Surviving severe COVID-19: Interviews with patients, informal carers and health professionals.

BACKGROUND: The COVID-19 pandemic has been associated with an unprecedented number of critical care survivors. Their experiences through illness and recovery are likely to be complex, but little is known about how best to support them. AIM: This study aimed to explore experiences of illness and recovery from the perspective of survivors, their relatives and professionals involved in their care. STUDY DESIGN: In-depth qualitative interviews were conducted with three stakeholder groups during the first wave of the pandemic. A total of 23 participants (12 professionals, 6 survivors and 5 relatives) were recruited from 5 acute hospitals in England and interviewed by telephone or video call. Data analysis followed the principles of Reflexive Thematic Analysis. FINDINGS: Three themes were generated from their interview data: (1) Deteriorating fast-a downhill journey from symptom onset to critical care; (2) Facing a new virus in a hospital-a remote place; and (3) Returning home as a survivor, maintaining normality and recovering slowly. CONCLUSIONS: Our findings highlight challenges in accessing care and communication between patients, hospital staff and relatives. Following hospital discharge, patients adopted a reframed 'survivor identity' to cope with their experience of illness and slow recovery process. The concept of survivorship in this patient group may be beneficial to promote and explore further. RELEVANCE TO CLINICAL PRACTICE: All efforts should be made to continue to improve communication between patients, relatives and health professionals during critical care admissions, particularly while hospital visits are restricted. Adapting to life after critical illness may be more challenging while health services are restricted by the impacts of the pandemic. It may be beneficial to promote the concept of survivorship, following admission to critical care due to severe COVID-19.

Treatments for the amelioration of persistent factors in complex anal fistula.

Anal fistulae are abnormal hollow connections between the wall of the anal canal and the perianal skin around the anus that have remained a burden on the medical sector for centuries. The complexity of this disease is attributed to a number of factors such as the degree of associated sphincter muscle, concomitant illnesses, existence of multiple fistulous tracts and the number of previous interventions. Persistence of a complex anal fistula can cause a decline in patient's physical quality of life as well as impact on the psychological status of patients who often suffer from anxiety and depression. Surgical intervention remains the gold standard for treatment, however; the risk of incontinence and high recurrence potential has led to interest into developing alternative treatment approaches such as the use of biologics, bioactives and biomaterials. One potential reason for these varied outcomes could be the multifactorial interplay between genetic, immune-related, environmental, and microbial persistence factors on tissue regeneration. Recent observations have proposed that adverse inflammatory mediators may contribute more than microbial factors. The moderate to high success rates of biotechnological advances (mesenchymal stem cells and biomaterial scaffolds) show promise as therapies for the amelioration of adverse persistent factors while facilitating a means to closing the fistula tract. The purpose of this review is to outline recent advances in biologics and combination therapies to treat persistent factors associated with complex anal fistula.

High-sensitivity troponin T in marathon runners, marathon runners with heart disease and collapsed marathon runners.

Endurance exercise is an established cause of cardiac troponin (cTn) elevation, of further interest is whether this rise represents clinical significance. This study compared cTnT rise in three cohorts of marathon runners using a high-sensitivity assay; control runners, those with known heart disease and runners who collapsed at the finish line. Control runners (n = 126) and runners with heart disease (n = 12) were prospectively recruited with cTnT levels measured pre-race and at race completion. Collapsed runners (n = 15) were retrospectively recruited. A mixed model ANCOVA was used to compare the three groups. Pre-race median cTnT for the control group and heart disease groups was 3.9 ng/L (IQR 3.1 ng/L) and 4.1 ng/L (IQR 3.4 ng/L). Post-race values for the three groups were control 45.6 ng/L (IQR 42.5 ng/L), heart disease 41.2 ng/L (IQR 36.1 ng/L), and collapsed 41.9 ng/L (IQR 57.8 ng/L). Post-race cTnT and cTnT change were significantly correlated with pre-race cTnT within the control group (r = 0.38 and 0.30, P < 0.01). There was no difference in post-race cTnT (adjusted for pre-race cTnT) between the three groups. None of the runners reported symptoms suggestive of acute myocardial infarction on follow-up. These results demonstrate that marathon running is associated with an asymptomatic cTnT rise for all runners, and this rise is significantly correlated to baseline cTnT levels, in addition, marathon runners with pre-existing cardiac pathology or who collapse at the finish line do not exhibit an increased cTnT rise compared to healthy runners.

A New World for Chemical Synthesis?

This perspective seeks to provide an overarching vision of the current state of chemical synthesis methodology using machinery as enabling tools. It highlights current capabilities and limitations in this highly digitallyconnected world and suggests areas where new opportunities may arise in the future by going well beyond our present levels of innovation and automation. There is a new need for improved downstream processing tools, advanced reactor design, computational predictive algorithms and integration of robotic systems to maximise the human resource to facilitate a new era in the assembly of our functional materials.

Oxygen exposures at NASA's Neutral Buoyancy Lab: a 20-year experience.

Astronauts training for extravehicular activity (EVA) operations can spend many hours submerged underwater in a pressurized suit, called an extravehicular mobility unit (EMU), exposed to pressures exceeding 2 atmospheres absolute (ATA). To minimize the risk of decompression sickness (DCS) a 46% nitrox mixture is used. This limits the nitrogen partial pressure, decreasing the risk of DCS. The trade-off with using a 46% nitrox mixture is the increased potential for oxygen toxicity, which can lead to severe neurologic symptoms including seizures. Suited runs, which typically expose astronauts of 0.9-1.1 ATA for longer than six hours, routinely exceed the recommendation for central nervous system oxygen toxicity limits (CNSOTL) published by the National Oceanic and Atmospheric Administration (NOAA). Fortunately, in over 50,000 hours of suited training dives spanning 20 years of EVA training operations at NASA's Neutral Buoyancy Laboratory (NBL) there has never been an occurrence of oxygen toxicity. This lends support to anecdotal sentiment among certain members of the hyperbaric community that the NOAA CNSOTL recommendations might be overly conservative, at least for the oxygen pressure and time regime in which NBL operates. The NOAA CNSOTL recommendations are the result of expert consensus with a focus on safety and do not necessarily reflect rigorous experimental evidence. The data from the NBL suited dive operations provide a foundation of evidence that can help inform the expert discussion on dive-related neurologic oxygen toxicity performance and overnight recovery in young, healthy males.

Across-the-World Automated Optimization and Continuous-Flow Synthesis of Pharmaceutical Agents Operating Through a Cloud-Based Server.

The power of the Cloud has been harnessed for pharmaceutical compound production with remote servers based in Tokyo, Japan being left to autonomously find optimal synthesis conditions for three active pharmaceutical ingredients (APIs) in laboratories in Cambridge, UK. A researcher located in Los Angeles, USA controlled the entire process via an internet connection. The constituent synthetic steps for Tramadol, Lidocaine, and Bupropion were thus optimized with minimal intervention from operators within hours, yielding conditions satisfying customizable evaluation functions for all examples.

Elastically suspending the screw holes of a locked osteosynthesis plate can dampen impact loads.

Impact damping by elastic fixation is a principal engineering strategy to increase the durability of load-bearing structures exposed to prolonged dynamic loading. This biomechanical study evaluated axial impact damping provided by a novel dynamic locking plate. In this design, locking screw holes are elastically suspended within a silicone envelope inside the locking plate. Axial impact damping was assessed for 3 distinct fixation constructs applied to bridge a 10-mm fracture gap of a femoral diaphysis surrogate: a standard locking plate, a dynamic locking plate, and an Ilizarov ring fixator. First, the 3 fixation constructs were characterized by determining their axial stiffness. Subsequently, constructs were subjected to a range of axial impact loads to quantify damping of force transmission. Compared with standard locked plating constructs, dynamic plating constructs were 58% less stiff (P < .01) and Ilizarov constructs were 88% less stiff (P < .01). Impact damping correlated inversely with construct stiffness. Compared with standard plating, dynamic plating constructs and Ilizarov constructs dampened the transmission of impact loads by up to 48% (P < .01) and 74% (P < .01), respectively. In conclusion, lower construct stiffness correlated with superior damping of axial impact loads. Dynamic locking plates provide significantly greater impact damping compared with standard locking plates.

Organic synthesis: march of the machines.

Organic synthesis is changing; in a world where budgets are constrained and the environmental impacts of practice are scrutinized, it is increasingly recognized that the efficient use of human resource is just as important as material use. New technologies and machines have found use as methods for transforming the way we work, addressing these issues encountered in research laboratories by enabling chemists to adopt a more holistic systems approach in their work. Modern developments in this area promote a multi-disciplinary approach and work is more efficient as a result. This Review focuses on the concepts, procedures and methods that have far-reaching implications in the chemistry world. Technologies have been grouped as topics of opportunity and their recent applications in innovative research laboratories are described.

A systems approach towards an intelligent and self-controlling platform for integrated continuous reaction sequences.

Performing reactions in flow can offer major advantages over batch methods. However, laboratory flow chemistry processes are currently often limited to single steps or short sequences due to the complexity involved with operating a multi-step process. Using new modular components for downstream processing, coupled with control technologies, more advanced multi-step flow sequences can be realized. These tools are applied to the synthesis of 2-aminoadamantane-2-carboxylic acid. A system comprising three chemistry steps and three workup steps was developed, having sufficient autonomy and self-regulation to be managed by a single operator.

Machine-Assisted Organic Synthesis.

In this Review we describe how the advent of machines is impacting on organic synthesis programs, with particular emphasis on the practical issues associated with the design of chemical reactors. In the rapidly changing, multivariant environment of the research laboratory, equipment needs to be modular to accommodate high and low temperatures and pressures, enzymes, multiphase systems, slurries, gases, and organometallic compounds. Additional technologies have been developed to facilitate more specialized reaction techniques such as electrochemical and photochemical methods. All of these areas create both opportunities and challenges during adoption as enabling technologies.

Flow chemistry meets advanced functional materials.

Flow chemistry and continuous processing techniques are beginning to have a profound impact on the production of functional materials ranging from quantum dots, nanoparticles and metal organic frameworks to polymers and dyes. These techniques provide robust procedures which not only enable accurate control of the product material's properties but they are also ideally suited to conducting experiments on scale. The modular nature of flow and continuous processing equipment rapidly facilitates reaction optimisation and variation in function of the products.

Advances in Dynamization of Plate Fixation to Promote Natural Bone Healing.

The controlled dynamization of fractures can promote natural fracture healing by callus formation, while overly rigid fixation can suppress healing. The advent of locked plating technology enabled new strategies for the controlled dynamization of fractures, such as far cortical locking (FCL) screws or active plates with elastically suspended screw holes. However, these strategies did not allow for the use of non-locking screws, which are typically used to reduce bone fragments to the plate. This study documents the first in vivo study on the healing of ovine tibia osteotomies stabilized with an advanced active plate (AAP). This AAP allowed plate application using any combination of locking and non-locking screws to support a wide range of plate application techniques. At week 9 post-surgery, tibiae were harvested and tested in torsion to failure to assess the healing strength. The five tibiae stabilized with an AAP regained 54% of their native strength and failed by spiral fracture through a screw hole, which did not involve the healed osteotomy. In comparison, tibiae stabilized with a standard locking plate recovered 17% of their strength and sustained failure through the osteotomy. These results further support the stimulatory effect of controlled motion on fracture healing. As such, the controlled dynamization of locked plating constructs may hold the potential to reduce healing complications and may shorten the time to return to function. Integrating controlled dynamization into fracture plates that support a standard fixation technique may facilitate the clinical adoption of dynamic plating.

Technical improvements in preparing 3D printed anatomical models for comminuted fracture preoperative planning.

Preoperative planning of comminuted fracture repair using 3D printed anatomical models is enabling surgeons to visualize and simulate the fracture reduction processes before surgery. However, the preparation of such models can be challenging due to the complexity of certain fractures, particularly in preserving fine detail in bone fragments, maintaining the positioning of displaced fragments, and accurate positioning of multiple bones. This study described several key technical considerations for preparing 3D printed anatomical models for comminuted fracture preoperative planning. An optimized segmentation protocol was developed that preserves fine detail in bone fragments, resulting in a more accurate representation of the fracture. Additionally, struts were manually added to the digital model to maintain the positioning of displaced fragments after fabrication, reducing the likelihood of errors during printing or misrepresentation of fragment positioning. Magnets were also used to enable separation and visualization of accurate positioning of multiple bones, making it easier to visualize fracture components otherwise obscured by the anatomy. Finally, the infill for non-target structures was adjusted to minimize print time and material wastage. These technical optimizations improved the accuracy and efficiency of preparing 3D printed anatomical models for comminuted fracture preoperative planning, improving opportunities for surgeons to better plan surgical treatment in advance, reducing the likelihood of errors, with the goal of improving surgical outcomes.

Marathon running and cell-cycle arrest biomarkers of acute kidney injury.

OBJECTIVES: Endurance exercise is known to cause a rise in serum creatinine. It is not known to what extent this rise reflects renal stress and a potential acute kidney injury (AKI). Increases in Insulin Like Growth Factor Binding Protein 7 (IGFBP7) and Tissue Inhibitor of Metalloprotinases-2 (TIMP-2), urinary biomarkers of cell cycle arrest and renal stress, are associated with the development of AKI in clinical populations. DESIGN: Repeated measures study. METHODS: Runners were recruited at the 2019 Brighton Marathon (UK) and provided urine and blood samples at baseline, immediately post-race and 24 h post-race. Serum creatinine, urinary creatinine and urinary IGFBP7 and TIMP-2 were analysed from the samples. RESULTS: Seventy nine participants (23 females, 56 males), aged 43 ±â€¯10 yrs. (mean ±â€¯SD), finish time 243 ±â€¯40mins were included for analysis. Serum creatinine increased over the race by 40 ±â€¯26% (p < 0.001), TIMP-2 increased by 555 ±â€¯697% (p < 0.001) and IGFBP7 increased by 1094 ±â€¯1491% (p < 0.001) over the race. A subset of twenty-two participants supplied samples 24 h post-race, reporting values similar to baseline for all variables. CONCLUSIONS: This study is the first to report large rises in IGFBP7 and TIMP-2 following marathon running. This suggests that rises in creatinine are not fully explained by changes in production and clearance and marathon running induces a state of kidney stress and potential injury.

Substantial Loss of Skeletal Muscle Mass Occurs After Femoral Fragility Fracture.

BACKGROUND: Femoral fragility fractures in older adults can result in devastating loss of physical function and independence. Skeletal muscle atrophy likely contributes to disability. The purpose of this study was to characterize the change in skeletal muscle mass, investigate the relationship with malnutrition and physical function, and identify risk factors for skeletal muscle loss. METHODS: Adults ≥65 years of age who were treated with operative fixation of an isolated femoral fragility fracture were enrolled in this multicenter, prospective observational study. Skeletal muscle mass was assessed within 72 hours of admission using multifrequency bioelectrical impedance analysis, which was repeated at 6 weeks, 3 months, and 6 months. Sarcopenia was defined by sex-specific cutoffs for the appendicular skeletal muscle mass index. The Mini Nutritional Assessment was used to measure nutritional status at the time of injury. Physical function was measured using the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function domain. Linear mixed models were used to evaluate changes in skeletal muscle mass and PROMIS Physical Function scores over time and to evaluate factors associated with skeletal muscle mass changes. RESULTS: Ninety participants (74% female) with a mean age of 77.6 ± 9.0 years were enrolled. At the time of injury, 30 (33%) were sarcopenic and 44 (49%) were at risk for malnutrition or had malnutrition. Older age was associated with lower skeletal muscle mass (age of ≥75 versus <75 years: least squares mean [and standard error], -3.3 ± 1.6 kg; p = 0.042). From the time of injury to 6 weeks, participants lost an average of 2.4 kg (9%) of skeletal muscle mass (95% confidence interval [CI] = ‒3.0 to ‒1.8 kg; p < 0.001). This early loss did not recover by 6 months (1.8 kg persistent loss compared with baseline [95% CI = ‒2.5 to ‒1.1 kg]; p < 0.001). Participants with normal nutritional status lost more skeletal muscle mass from baseline to 6 weeks after injury compared with those with malnutrition (1.3 kg more loss [standard error, 0.6 kg]; p = 0.036). A 1-kg decrease in skeletal muscle mass was associated with an 8-point decrease in the PROMIS Physical Function (model parameter estimate, 0.12 [standard error, 0.04]; p = 0.002). CONCLUSIONS: We found that older adults with femoral fragility fractures lost substantial skeletal muscle mass and physical function. Participants with adequate baseline nutrition actually lost more muscle mass than those who were malnourished, indicating that future investigations of interventions to prevent muscle loss should focus on older adults regardless of nutritional status. LEVEL OF EVIDENCE: Prognostic Level II . See Instructions for Authors for a complete description of levels of evidence.

Using Smartwatches to Observe Changes in Activity During Recovery From Critical Illness Following COVID-19 Critical Care Admission: 1-Year, Multicenter Observational Study.

BACKGROUND: As a sequela of the COVID-19 pandemic, a large cohort of critical illness survivors have had to recover in the context of ongoing societal restrictions. OBJECTIVE: We aimed to use smartwatches (Fitbit Charge 3; Fitbit LLC) to assess changes in the step counts and heart rates of critical care survivors following hospital admission with COVID-19, use these devices within a remote multidisciplinary team (MDT) setting to support patient recovery, and report on our experiences with this. METHODS: We conducted a prospective, multicenter observational trial in 8 UK critical care units. A total of 50 participants with moderate or severe lung injury resulting from confirmed COVID-19 were recruited at discharge from critical care and given a smartwatch (Fitbit Charge 3) between April and June 2020. The data collected included step counts and daily resting heart rates. A subgroup of the overall cohort at one site-the MDT site (n=19)-had their smartwatch data used to inform a regular MDT meeting. A patient feedback questionnaire and direct feedback from the MDT were used to report our experience. Participants who did not upload smartwatch data were excluded from analysis. RESULTS: Of the 50 participants recruited, 35 (70%) used and uploaded data from their smartwatch during the 1-year period. At the MDT site, 74% (14/19) of smartwatch users uploaded smartwatch data, whereas 68% (21/31) of smartwatch users at the control sites uploaded smartwatch data. For the overall cohort, we recorded an increase in mean step count from 4359 (SD 3488) steps per day in the first month following discharge to 7914 (SD 4146) steps per day at 1 year (P=.003). The mean resting heart rate decreased from 79 (SD 7) beats per minute in the first month to 69 (SD 4) beats per minute at 1 year following discharge (P<.001). The MDT subgroup's mean step count increased more than that of the control group (176% increase vs 42% increase, respectively; +5474 steps vs +2181 steps, respectively; P=.04) over 1 year. Further, 71% (10/14) of smartwatch users at the MDT site and 48% (10/21) of those at the control sites strongly agreed that their Fitbit motivated them to recover, and 86% (12/14) and 48% (10/21), respectively, strongly agreed that they aimed to increase their activity levels over time. CONCLUSIONS: This is the first study to use smartwatch data to report on the 1-year recovery of patients who survived a COVID-19 critical illness. This is also the first study to report on smartwatch use within a post-critical care MDT. Future work could explore the role of smartwatches as part of a randomized controlled trial to assess clinical and economic effectiveness. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.12968/ijtr.2020.0102.

Ex vivo experimental characterizations for understanding the interrelationship between tissue mechanics and collagen microstructure of porcine mitral valve leaflets.

Unidirectional blood flow in the left side of the heart is regulated by the mitral valve. To better understand the mitral valve function, researchers have examined the structural and mechanical properties of the mitral valve leaflets; however, limitations of the previous studies include the use of mechanics- and structure-altering tissue modifications (e.g., optical clearing) that limit the ability to quantify the unique load-dependent reorientation and realignment of the collagen fibers as well as their interrelation with the valve tissue mechanics. Herein, we aimed to circumvent these limitations by utilizing an integrated polarized-light imaging and biaxial testing system for understanding the mechanics-microstructure interrelationship for porcine mitral valve leaflets. We further performed constitutive modeling and evaluated the accuracy of the affine fiber kinematics theory. From the tissue mechanics perspective, the posterior leaflet was more extensible in the radial direction than the anterior leaflet (14.2% difference in radial tissue stretch), while exhibiting smaller collagen and elastin moduli based on the determined constitutive model parameters. From the collagen microstructure's standpoint, the posterior leaflet had smaller increases in optical anisotropy (closely related to the degree of fiber alignment) than the anterior leaflet (32.8±7.7% vs. 50.0±19.7%). Further, the leaflets were found to possess two distinct fiber families - one family oriented along the circumferential tissue direction, and another more disperse family with a 30°-40° offset from the first fiber family. Finally, affine fiber kinematics consistently underpredicted the collagen fiber reorientations Overall, this study improved our understanding of the mitral valve leaflets that is essential for facilitating tissue-emulated valve replacement and cardiac valve modeling frameworks.

An efficient and reliable chemical inventory system at a growing drug discovery company.

Within a growing drug discovery company, hundreds of scientists take and move reagent chemicals on a daily basis. Conveniently updating the locations of tens of thousands of chemical containers in an electronic system is a big challenge. We have an electronic inventory system, but keeping the chemical records up to date relied on scientists finding an available computer in the lab and logging into a system whenever they took or moved a chemical container, taking several minutes. It was all too easy to think that the task could be deferred until later, but the scientist may then forget all about it, leaving the database inaccurate. As a result, searching for the chemicals we need can take a frustratingly long time if they are not where they should be. We have developed an efficient and reliable system, namely ScanStation, to solve this issue. It relies on a low-cost Raspberry Pi attached to a touch screen connected with a barcode scanner. This equipment is always on and placed in strategic locations around all our labs and chemical stores. This new process is much easier. There is no need to remove gloves to log into the computer, and it is just a scan on the barcode and is done. Now when we check the database for a chemical, we get an instant answer that reliably tells us where to find it. All the time we save have a real benefit in our productivity and our scientists can focus on discovering new medicines.

2010 mid-America Orthopaedic Association Physician in Training Award: healing complications are common after locked plating for distal femur fractures.

BACKGROUND: Several mechanical studies suggest locking plate constructs may inhibit callus necessary for healing of distal femur fractures. However, the rate of nonunion and factors associated with nonunion are not well established. QUESTIONS/PURPOSES: We (1) determined the healing rate of distal femur fractures treated with locking plates, (2) assessed the effect of patient injury and treatment variables on fracture healing, and (3) compared callus formation in fractures that healed with those that did not heal. PATIENTS AND METHODS: We retrospectively reviewed 82 patients treated with 86 distal femur fractures using lateral locking plates. We reviewed all charts and radiographs to determine patient and treatment variables and then determined the effects of these variables on healing. We quantitatively measured callus at 6, 12, and 24 weeks. The minimum time for telephone interviews and SF-36v2(TM) scores was 1 year (mean, 4.2 years; range, 1-7.2 years). RESULTS: Fourteen fractures (20%) failed to unite. Demographics and comorbidities were similar in patients who achieved healing compared with those who had nonunions. There were more empty holes in the plate adjacent to fractures that healed; comminuted fractures failed to heal more frequently than less comminuted fractures. Less callus formed in fractures with nonunions and in patients treated with stainless steel plates compared with titanium plates. Complications occurred in 28 of 70 fractures (40%), 19 of which had additional surgery. CONCLUSIONS: We found a high rate of nonunion in distal femur fractures treated with locking plates. Nonunion presented late without hardware failure and with limited callus formation suggesting callus inhibition rather than hardware failure is the primary problem. Mechanical factors may play a role in the high rate of nonunion.

Characterization of the mechanical properties of bovine cortical bone treated with a novel tissue sterilization process.

Over the past decade chemical processing and engineering of musculoskeletal tissue (tendon and bone) has improved dramatically. The use of bone allograft and xenograft in reconstructive orthopedic and maxillofacial surgeries is increasing, yet severe complications can occur if the material is contaminated in any way. A novel tissue sterilization process, BioCleanse®, has been developed to clean and sterilize musculoskeletal tissue for implantation. The present study was designed to determine the effect of this novel cleaning process on the biomechanical properties of bovine cortical bone prior to implantation. The mechanical properties of treated bovine bone material were compared to human samples with respect to failure under compression, shear and three-point bending. The data demonstrate that bovine bone treated with the novel sterilization procedure has favorable biomechanical properties compared to that of human bone treated in a similar fashion.