Descriptive account of 18 adults with known HIV infection hospitalised with SARS-CoV-2 infection.

OBJECTIVE: To report on the clinical characteristics and outcome of 18 people living with HIV (PLWH) hospitalised with SARS-CoV-2 infection in a London teaching hospital. METHODS: The hospital notes of 18 PLWH hospitalised with SARS-CoV-2 infection were retrospectively reviewed alongside data concerning their HIV demographics from an established HIV Database. RESULTS: The majority (16/18) had positive PCR swabs for SARS-CoV-2, and two had negative swabs but typical COVID-19 imaging and history. Most were male (14/18, 78%), median age 63 years (range 47-77 years). Two-thirds were migrants, nine (50%) of Black, Asian and minority ethnicity (BAME). All were diagnosed with HIV for many years (range 8-31 years), and all had an undetectable HIV viral load (<40 copies/mL). The median CD4 prior to admission was 439 (IQR 239-651), and 10/16 (63%) had a CD4 nadir below 200 cells/mm3. Almost all (17/18) had been diagnosed with at least one comorbidity associated with SARS-CoV-2 prior to admission. 3/18 patients died. None received mechanical ventilation. Hospital stay and clinical course did not appear prolonged (median 9 days). CONCLUSIONS: Our data suggest that PLWH may not necessarily have prolonged or complex admissions to hospital when compared with the general hospital and national population admitted with COVID-19. Many had low nadir CD4 counts and potentially impaired functional immune restoration. The PLWH group was younger than generally reported for COVID-19, and the majority were male with multiple complex comorbidities. These patients had frequent contact with hospital settings increasing potential for nosocomial acquisition and increased risk of severe COVID-19.

Parameter Reduction and Optimisation for Point Cloud and Occupancy Mapping Algorithms.

Occupancy mapping is widely used to generate volumetric 3D environment models from point clouds, informing a robotic platform which parts of the environment are free and which are not. The selection of the parameters that govern the point cloud generation algorithms and mapping algorithms affects the process and the quality of the final map. Although previous studies have been reported in the literature on optimising major parameter configurations, research in the process to identify optimal parameter sets to achieve best occupancy mapping performance remains limited. The current work aims to fill this gap with a two-step principled methodology that first identifies the most significant parameters by conducting Neighbourhood Component Analysis on all parameters and then optimise those using grid search with the area under the Receiver Operating Characteristic curve. This study is conducted on 20 data sets with specially designed targets, providing precise ground truths for evaluation purposes. The methodology is tested on OctoMap with point clouds created by applying StereoSGBM on the images from a stereo camera. A clear indication can be seen that mapping parameters are more important than point cloud generation parameters. Moreover, up to 15% improvement in mapping performance can be achieved over default parameters.

An Occupancy Mapping Method Based on K-Nearest Neighbours.

OctoMap is an efficient probabilistic mapping framework to build occupancy maps from point clouds, representing 3D environments with cubic nodes in the octree. However, the map update policy in OctoMap has limitations. All the nodes containing points will be assigned with the same probability regardless of the points being noise, and the probability of one such node can only be increased with a single measurement. In addition, potentially occupied nodes with points inside but traversed by rays cast from the sensor to endpoints will be marked as free. To overcome these limitations in OctoMap, the current work presents a mapping method using the context of neighbouring points to update nodes containing points, with occupancy information of a point represented by the average distance from a point to its k-Nearest Neighbours. A relationship between the distance and the change in probability is defined with the Cumulative Density Function of average distances, potentially decreasing the probability of a node despite points being present inside. Experiments are conducted on 20 data sets to compare the proposed method with OctoMap. Results show that our method can achieve up to 10% improvement over the optimal performance of OctoMap.

A high yielding IFNAR1 ECD mammalian expression process for use in autoimmune disease drug development.

Interferon-alpha receptor 1 (IFNAR1) is a target of interest for recombinant biotherapeutics that block the JAK/STAT pathway. This pathway is believed to play a role in many diseases including Hepatitis B and C, Herpes Simplex, Multiple Sclerosis, and other autoimmune disorders. By using IFNAR1 as a target to block Type I IFN from binding to the JAK/STAT pathway and prevent activation of this target, autoimmune disease progression can be modulated. Current IFNAR1 extracellular domain (ECD) expression and purification protocols are labor intensive with low product yield and limited scalability. In this work, we evaluate three different expression systems (baculovirus, human embryonic kidney 293 (HEK293×), and Chinese hamster ovary (CHO)) to improve expression of IFNAR1 ECD. We demonstrate the benefits of utilizing mammalian CHO cell transient transfection to increase expression titer, as well as an improved two-step purification process performed using immobilized metal affinity chromatography (IMAC) as the capture step and Ceramic Hydroxyapatite (CHT) Type II for HMW impurity removal in flow through mode. This process showed an 20-fold increase in productivity compared to the baseline process as measured by grams purified per liter of cell culture fluid. Lastly, the improved process showed good scalability, enabling efficient purification of 3.6 g of product from a 30 L scale bioreactor.

Characterization and quantification of succinimide using peptide mapping under low-pH conditions and hydrophobic interaction chromatography.

Characterization of asparagine deamidation and aspartic acid isomerization is an important aspect of biotherapeutic protein analysis due to the potential negative effect of these modifications on drug efficacy and stability. Succinimide has long been known to be an intermediate product of asparagine deamidation and aspartic acid isomerization, but despite the key role of succinimide in these reactions, its analysis remains challenging due to its instability. We have developed a paradigm in which two interlinked analytical methods are used to develop an optimized approach to analyze succinimide. In the first method, low-pH protein digestion is used for detailed characterization of succinimide with peptide mapping. At low pH, succinimide is stable and can be analyzed with accurate mass measurements and tandem mass spectrometry to confirm its identity and localize its modification site. These results are then used to establish a hydrophobic interaction chromatography (HIC)-based method that can be used for release and stability studies. In this method, unmodified protein, deamidated products, and succinimide are well separated and quantified. Good correlation was obtained between the data from low-pH protein digestion-based peptide mapping and the HIC-based method. Method qualification showed that the HIC-based method is robust, accurate, and precise and has excellent linearity.

Platypnea-Orthodeoxia Syndrome: A Case of Chronic Paroxysmal Hypoxemia.

A 75-year-old man with chronic (30-year) unexplained paroxysmal hypoxemia presented with postural hypoxemia and desaturation consistent with a clinical manifestation of platypnea-orthodeoxia syndrome. His history included a lack of significant past pulmonary disease, yet with intermittent need for oxygen supplementation. On admission he was found to have an interatrial shunt through a patent foramen ovale. Device closure by percutaneous catheterization led to sustained resolution of symptoms. Platypnea-orthodeoxia syndrome is a rare but important consideration in the differential diagnosis of hypoxemia, as it represents a potentially curable cause of hypoxemia, with missed diagnosis leading to possible patient morbidity if untreated. Even more importantly, an astute and careful history and physical examination are integral to the diagnosis of this rare but likely under-recognized syndrome.

21†Daily dynamic discharge - a whole system solution to ED crowding.

INTRODUCTION: ED crowding is associated with increased mortality, poor staff and patient experience, an increased inpatient length of stay and poor compliance with the four-hour emergency access standard.1 Where crowding is caused by exit block, the focus needs to be on whole system patient management, reducing the temporal mismatch between admissions and discharges since at times of peak demand hospitals may become gridlocked until patients are discharged.In an attempt to tackle exit block, the Scottish Government Unscheduled Care Team have implemented the Daily Dynamic Discharge (DDD) approach, which aims to increase the number of inpatient discharges by 12 pm, thus enabling more timeous flow through the ED. METHODS: A series of meetings were held between the Unscheduled Care Team and the clinical and managerial staff of Dumfries and Galloway Royal Infirmary over a two-week period to train staff on implementing the elements of the Daily Dynamic Discharge approach. These included holding a daily whiteboard meeting with input from the multidisciplinary team, early determination of an Estimated Date of Discharge (EDD) for each patient, and conducting 'golden hour' ward rounds whereby the highest acuity patients were seen first followed by those who were expected to be discharged that day, thus increasing the number of discharges by 12 pm. RESULTS: Over a twelve-week period the average number of weekly discharges increased from 26.5 to 30.2, i.e., an average increase of 3.7 discharges per week. Average length of stay dropped from 6.8 days to 6.2 days, a saving of 0.6 days.The median discharge time was 32 min earlier once DDD had been implemented. Previously, a third (33%) of patients were discharged before 4 pm; after implementation, this rose to 44%. DISCUSSION: Emergency Department activity, and particularly crowding, is the barometer for the rest of the hospital, and the only way to guarantee that patients who require admission, get into the right bed, and in a timely way, is to ensure that the downstream wards discharge sufficient numbers early in the day to accommodate admissions from the ED.The DDD approach has been shown to be effective in increasing the number of discharges by 12 pm, smoothing the admission/discharge profile, and is now being adopted in other hospitals throughout Scotland. REFERENCE: Richardson DB. Increase in patient mortality at 10 days associated with emergency department overcrowding. Med J Aust2006;184(5):213-216.

Cotton Fever: Does the Patient Know Best?

Fever and leukocytosis have many possible etiologies in injection drug users. We present a case of a 22-year-old woman with fever and leukocytosis that were presumed secondary to cotton fever, a rarely recognized complication of injection drug use, after an extensive workup. Cotton fever is a benign, self-limited febrile syndrome characterized by fevers, leukocytosis, myalgias, nausea and vomiting, occurring in injection drug users who filter their drug suspensions through cotton balls. While this syndrome is commonly recognized amongst the injection drug user population, there is a paucity of data in the medical literature. We review the case presentation and available literature related to cotton fever.

Platelet mimicry: The emperor's new clothes?

Here we critically examine whether coating of nanoparticles with platelet membranes can truly disguise them against recognition by elements of the innate immune system. We further assess whether the "cloaking technology" can sufficiently equip nanoparticles with platelet-mimicking functionalities to include in vivo targeting of damaged blood vessels and binding to platelet-adhering opportunistic pathogens. We present views for improved, and pharmaceutically viable nanoparticle design strategies.

Aggregates of α-chymotrypsinogen anneal to access more stable states.

Non-native protein aggregates present a variety of problems in fundamental and applied biochemistry and biotechnology, from quality and safety issues in pharmaceutical development to their association with a number of chronic diseases. The aggregated, often amyloid, protein state is often considered to be more thermodynamically and kinetically stable than (partially) unfolded or folded monomers except under highly denaturing conditions. However, evolution of the structure and stability of aggregated states has received much less attention. Here it is shown that under mildly-denaturing conditions (elevated temperature or [urea]), where the native monomer (N) is slightly favored compared to the unfolded state (U), α-chymotrypsinogen A (aCgn) non-native aggregates undergo a structural relaxation or annealing process to reach even more stable states. The annealed aggregates are more resistant to dissociation than aggregates that do not undergo this relaxation process. Aggregates without annealing dissociate via linear chain depolymerization, and annealing is accelerated under conditions that promote slow dissociation (partially denaturing conditions). This is consistent with a free energy landscape with multiple barriers and local minima that allows for a kinetic competition between aggregate dissociation and structural relaxation to more stable aggregate states. This highlights added complexities for protein refolding or aggregate dissociation processes, and may explain why it is often difficult to completely recover monomeric protein from aggregates.

Sonar target enhancement by shrinkage of incoherent wavelet coefficients.

Background reverberation can obscure useful features of the target echo response in broadband low-frequency sonar images, adversely affecting detection and classification performance. This paper describes a resolution and phase-preserving means of separating the target response from the background reverberation noise using a coherence-based wavelet shrinkage method proposed recently for de-noising magnetic resonance images. The algorithm weights the image wavelet coefficients in proportion to their coherence between different looks under the assumption that the target response is more coherent than the background. The algorithm is demonstrated successfully on experimental synthetic aperture sonar data from a broadband low-frequency sonar developed for buried object detection.

Clinical and neuroradiographic features of fentanyl inhalation-induced leukoencephalopathy.

A man in his late 40s with no known past medical history was unresponsive for an unknown period of time. Crushed pills and white residue were found on a nearby table. On presentation he was obtunded and unresponsive to verbal commands but withdrawing to painful stimuli. The initial urine drug screen was negative, but a urine fentanyl screen was subsequently positive with a level of 137.3 ng/mL. MRI of the brain showed reduced diffusivity and fluid attenuated inversion recovery (FLAIR) hyperintensity symmetrically in the bilateral supratentorial white matter, cerebellum and globus pallidus. Alternative diagnoses such as infection were considered, but ultimately the history and workup led to a diagnosis of fentanyl-induced leukoencephalopathy. Three days after admission the patient became able to track, respond to voice and follow basic one-step commands. The patient does not recall the mechanism of inhalation. While there are case reports of heroin-induced leukoencephalopathy following inhaled heroin use and many routes of fentanyl, this is the first reported case of a similar phenomenon due to fentanyl inhalation.

Complement activation by PEG-functionalized multi-walled carbon nanotubes is independent of PEG molecular mass and surface density.

Carboxylated (4%) multi-walled carbon nanotubes were covalently functionalized with poly(ethylene glycol)1000 (PEG1000), PEG1500 and PEG4000 with a PEG loading of approximately 11% in all cases. PEG loading generated non-uniform and heterogeneous higher surface structures and increased nanotube width considerably, but all PEGylated nanotube species activated the complement system in human serum equally. Increased PEG loading, through adsorption of methoxyPEG2000(or 5000)-phospholipid conjugates, generated fewer complement activation products; however, complement activation was never completely eliminated. Our observations address the difficulty in making carbon nanotubes more compatible with innate immunity through covalent PEG functionalization as well as double PEGylation strategies. FROM THE CLINICAL EDITOR: Complement-mediated toxicity is a major limiting factor in certain nanomedicine applications. This study clarifies that PEGylation of carbon nanotubes is unlikely to address this complication.

Turning the world upside down: reversal-of-vision metamorphopsia in a patient with syncope.

An elderly man with recurrent syncope was admitted with a globe rupture following a syncopal attack. After an initial unremarkable evaluation, the patient reported inversion of the room's wall clock during a bedside evaluation. This symptom is called reversal-of-vision metamorphopsia (RVM) and is a rare visual disturbance that typically results from organic processes localised to the retina and/or posterior cortex of the brain or in some cases is psychogenic in nature. In this case, both the syncope and RVM were caused by impaired circulation in the posterior cortex, and management included an antiplatelet agent, statin and permissive blood pressure targets, which resulted in the correction of RVM.

Implementation of a Nurse-Driven Medication Ordering Protocol to Improve Clinician and Nursing Experiences.

ABSTRACT: Paging and text messaging to request new orders remain common means of communication between clinicians and nurses in the hospital setting. However, sending and triaging multiple pages can lead to interruptions in other clinical duties. A medication order delegation protocol allowing for nurse-driven ordering of low-risk medications was developed with an objective of decreasing potentially avoidable pages. The aim of this study was to evaluate the impact of implementing this protocol on nurse and clinician perceptions of clerical burden and satisfaction. A survey assessing satisfaction with the process of obtaining medications in this protocol and the perception of clerical burden associated with ordering them before and after delegation protocol implementation was completed by over 160 clinicians and nurses. Survey respondents reported increased satisfaction and decreased clerical burden associated with the implementation of the delegation protocol. These results suggest the potential for delegation protocols to limit clerical burden associated with paging.

Real world use of dolutegravir two drug regimens.

BACKGROUND: Since 2015, we prescribed dolutegravir (DTG)-based two drug regimens (DTG-2DR) for 620 people [total cohort 3133 (19.8%)]. METHOD: Clinic database search 1 January 15 to 31 October 21. Demographic, tolerability and HIV related data analysed. RESULTS: In total, 620 people identified; 561 had complete data. 446 male (79.5%); median age 54 years (interquartile range 46, 59). 343 (61.1%) MSM. Nine people who initiated naïvely achieved viral suppression (100%). 546/552 (99.0%) switched or continued and were suppressed at data censor. 460/552 (83.3%) received DTG-lamivudine (DTG/3TC), 74/552 (13.4%) received DTG-rilpivirine (DTG/RPV) and 18/552 (3.3%) received DTG-emtricitabine (DTG/FTC). 70 (12.5%) switched off DTG-2DR (55 DTG/3TC, 13 DTG/RPV, two DTG/FTC) due to side-effects. 41 episodes of blip (1 off >50 copies/ml) occurred in 30 people (5.3%). 11/41 on DTG-RPV [ n  = 7 multi-tablet regimen (MTR), n  = 4 single tablet regimen (STR)]. 27/41 DTG-3TC, 3/41 DTG/FTC ( n  = 26 MTR, n  = 4 STR). Six people (1.1%) failed (confirmed viral load >200 copies/ml or persistent low level viraemia) ( n  = 4 DTG-3TC STR, n  = 1 DTG-3TC MTR, n  = 1 DTG-RPV MTR). Four failures due to low level viraemia, one due to non-adherence and one due to high viral load. Resistance tests performed for 5/6 - mutations detected only in latter person with high viral load failure (on DTG-3TC MTR) who developed triple class resistance. CONCLUSION: Majority of experience is in DTG/3TC stable switch. Minority of patients developed side-effects. Low number of virological failures, one developed integrase inhibitor resistance. Viral failure associated with MTR, commensurate with trial data showing no failure with resistance if DTG/3TC STR used. Overall DTG-2DR demonstrates high efficacy in real-world setting.

Cross-sectional study evaluating the impact of SARS-CoV-2 variants on Long COVID outcomes in UK hospital survivors.

OBJECTIVES: COVID-19 studies report on hospital admission outcomes across SARS-CoV-2 waves of infection but knowledge of the impact of SARS-CoV-2 variants on the development of Long COVID in hospital survivors is limited. We sought to investigate Long COVID outcomes, aiming to compare outcomes in adult hospitalised survivors with known variants of concern during our first and second UK COVID-19 waves, prior to widespread vaccination. DESIGN: Prospective observational cross-sectional study. SETTING: Secondary care tertiary hospital in the UK. PARTICIPANTS: This study investigated Long COVID in 673 adults with laboratory-positive SARS-CoV-2 infection or clinically suspected COVID-19, 6 weeks after hospital discharge. We compared adults with wave 1 (wildtype variant, admitted from February to April 2020) and wave 2 patients (confirmed Alpha variant on viral sequencing (B.1.1.7), admitted from December 2020 to February 2021). OUTCOME MEASURES: Associations of Long COVID presence (one or more of 14 symptoms) and total number of Long COVID symptoms with SARS-CoV-2 variant were analysed using multiple logistic and Poisson regression, respectively. RESULTS: 322/400 (wave 1) and 248/273 (wave 2) patients completed follow-up. Predictors of increased total number of Long COVID symptoms included: pre-existing lung disease (adjusted count ratio (aCR)=1.26, 95% CI 1.07, 1.48) and more COVID-19 admission symptoms (aCR=1.07, 95% CI 1.02, 1.12). Weaker associations included increased length of inpatient stay (aCR=1.02, 95% CI 1.00, 1.03) and later review after discharge (aCR=1.00, 95% CI 1.00, 1.01). SARS-CoV-2 variant was not associated with Long COVID presence (OR=0.99, 95% CI 0.24, 4.20) or total number of symptoms (aCR=1.09, 95% CI 0.82, 1.44). CONCLUSIONS: Patients with chronic lung disease or greater COVID-19 admission symptoms have higher Long COVID risk. SARS-CoV-2 variant was not predictive of Long COVID though in wave 2 we identified fewer admission symptoms, improved clinical trajectory and outcomes. Addressing modifiable factors such as length of stay and timepoint of clinical review following discharge may enable clinicians to move from Long COVID risk stratification towards improving its outcome.

Thoracic endometriosis unmasked by ovarian hyperstimulation for in vitro fertilization.

Thoracic endometriosis syndrome is a well-described, rare manifestation of endometriosis. We present a case of a 35-year old woman undergoing controlled ovarian stimulation prior to in vitro fertilization (IVF) who developed bilateral hemorrhagic pleural effusions. She was initially diagnosed with ovarian hyperstimulation syndrome, a complication of infertility therapy; however, she was later found to have occult thoracic endometriosis. We describe ovarian hyperstimulation syndrome and review the manifestations of thoracic endometriosis syndrome. Although endometriosis is a hormone-dependent disease, the rate of IVF complications related to endometriosis is low.

Leveraging light chain binding avidity for control of mispaired byproducts during production of asymmetric bispecific antibodies.

Many biotherapeutic formats leverage antibody light chain affinity chromatography to enable robust manufacturing processes and to streamline process development. These include multi-specific antibody and antibody fragment platforms which are often designed for specific capture purification methods that can provide efficient removal of commonly expressed product-related impurities. Recently, several accounts of product-related impurity separation by leveraging binding avidity during affinity chromatography have been described in the literature. However, a more comprehensive evaluation of avidity-based separations, particularly for light chain affinity media with specificity for constant regions of antibody light chains, is valuable for development of emerging multi-specific and fragment antibody formats. Results in this work demonstrate the capability of camelid antibody-based light chain affinity media to separate asymmetric bispecific antibody heterodimers from impurities possessing more than one light chain of the same class that the media binds to, including mispaired variants, aggregates, and fragment impurities. Largest resolution for respective mispaired species were provided by CaptureSelect KappaXP and LambdaXP chromatography media. The addition of elution modifiers provided increased impurity separation, with CaptureSelect KappaXP requiring up to 500 mM concentrations of elution modifiers to produce substantial improvements to resolution, and LambdaXP showing much higher sensitivity. Isocratic elution methods developed for lambda light chain affinity chromatography media provided near complete removal of mispaired variants, and substantial removal of aggregates and fragment impurities. Addition of just 20 mM of elution modifiers such as NaCl are shown to drive increased binding strength and separation of heterodimer species from impurities on CaptureSelect LambdaXP. These results provide scalable and transferable methods for product-related impurity control for various biotherapeutic modalities by lambda light chain affinity chromatography.