The effect of COVID-19 on orthopaedics in Aotearoa New Zealand-a survey of orthopaedic surgeons and training registrars.

AIM: This study aimed to assess the impact of COVID-19 on orthopaedic practice in New Zealand, with a focus on training and mental health. METHODS: An online survey was sent to the 385 consultant orthopaedic surgeons and registrars in New Zealand registered with the New Zealand Orthopaedic Association (NZOA). The survey consisted of 27 questions relating to demographics, the effects of COVID-19 on orthopaedic departments, on training, on mental health and the utilisation of telehealth and online teaching. RESULTS: In total, 189 of 385 NZOA members (49%) completed the survey. Of the 51 orthopaedic registrars surveyed, 55% felt that their training had been moderately affected, while 17% felt it had been significantly affected. Of those surveyed, 65% felt the pandemic had at least a mild effect on their mental health. Seven percent of registrars described a significant impact on their mental health compared to 2% of consultants (p=0.029). Overall, 46.5% felt they were more burnt out because of the pandemic, which was significantly higher in registrars compared to consultants (51% vs 44%, respectively; p=0.029). CONCLUSIONS: Despite the comparatively low number of COVID-19 cases, hospitalisations and deaths, the effects for orthopaedic surgeons and training registrars have been significant.

Resolution of Right Hemidiaphragm Paralysis following Cervical Foraminotomies.

INTRODUCTION: Hemidiaphragm paralysis secondary to phrenic nerve palsy is a well-recognised medical condition. There are few case reports in the literature documenting resolution of hemidiaphragm paralysis following cervical spine surgery. This case report documents our experience with one such case. CASE PRESENTATION: A 64-year-old man was referred to the orthopaedic service with right hemidiaphragm paralysis. He had a previous history of asbestos exposure and polio and was initially seen and investigated by the respiratory physicians. He also reported intermittent neck pain and an MRI scan showed right-sided cervical foraminal stenosis. He underwent posterior right C3/4 and C4/5 foraminotomies, and by three months postoperatively, his hemidiaphragm paralysis had resolved and his shortness of breath had also improved. CONCLUSION: This report documents a unique case of resolution of hemidiaphragm paralysis following posterior unilateral cervical foraminotomies.

Real-Time Monitoring of Post-Surgical and Post-Traumatic Eye Injuries Using Multilayered Electrical Biosensor Chip.

Lack of current techniques for the early monitoring of bleb leaks and other post-traumatic or post-surgical ocular injury has posed an unmet clinical need for the development of new techniques. Present evaluation techniques use either subjective or nonquantitative approaches. At present, there are no FDA approved ocular devices that can directly measure ascorbic acid (AA) concentration levels for both tear film (TF) and aqueous humor (AH) at point-of-care (POC) level. Toward this aim, we present a novel POC quantitative assay, called the ocular biosensor device, which can be used to evaluate the integrity of the anterior surface of the eye by measuring the concentration of AA in TF and AH. Herein, we utilize a novel scientific engineering approach for the development of a disposable paper based POC ocular biosensor strip. A grafted poly(styrene)-block-poly(acrylic acid) (PS-b-PAA) and graphene platelet composite with contour based µ-electrodes design (CBµE) exhibit a highly sensitive platform to perform electrochemical immunosensing technique to study clinical samples that have small volumes like tear fluid. Samples used in this study were collected clinically from subjects undergoing therapeutic anterior chamber paracentesis. The proposed biosensor reports the level of AA concentration on an electronic screen, making the results easy to read, efficient, and reliable.

Quadrate lobe: a reliable landmark for bile duct anatomy during laparoscopic cholecystectomy.

BACKGROUND: This investigation was undertaken to determine whether the shape of the inferior surface quadrate lobe (segment IV) can assist in defining a safe starting point for dissection during laparoscopic cholecystectomy. METHODS: Patients undergoing laparoscopic cholecystectomy were prospectively audited. Intraoperative cholangiograms and photographs of the quadrate lobe were reviewed measuring the angle between the cystic duct and common bile duct and its relationship to quadrate shape. RESULTS: The results of 56 patients were included. The shape of the inferior surface of the quadrate lobe was rectangular in 35, pyramidal in 13 and square in eight patients. The median cystic/bile duct angle was 43°, 37° and 26° for square, rectangular and pyramidal quadrate shapes, respectively. The angle for pyramidal-shaped lobes was narrower than that for rectangular or square lobes (P < 0.05). Regression analysis showed an inverse relationship between the shape ratio and the cystic/bile duct angle (P = 0.015). CONCLUSION: This investigation confirms a relationship between the shape of the inferior surface of the quadrate lobe and the cystic/bile duct angle and suggests that the anatomy of the inferior surface of the quadrate lobe can be used to define an optimal starting point for dissection of the biliary cystic triangle.

The effect of a non-surgical orthopaedic physician on wait times to see a paediatric orthopaedic surgeon.

AIMS: High referral volumes to paediatric orthopaedic surgeons create long clinic waiting lists. The use of extended scope roles for doctors and health professionals is one strategy to address these wait times. We completed a 6-month trial of a non-surgical paediatric orthopaedic physician role (NSP) to help manage non-urgent referrals to our service from local general practitioners (GPs). METHODS: For a 6-month period, the majority of non-urgent GP referrals were assessed by a US-trained NSP. Wait times were compared between this period and the same time period in the previous year. Family and referrer satisfaction was determined through postal surveys. RESULTS: Over the trial period, the NSP saw a total of 155 new patient referrals, which represented 49% of all non-urgent GP referrals for the period. Before the trial, only 75% of non-urgent referrals were seen within 131 days (19 weeks) with 10% waiting more than 215 days (31 weeks). By the end of the trial, 75% of referrals were seen within 55 days (8 weeks) and 90% within 61 days (9 weeks). The most common outcome was discharge with management advice. 12% of patients were referred on to an orthopaedic surgeon but only 1% went on to a surgical wait list. Families and referrers reported high levels of satisfaction and only three patients discharged by the NSP were referred back for orthopaedic surgeon review. CONCLUSION: The NSP role was effective at reducing clinic wait times for patients with non-urgent paediatric orthopaedic conditions, while maintaining family and referrer satisfaction.

Knockout of the tetraspanin Cd9 in the TRAMP model of de novo prostate cancer increases spontaneous metastases in an organ-specific manner.

Prostate cancer is an extremely heterogeneous disease; patients that do progress to late-stage metastatic prostate cancer have limited treatment options, mostly palliative. Molecules involved in the metastatic cascade may prove beneficial in stratifying patients to assign appropriate treatment modalities and may also prove to be therapeutic antimetastatic targets. The tetraspanin group of molecules are integral membrane proteins that associate with motility-related proteins such as integrins. Clinical studies have mostly shown that reduced expression levels of the tetraspanin CD9 are correlated with tumour progression in a range of cancers. Furthermore, functional studies have shown CD9 to be involved in cell motility and adhesion and that it may influence metastasis. The effects of endogenous CD9 on prostate cancer initiation and progression were analysed by crossing a Cd9-/- (KO) murine model with a model of de novo developing and spontaneously metastasising prostate cancer, namely the transgenic adenocarcinoma of mouse prostate model. Our study demonstrates for the first time that ablation of Cd9 had no detectable effect on de novo primary tumour onset, but did significantly increase metastasis to the liver but not the lungs.

Genetic ablation of the tetraspanin CD151 reduces spontaneous metastatic spread of prostate cancer in the TRAMP model.

Tetraspanins are integral membrane proteins that associate with motility-related molecules such as integrins. Experimental studies have indicated that they may be important regulators of tumor invasion and metastasis, and high expression of the tetraspanin CD151 has been linked to poor prognosis in a number of cancers. Here, we show for the first time that genetic ablation of CD151 inhibits spontaneous metastasis in a transgenic mouse model of de novo tumorigenesis. To evaluate the effects of CD151 on de novo prostate cancer initiation and metastasis, a Cd151(-/-) (KO) murine model was crossed with the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model. Mice were analyzed for initiation of prostate tumor by palpation and primary tumors were analyzed by immunohistochemistry. Liver and lungs were examined for incidence and size of spontaneous metastatic lesions by histopathology. Knocking-out Cd151 had no significant effect on prostate cancer initiation or on expression of markers of proliferation, apoptosis, or angiogenesis in primary tumors. However, it did significantly decrease metastasis in a site-specific fashion, notably to the lungs but not the liver. Thus, CD151 acts principally as promoter of metastasis in this model. Prostate cancer is the second highest cause of cancer-related deaths in men in most Western countries, with the majority of deaths attributed to late-stage metastatic disease. CD151 may prove to be a valuable prognostic marker for treatment stratification and is a possible antimetastatic target.

Improved small-molecule macroarray platform for the rapid synthesis and discovery of antibacterial chalcones.

Bacterial resistance to current antibiotics is a major global health threat. Consequently, there is an urgent need for the identification of new antibacterial agents. We are applying the small-molecule macroarray platform to rapidly synthesize and screen compounds for activity against methicillin-resistant Staphylococcus aureus (MRSA). Herein, we report the synthesis of a 1,3-diphenyl-2-propen-1-one (chalcone) macroarray using a Rink-amide linker-derivatized cellulose support. The Rink linker allowed for the incorporation of a broader array of library building blocks relative to our previous syntheses because milder reaction conditions could be utilized; significantly higher compound loadings were also achieved (~80% vs ~15%). Analysis of the 174-member chalcone macroarray in off-support antibacterial screening assays revealed three chalcones with minimum inhibitory concentration (MIC) values against MRSA comparable to currently used antibacterial drugs and low hemolytic activities. These results serve to further showcase and extend the utility of the small molecule macroarray for antibacterial discovery.

A class of selective antibacterials derived from a protein kinase inhibitor pharmacophore.

As the need for novel antibiotic classes to combat bacterial drug resistance increases, the paucity of leads resulting from target-based antibacterial screening of pharmaceutical compound libraries is of major concern. One explanation for this lack of success is that antibacterial screening efforts have not leveraged the eukaryotic bias resulting from more extensive chemistry efforts targeting eukaryotic gene families such as G protein-coupled receptors and protein kinases. Consistent with a focus on antibacterial target space resembling these eukaryotic targets, we used whole-cell screening to identify a series of antibacterial pyridopyrimidines derived from a protein kinase inhibitor pharmacophore. In bacteria, the pyridopyrimidines target the ATP-binding site of biotin carboxylase (BC), which catalyzes the first enzymatic step of fatty acid biosynthesis. These inhibitors are effective in vitro and in vivo against fastidious gram-negative pathogens including Haemophilus influenzae. Although the BC active site has architectural similarity to those of eukaryotic protein kinases, inhibitor binding to the BC ATP-binding site is distinct from the protein kinase-binding mode, such that the inhibitors are selective for bacterial BC. In summary, we have discovered a promising class of potent antibacterials with a previously undescribed mechanism of action. In consideration of the eukaryotic bias of pharmaceutical libraries, our findings also suggest that pursuit of a novel inhibitor leads for antibacterial targets with active-site structural similarity to known human targets will likely be more fruitful than the traditional focus on unique bacterial target space, particularly when structure-based and computational methodologies are applied to ensure bacterial selectivity.

Rapid identification of antibacterial agents effective against Staphylococcus aureus using small-molecule macroarrays.

There is an urgent, global need for the development of new antibacterial agents. We have applied the small-molecule macroarray approach to the synthesis and screening of antibacterial compounds active against the Gram-positive pathogen Staphylococcus aureus. Several macroarrays of 1,3-diphenyl-2-propen-1-ones (chalcones), cyanopyridines, and pyrimidines were synthesized on a planar cellulose support system on the order of days. This support system was found to be highly compatible with antibacterial assay formats, including disk-diffusion and agar-overlay visualization methods. Further, sufficient compound was isolated from each spot of the macroarray for both compound characterization and minimum inhibitory concentration (MIC) estimation. Analysis of the small-molecule macroarrays in these assays uncovered a set of antibacterial agents with in vitro MIC values against methicillin-resistant S. aureus comparable to certain antibacterial drugs in use today.

Discovery of fluorescent cyanopyridine and deazalumazine dyes using small molecule macroarrays.

[structure: see text] Small molecule macroarrays of cyanopyridines and deazalumazines were generated in high purities via spatially addressed synthesis on planar cellulose supports. Examination of the spectral properties of the heterocycles both on and off of the planar support revealed a set of promising new fluorescent dyes that exhibit high quantum yields, low pH dependence, and high sensitivity to solvent polarity.

Microwave-accelerated SPOT-synthesis on cellulose supports.

[reaction: see text] We demonstrate that microwave irradiation can dramatically accelerate reaction rates for spatially addressable library synthesis on planar membrane supports. The development of a robust support/linker system, microwave-assisted synthesis of small molecule test libraries, and methods for solid-phase scale-up on cellulose are described.