and two hierarchical approaches based on clinical practice and class separability properties. Two-stage classification schemes based on hierarchical decomposition boost the classification accuracy from 91% for the single-classifier monolithic approach to 99%, matching the theoretical upper limit reported in the literature for the accuracy of classifying the dataset. Such models are also simpler, achieving up to 47% reduction in the number of input variables required, thus reducing the cost and improving the convenience of performing the medical diagnostic tests required. Automatic selection of only relevant inputs by the simpler abductive network models synthesized provides greater insight into the diagnosis problem and the diagnostic value of various disease markers. The problem decomposition approach helps plan more efficient diagnostic tests and provides improved support for the decision-making process. Findings are compared with established guidelines of clinical practice, results of data analysis, and outcomes of previous informatics-based studies on the dataset.