Information-seeking behaviour in patients exploring orthognathic surgery: A qualitative study.

OBJECTIVE: To explore how orthognathic patients seek information during decision-making. DESIGN: Qualitative, cross-sectional study. SETTING: A hospital in Cumbria, UK. PARTICIPANTS: Prospective orthognathic patients. METHODS: Participants were purposively recruited from joint orthognathic clinics after the original consultation. Semi-structured interviews were conducted via remote video call with nine participants aged 18-30 years. Data collection and reflexive thematic analysis occurred in parallel until thematic saturation was achieved. RESULTS: The central finding of this research was that patients were making informed decisions about orthognathic surgery. Four themes were identified to support this central finding including the following: (1) selective engagement with orthognathic information sources; (2) the central role of patient-specific information from professionals and peers; (3) Internet use to supplement standard information resources; and (4) concerns over information found online. The preferred source of information was verbal from the clinical team as it was trusted and person-specific. Past patients were identified as valued sources of information and establishing contact through digital social media networks was found to be a convenient alternative to face-to-face. Online information found was valued but concerns included information overload, problems establishing applicability and concerns over its credibility. CONCLUSION: Orthognathic patients were making informed decisions about their treatment. This study highlights the central role of the patient-clinician interaction in decision-making, especially in providing patient-specific information. Insight into the nuances of information-seeking behaviours will better inform clinical care. Since patients frequently access online information that is decision-relevant, encouraging patients to discuss online searches will support the shared decision-making process and alleviate any concerns with information found. During consultation, explaining the purpose of an information aid rather than expecting patients to read them separately, may further enhance its usefulness in decision-making. This study identified an unmet need for visual aids, such as real-time images of postoperative recovery. These findings can inform the design of future information resources.

A COnsensus-based Standards for the selection of health Measurement INstruments systematic review of orthognathic patient-reported outcome measures.

INTRODUCTION: This systematic review aimed to identify and appraise the validity studies of patient-reported outcome measures (PROMs) reporting the outcomes of combined orthodontic-orthognathic surgery in treating dentofacial deformity. METHODS: The search strategy was conducted using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) Systematic Review methodology. The following databases were searched for original studies outlining the development and/or validation of PROMs produced to measure the outcomes of combined orthognathic-orthodontic treatment: EMBASE, MEDLINE, PsycInfo and Scopus. Publications were limited to the English language. Eligibility criteria were applied when considering the studies. Primarily, the psychometric properties and quality of orthognathic-specific PROMs were investigated. Screening of eligible studies was conducted independently by 2 reviewers. Assessment of the methodological quality of the studies and data extraction was conducted by 1 reviewer and assisted by a second reviewer. The COSMIN methodology guided data extraction and analysis, which were divided into 3 stages-a synopsis of studies, evaluation of methodological quality, and summary of evidence. RESULTS: A total of 8695 papers were found; 12 studies met the criteria for inclusion. Regarding the COSMIN Checklist for Assessing Study Qualities, there was evidence that the Orthognathic Quality of Life Questionnaire was the most extensively tested orthognathic-specific PROM in the current literature. The reported evidence was incomplete, as not all psychometric properties had been reliably tested. CONCLUSIONS: Clinicians must use validated PROMs when analyzing patient-reported outcomes. The Orthognathic Quality of Life Questionnaire was shown to be the highest quality orthognathic-specific PROM in the literature but requires contemporary evaluation to suitably reflect the COSMIN guidance.

Cephalosporin Prodrug Inhibitors Overcome Metallo-ß-Lactamase Driven Antibiotic Resistance.

The increasing prevalence of metallo-ß-lactamase (MBL)-expressing bacteria presents a worrying trend in antibiotic resistance. MBLs rely on active site zinc ions for their hydrolytic activity and the pursuit of MBL-inhibitors has therefore involved the investigation of zinc chelators. To ensure that such chelators specifically target MBLs, a series of cephalosporin prodrugs of two potent zinc-binders: dipicolinic acid (DPA) and 8-thioquinoline (8-TQ) was prepared. Although both DPA and 8-TQ bind free zinc very tightly (Kd values in the low nm range), the corresponding cephalosporin conjugates do not. The cephalosporin conjugates are efficiently hydrolyzed by MBLs to release DPA or 8-TQ, as confirmed by using both NMR and LC-MS studies. Notably, the cephalosporin prodrugs of DPA and 8-TQ show potent inhibitory activity against NDM, VIM, and IMP classes of MBLs and display potent synergy with meropenem against MBL-expressing clinical isolates of K. pneumoniae and E. coli.

End-of-Life Experiences for Cancer Patients Dying in Hospital with COVID-19.

Despite a wealth of research regarding COVID-19, little evidence exists about cancer patients' specific needs and experiences at end-of-life. This study retrospectively describes the care of 34 hospitalised cancer patients dying with COVID-19. The palliative care needs of patients were described. The main domains of end-of-life care service provision were evaluated including treatment of pain and other symptoms, communication and decision making at end-of-life and level of involvement of the palliative care team. Physical symptoms were managed with relatively low doses of end-of-life medications. High levels of patient and family anxiety, however, highlight the complexity of death from a stigmatised disease. Prompt acknowledgement of the vulnerability of advanced cancer patients with COVID-19 can facilitate proactive symptom management, anticipatory communication and enhance family support.

Synthesis and Structure-Activity Studies of ß-Barrel Assembly Machine Complex Inhibitor MRL-494.

In the hunt for new antibiotics with activity against Gram-negative pathogens, the outer membrane ß-barrel assembly machine (BAM) complex has become an increasingly interesting target. The recently reported BAM complex inhibitor, MRL-494, was discovered via a screening campaign for molecules that target the outer membrane. Notably, MRL-494 was reported to be an unintended byproduct generated during the synthesis of an unrelated compound, and as such no synthesis of the compound was disclosed. We here present a convenient and reliable route for the synthesis of MRL-494 that scales well. The antibacterial activity measured for synthesized MRL-494 matches that reported in the literature. Furthermore, MRL-494 was found to exhibit potent synergistic activity with rifampicin against Gram-negative bacteria, including E. coli, K. pneumoniae, A. baumannii, and P. aeruginosa. MRL-494 was also found to cause outer membrane disruption and induction of the Rcs stress response pathway. In addition, we undertook a focused structure-activity study specifically aimed at elucidating the roles played by the two guanidine moieties contained within the structure of MRL-494.

Mechanistic Investigations of Metallo-ß-lactamase Inhibitors: Strong Zinc Binding Is Not Required for Potent Enzyme Inhibition*.

Metallo-ß-lactamases (MBLs) are zinc-dependent bacterial enzymes that inactivate essentially all classes of ß-lactam antibiotics including last-resort carbapenems. At present there are no clinically approved MBL inhibitors, and in order to develop such agents it is essential to understand their inhibitory mechanisms. Herein, we describe a comprehensive mechanistic study of a panel of structurally distinct MBL inhibitors reported in both the scientific and patent literature. Specifically, we determined the half-maximal inhibitory concentration (IC50 ) for each inhibitor against MBLs belonging to the NDM and IMP families. In addition, the binding affinities of the inhibitors for Zn2+ , Ca2+  and Mg2+  were assessed by using isothermal titration calorimetry (ITC). We also compared the ability of the different inhibitors to resensitize a highly resistant MBL-expressing Escherichia coli strain to meropenem. These investigations reveal clear differences between the MBL inhibitors studied in terms of their IC50 value, metal binding ability, and capacity to synergize with meropenem. Notably, our studies demonstrate that potent MBL inhibition and synergy with meropenem are not explicitly dependent on the capacity of an inhibitor to strongly chelate zinc.

Novel Cephalosporin Conjugates Display Potent and Selective Inhibition of Imipenemase-Type Metallo-ß-Lactamases.

In an attempt to exploit the hydrolytic mechanism by which ß-lactamases degrade cephalosporins, we designed and synthesized a series of novel cephalosporin prodrugs aimed at delivering thiol-based inhibitors of metallo-ß-lactamases (MBLs) in a spatiotemporally controlled fashion. While enzymatic hydrolysis of the ß-lactam ring was observed, it was not accompanied by inhibitor release. Nonetheless, the cephalosporin prodrugs, especially thiomandelic acid conjugate (8), demonstrated potent inhibition of IMP-type MBLs. In addition, conjugate 8 was also found to greatly reduce the minimum inhibitory concentration of meropenem against IMP-producing bacteria. The results of kinetic experiments indicate that these prodrugs inhibit IMP-type MBLs by acting as slowly turned-over substrates. Structure-activity relationship studies revealed that both phenyl and carboxyl moieties of 8 are crucial for its potency. Furthermore, modeling studies indicate that productive interactions of the thiomandelic acid moiety of 8 with Trp28 within the IMP active site may contribute to its potency and selectivity.

Small Molecule Carboxylates Inhibit Metallo-ß-lactamases and Resensitize Carbapenem-Resistant Bacteria to Meropenem.

In the search for new inhibitors of bacterial metallo-ß-lactamases (MBLs), a series of commonly used small molecule carboxylic acid derivatives were evaluated for their ability to inhibit New Delhi metallo-ß-lactamase (NDM)-, Verona integron-encoded metallo-ß-lactamase (VIM)-, and imipenemase (IMP)-type enzymes. Nitrilotriacetic acid (3) and N-(phosphonomethyl)iminodiacetic acid (5) showed promising activity especially against NDM-1 and VIM-2 with IC50 values in the low-to-sub µM range. Binding assays using isothermal titration calorimetry reveal that 3 and 5 bind zinc with high affinity with dissociation constant (Kd) values of 121 and 56 nM, respectively. The in vitro biological activity of 3 and 5 against E. coli expressing NDM-1 was evaluated in checkerboard format, demonstrating a strong synergistic relationship for both compounds when combined with Meropenem. Compounds 3 and 5 were then tested against 35 pathogenic strains expressing MBLs of the NDM, VIM, or IMP classes. Notably, when combined with Meropenem, compounds 3 and 5 were found to lower the minimum inhibitory concentration (MIC) of Meropenem up to 128-fold against strains producing NDM- and VIM-type enzymes.

Rare cutaneous myiasis of the face due to Lund's fly (Cordylobia rodhaini) in a British traveller returning from Uganda.

We present a rare cause for cutaneous furuncular myiasis in a 55-year-old British traveller returning from Uganda. Initially presenting with what appeared to be a cellulitic furuncle on her forehead, she returned to the emergency department 3 days later with extensive preseptal periorbital swelling and pain. Occlusive treatment with petroleum jelly was applied and one larva manually extracted and sent to London School of Tropical Medicine for examination. It was identified as Lund's Fly (Cordylobia rodhaini), a rare species from the rainforests of Africa with only one other case reported in the UK since 2015. Ultrasound imaging identified another larva, necessitating surgical exploration and cleaning. The lesion subsequently healed completely and the patient remains well.