Treatment-induced and Pre-existing Anti-peg Antibodies: Prevalence, Clinical Implications, and Future Perspectives.

Polyethylene glycol (PEG) is a versatile polymer that is used in numerous pharmaceutical applications like the food industry, a wide range of disinfectants, cosmetics, and many commonly used household products. PEGylation is the term used to describe the covalent attachment of PEG molecules to nanocarriers, proteins and peptides, and it is used to prolong the circulation half-life of the PEGylated products. Consequently, PEGylation improves the efficacy of PEGylated therapeutics. However, after four decades of research and more than two decades of clinical applications, an unappealing side of PEGylation has emerged. PEG immunogenicity and antigenicity are remarkable challenges that confound the widespread clinical application of PEGylated therapeutics - even those under clinical trials - as anti-PEG antibodies (Abs) are commonly reported following the systemic administration of PEGylated therapeutics. Furthermore, pre-existing anti-PEG Abs have also been reported in healthy individuals who have never been treated with PEGylated therapeutics. The circulating anti-PEG Abs, both treatment-induced and pre-existing, selectively bind to PEG molecules of the administered PEGylated therapeutics inducing activation of the complement system, which results in remarkable clinical implications with varying severity. These include increased blood clearance of the administered PEGylated therapeutics through what is known as the accelerated blood clearance (ABC) phenomenon and initiation of serious adverse effects through complement activation-related pseudoallergic reactions (CARPA). Therefore, the US FDA industry guidelines have recommended the screening of anti-PEG Abs, in addition to Abs against PEGylated proteins, in the clinical trials of PEGylated protein therapeutics. In addition, strategies revoking the immunogenic response against PEGylated therapeutics without compromising their therapeutic efficacy are important for the further development of advanced PEGylated therapeutics and drug-delivery systems.

Tracheostomy insertion in COVID-19: insertion practice and factors leading to unplanned tube exchange.

Background: Tracheostomy insertion in patients with coronavirus disease 2019 (COVID-19) presents unique challenges. Patients frequently have high ventilatory requirements, and as an aerosol generating procedure, tracheostomy insertion creates the potential for staff transmission. Problems with tracheostomies contribute to morbidity and mortality, and tracheostomy changes may increase risks of staff transmission. We sought to quantify the incidence of clinically necessitated tracheostomy changes, establish the indications for change and investigate the incidence of staff transmission. Methods: We conducted a single institution, retrospective, observational cohort study of all intensive care unit (ICU) patients with COVID-19 who had a tracheostomy between March 2020 and April 2021. The institution is a large tertiary referral centre in Ireland. Results: Forty-three patients had a tracheostomy during the study period. All were a Shiley™ Flexible Adult Taperguard or Shiley™ XLT Tracheostomy. 14 patients (33%) required a tracheostomy change, with the majority (57%) involving a change from a standard size to an extended length tracheostomy. Persistent leak was the most common indication for change (71.6%). Other indications included patient-ventilator dyssynchrony, persistent cough and accidental decannulation. No staff transmission of COVID-19 occurred during this study. Conclusions: The incidence of tracheostomy change was 33%, highlighting the importance of selecting the right tracheostomy for each patient. We discuss how key characteristics of tracheostomies such as type, size, length and inner diameter may impact flow, resistance and work of breathing, leading to unplanned tracheostomy change. No staff transmission occurred arising from tracheostomy insertion, adding to increasing evidence that tracheostomy insertion in COVID-19 appears safe with adherence to guidelines describing the correct use of personal protective equipment.

Polyethylene glycol (PEG): The nature, immunogenicity, and role in the hypersensitivity of PEGylated products.

Polyethylene glycol (PEG) is a versatile polymer that is widely used as an additive in foods and cosmetics, and as a carrier in PEGylated therapeutics. Even though PEG is thought to be less immunogenic, or perhaps even non-immunogenic, with a variety of physicochemical properties, there is mounting evidence that PEG causes immunogenic responses when conjugated with other materials such as proteins and nanocarriers. Under these conditions, PEG with other materials can result in the production of anti-PEG antibodies after administration. The antibodies that are induced seem to have a deleterious impact on the therapeutic efficacy of subsequently administered PEGylated formulations. In addition, hypersensitivity to PEGylated formulations could be a significant barrier to the utility of PEGylated products. Several reports have linked the presence of anti-PEG antibodies to incidences of complement activation-related pseudoallergy (CARPA) following the administration of PEGylated formulations. The use of COVID-19 mRNA vaccines, which are composed mainly of PEGylated lipid nanoparticles (LNPs), has recently gained wide acceptance, although many cases of post-vaccination hypersensitivity have been documented. Therefore, our review focuses not only on the importance of PEGs and its great role in improving the therapeutic efficacy of various medications, but also on the hypersensitivity reactions attributed to the use of PEGylated products that include PEG-based mRNA COVID-19 vaccines.

The Diagnostic Accuracy of Noninvasive Methods to Measure the Intracranial Pressure: A Systematic Review and Meta-analysis.

BACKGROUND: Although invasive monitoring is the standard method for intracranial pressure (ICP) measurement, it is not without potential for serious complications. Noninvasive methods have been proposed as alternatives to invasive ICP monitoring. The study aimed to investigate the diagnostic accuracy of the currently available noninvasive methods for intracranial hypertension (ICH) monitoring. METHODS: We searched 5 databases for articles evaluating the diagnostic accuracy of noninvasive methods in diagnosing ICH in PubMed, Institute of Science Index, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase. The quantitative analysis was conducted if there were at least 2 studies evaluating a specific method. The accuracy measures included the sensitivity, specificity, likelihood ratios, and diagnostic odds ratio. RESULTS: We included 134 articles. Ultrasonographic optic nerve sheath diameter (US ONSD) had high diagnostic accuracy (estimated sensitivity of 90%; 95% confidence interval [CI], 87-92, estimated specificity of 88%; 95% CI, 84-91) while the magnetic resonance imaging (MRI) ONSD had estimated sensitivity of 77%; 95% CI, 64-87 and estimated specificity of 89%; 95% CI, 84-93, and computed tomography (CT) ONSD had estimated sensitivity of 93%; 95% CI, 90-96 and estimated specificity of 79%; 95% CI, 56-92. All MRI signs had a very high estimated specificity ranging from 90% to 99% but a low estimated sensitivity except for sinus stenosis which had high estimated sensitivity as well as specificity (90%; 95% CI, 75-96 and 96%; 95% CI, 91-99, respectively). Among the physical examination signs, pupillary dilation had a high estimated specificity (86%; 95% CI, 76-93). Other diagnostic tests to be considered included pulsatility index, papilledema, transcranial Doppler, compression or absence of basal cisterns, and ≥10 mm midline shift. Setting the cutoff value of ICH to ≥20 mm Hg instead of values <20 mm Hg was associated with higher sensitivity. Moreover, if the delay between invasive and noninvasive methods was within 1 hour, the MRI ONSD and papilledema had a significantly higher diagnostic accuracy compared to the >1 hour subgroup. CONCLUSIONS: Our study showed several promising tools for diagnosing ICH. Moreover, we demonstrated that using multiple, readily available, noninvasive methods is better than depending on a single sign such as physical examination or CT alone.

Results of meniscal injuries repair using different arthroscopic techniques.

AIM: Evaluation of clinical and radiological outcomes following meniscal repair using different arthroscopic techniques for all meniscal tears amenable for repair. METHODS: Sixty-one patients were involved in a prospective study; all cases presented with meniscal tears underwent arthroscopic meniscal repair from December 2016 to December 2017. Outcomes involved the site of tear, the repair technique, and associated injuries. The International Knee Documentation Committee Score (IKDC) and Tegner Lysholm Knee Score were used to analyze the clinical and functional outcomes postoperatively. RESULTS: Of the 61 patients, 50 patients (81.9%) had meniscal tear associated with isolated ligamentous ACL injury, 6 cases had corrective osteotomy with ACL reconstruction to correct concomitant genu varus, 2 cases (3.3%) had meniscal tear associated with isolated ligamentous PCL injury, and 9 patients (14.8%) presented with isolated meniscal tear; IKDC was preoperatively (44.52 ± 8.79), postoperatively at 6 months (90.97 ± 6.75) and at 12 months (92.27 ± 2.68) with P-value (0.001). Tegner Lysholm score was preoperatively (52.16 ± 12.22), postoperatively at 6 months (88.03 ± 6.84) and at 12 months (93.26 ± 2.95) with P-value (0.001). Fifty eight patients (95.1%) had no postoperative symptoms at 6 and 12 months' follow-up. The remaining 3 cases (4.9%) underwent partial meniscectomy due to persistent postoperative clinical symptoms with no signs of healing in MRI. CONCLUSIONS: Our study concluded that arthroscopic meniscal repair is an effective way in the management of meniscal tears regarding clinical and functional outcomes.

Arabic translation and validation of three knee scores, Lysholm Knee Score (LKS), Oxford Knee Score (OKS), and International Knee Documentation Committee Subjective Knee Form (IKDC).

AIM OF THE WORK: Translation and validation of three commonly used knee scores to Arabic language: the Lysholm Knee Score (LKS), the Oxford Knee Score (OKS), and IKDC Subjective Knee Form. METHODS: Our work focused on translation and validation of the LKS, OKS and IKDC. Construct validity was assessed by comparing the LKS, OKS, and IKDC Subjective Knee Form and previous Arabic translated version of Knee injury and Osteoarthritis Outcome Score (KOOS). Test-retest reliability, internal consistency, and construct validity were assessed, using Intraclass Correlation Coefficient (ICC), Cronbach's alpha, and Pearson correlation coefficient (r). RESULTS: Reliability was excellent for the Arabic IKDC subjective form (0.95), while the Arabic LKS and the Arabic OKS were good: 0.8 and 0.85, respectively. The Cronbach's ά was excellent for the Arabic LKS and Arabic OKS: 0.9 and 0.90, respectively, while the Arabic IKDC subjective form was good (0.89). Construct validity was high for the Arabic LKS and the Arabic OKS: 0.7 and 0.913, respectively, while the Arabic IKDC was moderate (0.4) in cases of ACL and meniscus injuries and mild (0.18) in cases of osteoarthritis. CONCLUSION: Arabic LKS and Arabic OKS were reliable and valid scores for patients complaining of ligamentous injuries, meniscus injuries, and osteoarthritis to be used for Arabic-speaking people, while the Arabic IKDC had excellent reliability and mild validity in cases of osteoarthritis and moderate validity in cases of ACL and meniscus injuries.

Agreement among ophthalmologists in marking the optic disc and optic cup in fundus images.

The purpose of this paper was to study the agreement between six ophthalmologists who manually marked the optic nerve head using fundus images. Four different parameters were considered from the manual marking images: (1) disc (area and centroid), (2) cup (area and centroid), (3) horizontal and vertical cup-to-disc ratios, and (4) including the previous two parameters for both horizontal and vertical cup-to-disc ratios, and investigated the comprehensive agreement and accuracy among all the ophthalmologists. The best agreement percentage for all the parameters combined was between ophthalmologists number one and three for 44 % of images, and the best accuracy was for ophthalmologist number one with 77.4 % of 315 total tested images. Our analysis shows that more than half of the images in the dataset were not agreed upon when considering all the parameters together.