Enzyme-Triggered Intestine-Specific Targeting Adhesive Platform for Universal Oral Drug Delivery.

Patient adherence to chronic therapies can be suboptimal, leading to poor therapeutic outcomes. Dosage forms that enable reduction in dosing frequency stand to improve patient adherence. Variation in gastrointestinal transit time, inter-individual differences in gastrointestinal physiology and differences in physicochemical properties of drugs represent challenges to the development of such systems. To this end, a small intestine-targeted drug delivery system is developed, where prolonged gastrointestinal retention and sustained release are achieved through tissue adhesion of drug pills mediated by an essential intestinal enzyme catalase. Here proof-of-concept pharmacokinetics is demonstrated in the swine model for two drugs, hydrophilic amoxicillin and hydrophobic levodopa. It is anticipated that this system can be applicable for many drugs with a diverse of physicochemical characteristics.

Implementing intact cord resuscitation in very preterm infants: feasibility and pitfalls.

The purpose of this study is to evaluate the feasibility of intact cord resuscitation (ICR) in very preterm infants using a custom-equipped mobile resuscitation trolley (LifeStart®). We collected maternal and neonatal data of all inborn infants < 32 weeks eligible for ICR per our protocol over 9 months from ICR implementation. We compared rates of ICR between the beginning and the end of the study period. We reviewed maternal and neonatal adverse events related to the procedure and direct outcomes. In order to assess potential quality improvements related to the procedure, we collected the same data in the infants born in the 9-month period preceding ICR implementation. Out of 44 infants born < 32 weeks during the period, 27 were eligible for ICR. Failure to initiate ICR occurred in 9/27, exclusively in the first 5.5 months of the study. In one infant, ICR was interrupted prior to 2 min due to placental abruption. No ICR procedure had to be interrupted due to insufficient cord length. Among the 18 infants who completed ICR, cord clamping timing increased significantly over the study period, from 3.0 [2.5-3.5] to 4.2 min [3.1-8.3] (p = 0.02). No significant maternal blood loss or wound complications were noted. No infant deaths were attributable to failure or direct consequence of ICR, and no infant experienced hypoxic respiratory failure (intubation, FiO2 ≥ 0.4), asphyxia (pH < 7.2), or blood pressure instability (< 2 SD) following stabilization. Hemoglobin level after cord clamping was higher in the ICR cohort than in the pre-implementation group. Seven out of 18 infants exposed to ICR had a temperature < 36.5 °C on admission.   Conclusion: ICR is feasible in very preterm infants. Temperature management requires special attention. Multidisciplinary simulation training before implementation and systematic post-implementation quality improvement meetings may significantly increase ICR program success. What is Known: • Because infants born < 32 weeks often require cardiorespiratory resuscitation at birth, they are not offered delayed cord clamping in the majority of neonatal intensive care units. • Recently, fully equipped mobile trolleys have been developed in order to allow bedside resuscitation with an intact cord. What is New: • Variable timing of cord clamping based on the infant's transition and respiratory stability, i.e., "physiology-based cord clamping," is safely achievable in very preterm infants. • Intact cord resuscitation requires specific equipment, operational protocols, and a high level of preparation from both obstetrical and neonatal teams, with a learning curve that can be streamlined by multidisciplinary simulation training.

Very Low Birth Weight Outcomes and Admission Temperature: Does Hyperthermia Matter?

National and international recommendations for thermal care at preterm birth include recommendations to avoid hypothermia and hyperthermia. There is limited evidence demonstrating harm resulting from admission hyperthermia. Our aim was to assess the relationships between admission temperature and outcomes in very low birth weight (VLBW) babies in a unit with low rates of hypothermia and a higher rate of hyperthermia. This was an observational study based on routinely collected data including demographics, admission temperature, survival and major morbidity outcomes. Subjects were 1104 consecutive inborn VLBW babies admitted to a Neonatal Intensive Care Unit in United Kingdom between 2010 and 2017. Results: 155 (14%) of babies were hypothermic (<36.5 °C) with only 21 (1.9%) < 36 °C, and 254 (23%) of babies were hyperthermic (>37.5 °C). The rate of major abnormality on cranial ultrasound scan was increased in the hyperthermic babies compared to the normothermic babies (37/239 (15.5%) vs. 54/601 (9%), relative risk (95% CI) 1.723 (1.166 to 2.546), p = 0.006). There was no difference in survival or other major morbidity in the hyperthermic babies compared to the normothermic babies. There was no association between hypothermia and survival or any major morbidity, although this probably reflects the low power of the study given the low rates of significant hypothermia. Higher admission temperature was associated with an increase in the risk of major cranial ultrasound abnormality using multiple logistic regression analysis (p = 0.007) with an increased odds ratio (95% CI) of 1.48 (1.11 to 1.97) for each degree of increase. We conclude that admission hyperthermia is independently associated with an increased risk of preterm brain injury. It is not possible to state whether this is a causative association, or whether the association is a consequence of a shared aetiology of perinatal infection.

Outcomes of Femoral Arterial Catheterisation in Neonates: A Retrospective Cohort Study.

BACKGROUND: To review the outcome of all femoral arterial catheter (FAC) insertions in a single, large neonatal unit over a 12 year period, we will describe the incidence of harms arising from FAC insertion and to identify risk factors associated with ischaemic injury. METHODS: Retrospective survey of data relating to all episodes of FAC insertion in a single neonatal intensive care unit over a 12 year period up to 2020. RESULTS: 146 FACs were inserted into 139 babies with a median (interquartile range) gestation and birth weight of 27 (24 to 37) weeks and 1092 (682 to 2870) g. Impaired limb perfusion occurred in 32 (22%). This was transient and recovered with no injury in 26 of the 32. There was an increased risk of impaired limb perfusion in babies with lower weight at the time of insertion; from 5.7% in babies over 3000 g to 34.7% in babies under 1000 g (relative risk 6.1 (1.5 to 24.6)). Six babies (4%) had ischaemic injury. Risk factors for ischaemic injury included weight below 1000 g (four cases), pre-existing partial arterial obstruction (two cases), concerns about limb perfusion prior to FAC insertion (two cases) and a delay in removing the FAC after recognition of the poor perfusion (five cases). Two clinicians inserted 71 (50%) FACs and had no associated injuries. CONCLUSIONS: FAC can be used in neonates, although there is a risk of ischaemic injury, particularly in very small babies. Our data can be used to inform decisions about patient selection for this procedure.

Plasma proteomics of SARS-CoV-2 infection and severity reveals impact on Alzheimer and coronary disease pathways

Identification of the plasma proteomic changes of Coronavirus disease 2019 (COVID-19) is essential to understanding the pathophysiology of the disease and developing predictive models and novel therapeutics. We performed plasma deep proteomic profiling from 332 COVID-19 patients and 150 controls and pursued replication in an independent cohort (297 cases and 76 controls) to find potential biomarkers and causal proteins for three COVID-19 outcomes (infection, ventilation, and death). We identified and replicated 1,449 proteins associated with any of the three outcomes (841 for infection, 833 for ventilation, and 253 for death) that can be query on a web portal (https://covid.proteomics.wustl.edu/). Using those proteins and machine learning approached we created and validated specific prediction models for ventilation (AUC>0.91), death (AUC>0.95) and either outcome (AUC>0.80). These proteins were also enriched in specific biological processes, including immune and cytokine signaling (FDR [≤] 3.72x10-14), Alzheimers disease (FDR [≤] 5.46x10-10) and coronary artery disease (FDR [≤] 4.64x10-2). Mendelian randomization using pQTL as instrumental variants nominated BCAT2 and GOLM1 as a causal proteins for COVID-19. Causal gene network analyses identified 141 highly connected key proteins, of which 35 have known drug targets with FDA-approved compounds. Our findings provide distinctive prognostic biomarkers for two severe COVID-19 outcomes (ventilation and death), reveal their relationship to Alzheimers disease and coronary artery disease, and identify potential therapeutic targets for COVID-19 outcomes.

The salivary and nasopharyngeal microbiomes are associated with SARS-CoV-2 infection and disease severity

Oral and upper respiratory microbiota play important roles in modulating host immune responses to viral infection. As emerging evidence suggests the host microbiome may be involved in the pathophysiology of COVID-19, we aimed to investigate associations between the oral and nasopharyngeal microbiome and COVID-19 severity. We collected saliva (n = 78) and nasopharyngeal swab (n = 66) samples from a COVID-19 cohort and characterized the microbiomes using 16S ribosomal RNA gene sequencing. We also examined associations between the salivary and nasopharyngeal microbiome and age, COVID-19 symptoms, and blood cytokines. SARS-CoV-2 infection status, but not COVID-19 severity, was associated with community-level differences in the oral and nasopharyngeal microbiomes. Salivary and nasopharyngeal microbiome alpha diversity negatively correlated with age and were associated with fever and diarrhea. Several bacterial genera were differentially abundant by COVID-19 severity, including oral Bifidobacterium, Lactobacillus, and Solobacterium, all of which were depleted in patients with severe COVID-19. Nasopharyngeal Paracoccus was depleted while nasopharyngeal Proteus, Cupravidus, and Lactobacillus were increased in patients with severe COVID-19. Further analysis revealed that the abundance of oral Bifidobacterium was negatively associated with plasma concentrations of known COVID-19 biomarkers interleukin 17F (IL-17F) and monocyte chemoattractant protein-1 (MCP-1). In conclusion, our results suggest COVID-19 disease severity is associated with the relative abundance of certain bacterial taxa.

Maintaining Normothermia in Preterm Babies during Stabilisation with an Intact Umbilical Cord.

BACKGROUND: We had experienced an increase in admission hypothermia rates during implementation of deferred cord clamping (DCC) in our unit. Our objective was to reduce the number of babies with a gestation below 32 weeks who are hypothermic on admission, whilst practising DCC and providing delivery room cuddles (DRC). METHOD: A 12 month quality improvement project set, in a large Neonatal Intensive Care Unit, from January 2020 to December 2020. Monthly rates of admission hypothermia (<36.5 °C) for all eligible babies, were tracked prospectively. Each hypothermic baby was reviewed as part of a series of Plan, Do, Study Act (PDSA) cycles, to understand potential reasons and to develop solutions. Implementation of these solutions included the dissemination of the learning through a variety of methods. The main outcome measure was the proportion of babies who were hypothermic (<36.5 °C) on admission compared to the previous 12 months. RESULTS: 130 babies with a gestation below 32 weeks were admitted during the study period. 90 babies (69.2%) had DCC and 79 babies (60%) received DRC. Compared to the preceding 12 months, the rate of hypothermia decreased from 25/109 (22.3%) to 13/130 (10%) (p = 0.017). Only 1 baby (0.8%) was admitted with a temperature below 36 °C and 12 babies (9.2%) were admitted with a temperature between 36 °C and 36.4 °C. Continued monitoring during the 3 months after the end of the project showed that the improvements were sustained with 0 cases of hypothermia in 33 consecutive admissions. CONCLUSIONS: It is possible to achieve low rates of admission hypothermia in preterm babies whilst providing DCC and DRC. Using a quality improvement approach with PDSA cycles is an effective method of changing clinical practice to improve outcomes.

Emergency Medicine Virtual Conference Participants' Engagement with Competing Activities.

INTRODUCTION: Residency didactic conferences transitioned to a virtual format during the COVID-19 pandemic. This format creates questions about effective educational practices, which depend on learner engagement. In this study we sought to characterize the competitive demands for learner attention during virtual didactics and to pilot methodology for future studies. METHODS: This was a prospective, observational, cohort study of attendees at virtual didactics from a single emergency medicine residency, which employed a self-report strategy informed by validated classroom assessments of student engagement. We deployed an online, two-question survey polling across six conference days using random signaled sampling. Participants reported all activities during the preceding five minutes. RESULTS: There were 1303 responses over 40 survey deployments across six nonadjacent days. Respondents were residents (63.4%); faculty (27.5%); fellows (2.3%); students (2%); and others (4.8%). Across all responses, about 85% indicated engagement in the virtual conference within the last five minutes of the polls. The average number of activities engaged in was 2.0 (standard deviation = 1.1). Additional activities included education-related (34.2%), work-related (21.1%), social (18.8%), personal (14.6%), self-care (13.4%), and entertainment (4.4%). CONCLUSION: Learners engage in a variety of activities during virtual didactics. Engagement appears to fluctuate temporally, which may inform teaching strategies. This information may also provide unique instructor feedback. This pilot study demonstrates methodology for future studies of conference engagement and learning outcomes.

Assessment of serological assays for identifying high titer convalescent plasma

The COVID-19 pandemic has been accompanied by the largest mobilization of therapeutic convalescent plasma (CCP) in over a century. Initial identification of high titer units was based on dose-response data using the Ortho VITROS IgG assay. The proliferation of SARS-CoV-2 serological assays and non-uniform application has led to uncertainty about their interrelationships. The purpose of this study was to establish correlations and analogous cutoffs between commercially available serological tests (Ortho, Abbott, Roche), a spike ELISA, and a virus neutralization assay using convalescent plasma from a cohort of 79 donors from April 2020. Relationships relative to FDA-approved cutoffs under the CCP EUA were identified by linear regression and receiver operator characteristic curves. Relative to the Ortho VITROS assay, the r2 of the Abbott, Roche, the anti-Spike ELISA and the neutralizing assay were 0.58, 0.5, 0.82, and 0.44, respectively. The best correlative index for establishing high-titer units was 3.82 S/C for the Abbott, 10.89 COI for the Roche, 1:1,202 for the anti-Spike ELISA, and 1:200 by the neutralization assay. The overall agreement using derived cutoffs compared to the CCP EUA Ortho VITROS cutoff of 9.5 was 92.4% for Abbott, 84.8% for Roche, 87.3% for the anti-S ELISA and 78.5% for the neutralization assay. Assays based on antibodies against the nucleoprotein (Roche, Abbott) and neutralizing antibody tests were positively associated with the Ortho assay, although their ability to distinguish FDA high-titer specimens was imperfect. The resulting relationships help reconcile results from the large body of serological data generated during the COVID-19 pandemic.

Recent innovations and new applications of outpatient parenteral antimicrobial therapy.

INTRODUCTION: Outpatient parenteral antimicrobial therapy (OPAT) is safe and effective for selected patients managed within an organized clinical service. Service configurations however are evolving, patient populations are changing and new evidence is emerging which challenges traditional OPAT practice. AREAS COVERED: This review will discuss evolving OPAT service delivery from the traditional model of infusion center toward nonspecialist, community and remotely delivered OPAT and the challenges this represents. We consider new patient populations including those with incurable infection or infections at the end of life and difficult to reach populations including people who inject drugs. The evidence base that underpins the multi-disciplinary approach to OPAT delivery will be examined and particularly the role of the antimicrobial pharmacist and specialist nurse. Evidence for new treatment options which challenge established OPAT practice including complex oral antibiotic regimens, long acting parenteral agents and drug stability in continuous infusion antibiotics will be considered. Finally we emphasize the central importance of antimicrobial stewardship and good clinical governance which should underpin OPAT practice. EXPERT OPINION: Changing patient populations, service structures and team roles coupled with a growing infection management evidence base means that OPAT services and practice must evolve. Challenging traditional practice is essential to ensure best patient outcomes and cost-efficiency.

Dependence and precarity in the platform economy.

The rapid growth of Uber and analogous platform companies has led to considerable scholarly interest in the phenomenon of platform labor. Scholars have taken two main approaches to explaining outcomes for platform work-precarity, which focuses on employment classification and insecure labor, and technological control via algorithms. Both predict that workers will have relatively common experiences. On the basis of 112 in-depth interviews with workers on seven platforms (Airbnb, TaskRabbit, Turo, Uber, Lyft, Postmates, and Favor) we find heterogeneity of experiences across and within platforms. We argue that because platform labor is weakly institutionalized, worker satisfaction, autonomy, and earnings vary significantly across and within platforms, suggesting dominant interpretations are insufficient. We find that the extent to which workers are dependent on platform income to pay basic expenses rather than working for supplemental income explains the variation in outcomes, with supplemental earners being more satisfied and higher-earning. This suggests platforms are free-riding on conventional employers. We also find that platforms are hierarchically ordered, in terms of what providers can earn, conditions of work, and their ability to produce satisfied workers. Our findings suggest the need for a new analytic approach to platforms, which emphasizes labor force diversity, connections to conventional labor markets, and worker dependence.

Tuberculosis bacillary load, an early marker of disease severity: the utility of tuberculosis Molecular Bacterial Load Assay.

In this comparative biomarker study, we analysed 1768 serial sputum samples from 178 patients at 4 sites in Southeast Africa. We show that tuberculosis Molecular Bacterial Load Assay (TB-MBLA) reduces time-to-TB-bacillary-load-result from days/weeks by culture to hours and detects early patient treatment response. By day 14 of treatment, 5% of patients had cleared bacillary load to zero, rising to 58% by 12th week of treatment. Fall in bacillary load correlated with mycobacterial growth indicator tube culture time-to-positivity (Spearmans r=-0.51, 95% CI (-0.56 to -0.46), p<0.0001). Patients with high pretreatment bacillary burdens (above the cohort bacillary load average of 5.5log10eCFU/ml) were less likely to convert-to-negative by 8th week of treatment than those with a low burden (below cohort bacillary load average), p=0.0005, HR 3.1, 95% CI (1.6 to 5.6) irrespective of treatment regimen. TB-MBLA distinguished the bactericidal effect of regimens revealing the moxifloxacin-20 mg rifampicin regimen produced a shorter time to bacillary clearance compared with standard-of-care regimen, p=0.008, HR 2.9, 95% CI (1.3 to 6.7). Our data show that the TB-MBLA could inform clinical decision making in real-time and expedite drug TB clinical trials.

Quality improvement programme to increase the rate of deferred cord clamping at preterm birth using the Lifestart trolley.

AIM: To increase the documented use of the Lifestart trolley to allow premature infants' (<32 weeks' gestation) resuscitation and stabilisation with an intact umbilical cord at delivery. DESIGN: A 13-month quality improvement programme from April 2018 to April 2019 was undertaken using Plan, Do, Study and Act (PDSA) cycles. Data were reviewed from 113 consecutive preterm (<32 weeks) deliveries to identify whether Lifestart was used and whether 2 min deferred cord clamping (DCC) occurred in eligible infants as per hospital policy. Episodes of non-compliance were analysed, causes established and interventions implemented to reduce similar future non-compliance. Data collected were presented graphically and included in alternate monthly newsletters to staff, which also included lessons learnt from the reviews of non-compliance. RESULTS: Documented use of the Lifestart rose from 10% at the start of the project to 79% in the final month. Not all babies are eligible for DCC. Within this project, 40 (35%) of preterm infants were not eligible to receive DCC. Of those that were eligible, the rate of DCC increased from 17% in the first 3 months to 92% in the last 3 months of the project (p<0.0001). IMPLICATIONS AND RELEVANCE: By undertaking regular PDSA cycles and improving education surrounding importance of DCC, we have noted a significant improvement in the use of Lifestart, which in turn facilitates DCC.The learning from this project has been used to create an instructional video to help maintain the improved compliance rates.

Highly Reliable Case Management.

Health care is a highly complex system that is prone to error. Professional case managers across the continuum of care are key stakeholders who can significantly impact the effectiveness and efficiency of health care delivery at the individual and population health levels. This article explores how professional case managers can use evidence-based practice and generative knowledge to improve professional practice. In addition, the authors provide examples of how to actively support continuous change and high reliability within an organization.

Tuberculosis bacillary load, an early marker of disease severity: the utility of tuberculosis Molecular Bacterial Load Assay

In this comparative biomarker study, we analysed 1768 serial sputum samples from 178 patients at 4 sites in Southeast Africa. We show that tuberculosis Molecular Bacterial Load Assay (TB-MBLA) reduces time-to-TB-bacillary-load-result from days/weeks by culture to hours and detects early patient treatment response. By day 14 of treatment, 5% of patients had cleared bacillary load to zero, rising to 58% by 12th week of treatment. Fall in bacillary load correlated with mycobacterial growth indicator tube culture time-to-positivity (Spearmans r=-0.51, 95% CI (-0.56 to -0.46), p<0.0001). Patients with high pretreatment bacillary burdens (above the cohort bacillary load average of 5.5log10eCFU/ml) were less likely to convert-to-negative by 8th week of treatment than those with a low burden (below cohort bacillary load average), p=0.0005, HR 3.1, 95% CI (1.6 to 5.6) irrespective of treatment regimen. TB-MBLA distinguished the bactericidal effect of regimens revealing the moxifloxacin-20 mg rifampicin regimen produced a shorter time to bacillary clearance compared with standard-of-care regimen, p=0.008, HR 2.9, 95% CI (1.3 to 6.7). Our data show that the TB-MBLA could inform clinical decision making in real-time and expedite drug TB clinical trials.