giddines

BACKGROUND: M5717 is the first plasmodium translation elongation factor 2 inhibitor to reach clinical development as an antimalarial. We aimed to characterise the safety, pharmacokinetics, and antimalarial activity of M5717 in healthy volunteers. METHODS: This first-in-human study was a two-part, single-centre clinical trial done in Brisbane, QLD, Australia. Part one was a double-blind, randomised, placebo-controlled, single ascending dose study in which participants were enrolled into one of nine dose cohorts (50, 100, 200, 400, 600, 1000, 1250, 1800, or 2100 mg) and randomly assigned (3:1) to M5717 or placebo...

The incidence of distal radioulnar joint instability following a distal radius fracture is estimated around one in three based upon clinical examination. Using a validated rig, we objectively measured distal radioulnar joint translation in vivo following distal radius fracture. Dorsopalmar translation of the distal radioulnar joint was measured in 50 adults with previous distal radius fractures. Measurements were compared with the uninjured wrist and against a database of previous measurements within healthy and clinically lax populations...

BACKGROUND: Traumatic injury is sudden and unexpected. It may lead to long-standing physical and physiological consequences. Approximately 10% of the world's disease burden is attributable to traumatic injuries. At the commencement of the study, there was limited information regarding civilian trauma patients' recovery following discharge from the hospital. There are several reasons for this including lack of available resources for follow-up by clinical staff and often trauma patients have multiple injuries, which can result in fragmented care...

OBJECTIVE: Prioritisation of important treatment uncertainties for 'Common Conditions Affecting the Hand and Wrist' via a UK-based James Lind Alliance Priority Setting Partnership. SETTING: This process was funded by a national charitable organisation and based in the UK. PARTICIPANTS: Anyone with experience of common conditions affecting the adult hand and wrist, including patients, carers and healthcare professionals. All treatment modalities delivered by a hand specialist, including therapists, surgeons or other allied professionals, were considered...

Multi-drug resistant (MDR) Klebsiella pneumoniae remains an urgent public health threat. While whole-genome sequencing has helped identify genetic changes underlying resistance, functional validation remains difficult due to a lack of genetic manipulation systems for MDR K. pneumoniae . CRISPR-Cas9 has revolutionized molecular biology, but its use was only recently adapted in bacteria by overcoming the lack of genetic repair systems. We describe a CRISPR-Cas9/lambda recombineering system utilizing a zeocin resistance cassette allowing efficient and versatile genetic manipulation of K...

INTRODUCTION: Falling studies, i.e. assessing what happens when an individual falls, have been conducted in controlled environments but not in field studies for ethical reasons; this potentially limits the validity and applicability of previous studies. We performed field studies on existing YouTube © videos of skateboarders falling. The aims of these studies were to measure the wrist angle at impact on videos of real unprotected falls and to study the dynamics of the upper limbs when falling...

We report six cases of complications from use of a thermal wand at wrist arthroscopy. Complications included skin necrosis, extensor tendon lesions and thermal articular cartilage damage, one with a catastrophic outcome. Thermal wands have the potential for substantial soft tissue damage causing severe harm to patients. The damage could be related to the design of the wands. User error poses an additional risk. These risks need to be appreciated and should be minimized. The complications indicate the need for careful use of the thermal wands to minimise risk including using only short bursts of thermal energy, the use of high flow irrigation with an outflow and trying to ensure that the collar of the device and not just the tip is within the joint...

Polymyxin resistance (PR) threatens the treatment of carbapenem-resistant Klebsiella pneumoniae (CRKP) infections. PR frequently arises through chemical modification of the lipid A portion of lipopolysaccharide. Various mutations are implicated in PR, including in three two-component systems-CrrA/B, PmrA/B, and PhoP/Q-and the negative regulator MgrB. Few have been functionally validated. Therefore, here we adapt a CRISPR-Cas9 system to CRKP to elucidate how mutations in clinical CRKP isolates induce PR. We demonstrate that CrrB is a positive regulator of PR, and common clinical mutations lead to the addition of both 4-amino-4-deoxy-L-arabinose (L-Ara4N) and phosophethanolamine (pEtN) to lipid A, inducing notably higher polymyxin minimum inhibitory concentrations than mgrB disruption...

The aim of the study was to assess the natural history of untreated flexor pollicis longus (FPL) tendon rupture in patients with rheumatoid arthritis (RA). We reviewed a cohort of patients to assess the long-term effect of conservative management. We reviewed nine of 11 consecutive patients. We assessed objective outcomes including ranges of motion and strength and subjective outcomes including pain and function scores. We assessed seven women and two men. They had a mean age of 67 (range 48-82) years. Six of the nine patients had no more symptoms on the side of their FPL rupture than in the other thumb...

No abstract text is available yet for this article.

BACKGROUND: Scaphoid fractures account for 90% of carpal fractures and occur predominantly in young men. The use of immediate surgical fixation to manage this type of fracture has increased, despite insufficient evidence of improved outcomes over non-surgical management. The SWIFFT trial compared the clinical effectiveness of surgical fixation with cast immobilisation and early fixation of fractures that fail to unite in adults with scaphoid waist fractures displaced by 2 mm or less. METHODS: This pragmatic, parallel-group, multicentre, open-label, two-arm, randomised superiority trial included adults (aged 16 years or older) who presented to orthopaedic departments of 31 hospitals in England and Wales with a clear bicortical fracture of the scaphoid waist on radiographs...

INTRODUCTION: Fracture-dislocation and pilon injuries of the proximal interphalangeal joints (PIPJ) continue to pose significant management challenges. Stable fracture configurations can be treated with extension block splinting or pinning. Unstable fractures usually require open or closed reduction and fixation either directly/internally onto the fracture using Kirschner wires, cerclage wires, screws or miniplates or indirectly/externally by ligamentotaxis using external fixators which can be dynamic or static...

The search for antimalarial chemotypes with modes of action unrelated to existing drugs has intensified with the recent failure of first-line therapies across Southeast Asia. Here, we show that the trisubstituted imidazole MMV030084 potently inhibits hepatocyte invasion by Plasmodium sporozoites, merozoite egress from asexual blood stage schizonts, and male gamete exflagellation. Metabolomic, phosphoproteomic, and chemoproteomic studies, validated with conditional knockdown parasites, molecular docking, and recombinant kinase assays, identified cGMP-dependent protein kinase (PKG) as the primary target of MMV030084...

BACKGROUND: Gut microbial imbalance may contribute to endotoxemia, inflammation, and oxidative stress in heart failure (HF). Changes occurring in the intestinal microbiota and inflammatory/oxidative milieu during HF progression and following left ventricular assist device (LVAD) or heart transplantation (HT) are unknown. We aimed to investigate variation in gut microbiota and circulating biomarkers of endotoxemia, inflammation, and oxidative stress in patients with HF (New York Heart Association, Class I-IV), LVAD, and HT...

Antimalarial drug resistance in the Plasmodium falciparum parasite poses a constant challenge for drug development. To mitigate this risk, new antimalarial medicines should be developed as fixed-dose combinations. Assessing the pharmacodynamic interactions of potential antimalarial drug combination partners during early phases of development is essential in developing the targeted parasitological and clinical profile of the final drug product. Here, we have studied the combination of M5717, a Plasmodium falciparum translation elongation factor 2 inhibitor, and pyronaridine, an inhibitor of hemozoin formation...

BACKGROUND: Platelet-rich plasma (PRP), as a promising alternative to traditional corticosteroid (CS), is now increasingly used in the treatment of elbow epicondylitis (EE) and plantar fasciitis (PF). To date, however, the synthesis of information on the clinical efficacy of PRP versus CS is limited with divergent conclusions. PURPOSE: To compare the clinical efficacy of PRP and CS injections in reducing pain and improving function in EE and PF. STUDY DESIGN: Systematic review and meta-analysis...

There are a number of possible assessments of functional outcomes for thumb carpometacarpal joint arthritis. The most important and easiest to measure is pain, but it is not the only material outcome. Functional scores for measuring the outcome of the treatment of thumb carpometacarpal joint arthritis have been recommended for some time, but are still not widely used even in published studies. It is also unclear which functional scores are the most valuable. Easily used scores, such as the Disabilities of the Arm Shoulder and Hand questionnaire, are freely available, but may not be sensitive enough to assess outcomes especially of thumb carpometacarpal joint arthroplasty...

Infections by multidrug-resistant bacteria (MDRB) remain a leading cause of morbidity and mortality after liver transplantation (LT). Gut dysbiosis characteristic of end-stage liver disease may predispose patients to intestinal MDRB colonization and infection, in turn exacerbating dysbiosis. However, relationships between MDRB colonization and dysbiosis after LT remain unclear. We prospectively recruited 177 adult patients undergoing LT at a single tertiary care center. 16 S V3-V4 rRNA sequencing was performed on 723 fecal samples collected pre-LT and periodically until one-year post-LT to test whether MDRB colonization was associated with decreased microbiome diversity...

No abstract text is available yet for this article.

BACKGROUND: Polymyxins are antimicrobials of last resort for the treatment of carbapenem-resistant Enterobacteriaceae, but resistance in 5% to >40% isolates has been reported. We conducted a genomic survey of clinical polymyxin-resistant (PR) Klebsiella pneumoniae to determine the molecular mechanisms of PR and the role of polymyxin exposure versus transmission in PR emergence. METHODS: We included 88 patients with PR K. pneumoniae from 2011-2018 and collected demographic, antimicrobial exposure, and infection data...