Background: Stillbirth is the death, in utero, of a fetus from 20 weeks’ gestation until immediately before birth. This may be spontaneous or can occur after termination for medical reasons (TFMR). The experience of stillbirth profoundly impacts subsequent pregnancies, with mothers frequently experiencing conflicted emotions, heightened anxiety, stress, symptoms of depression, fear, isolation, and a diminished sense of trust in a positive outcome. Supportive care options for individuals pregnant after a stillbirth or TFMR are needed to help meet their psychological and emotional needs. Individuals pregnant after a loss do not feel emotionally safe in their pregnancies; thus, the side effects and perception of safety in support interventions need to be explored. Purpose: This article reports participants’ experiences of safety, the harms, and adverse events in a study exploring massage as a support for individuals pregnant after a stillbirth. Methods: The study used questionnaires to collect side effect data and qualitative interviews to examine participants’ experience of safety. Results: The study found that 75% of participants experienced one or more side effects. Post-massage soreness (45.8%) was the most frequently reported side effect, followed by tiredness (43.1%). The main theme of the qualitative analysis was “safety: so much more than physical safety,” reflecting the importance of safety to study participants and that safety was much more than avoiding physical harm. Conclusion: Participants needed the massage space to feel safe, both environmentally and psychologically, to facilitate their capacity to engage. Having trained massage therapists was important as this helped reassure participants that mas-sage was a safe treatment for themselves and their baby.
Sesqui-chalcogenides serve as a critical bridge between traditional semiconductors and quantum materials, offering significant potential in applications such as thermoelectrics, phase change memory, and topological insulators. While considerable attention has been focused on antimony- and bismuth-based compounds, characterized by substantial property changes upon reduction in film thickness, indium-containing sesqui-chalcogenides like In2Te3 are emerging as promising candidates for photovoltaics and electronic devices. However, the effects of film thickness on the properties of In2Te3 remain largely unexplored. In this study, we investigate high-quality In2Te3 thin films grown by molecular beam epitaxy on Si(111) substrates across a thickness range from 2.7 to 24 nm. X-ray diffraction, reflective high-energy electron diffraction, and atomic force microscopy are employed to analyze both the crystal structure and film morphology. Additionally, broadband optical spectroscopy alongside femtosecond pump-probe measurements and Raman spectroscopy are utilized to assess optical and vibrational properties, respectively. This analysis reveals that material properties exhibit minimal dependence on film thickness - contrasting sharply with behavior observed in other chalcogenides such as Sb2Te3, Bi2Se3, or GeTe. This phenomenon can be attributed to the covalent bonding present in In2Te3, which differs from that in its antimony- and bismuth-containing counterparts.
Bottom-up on-surface synthesized nanoporous graphenes (NPGs), realized as 2D arrays of laterally covalently bonded pi-conjugated graphene nanoribbons (GNRs), are a family of carbon nanomaterials which are receiving increasing attention for nanoelectronics and biosensing. Recently, a so-called hybrid-NPG (hNPG) was synthesized, featuring an alternating sequence of doped and non-doped GNRs, resulting in a band staggering effect in its electronic structure. Such a feature is appealing for photo-catalysis, photovoltaics and even carbon nanocircuitry. However, to date, little is known about the transport properties of hNPG and its derivatives, which is key for most applications. Here, via Green's functions simulations, we study the quantum transport properties of hNPGs. We find that injected carriers in hNPG spread laterally through a number of GNRs, though such spreading may take place exclusively through GNRs of one type (doped or non-doped). We propose a simple model to discern the key parameters determining the electronic propagation in hNPGs and explore alternative hNPG designs to control the spreading/confinement and anisotropy of charge transport in these systems. For one such design, we find that it is possible to send directed electric signals with sub-nanometer precision for as long as one micrometer - a result first reported for any NPG.
This article investigates the memorialization of migrant women across transcultural landscapes, and analyses results from the Register of Migrant Women Landmarks in Europe (hereinafter RMWLE), central to the European Cooperation in Science and Technology (COST) action project “Women on the Move” (CA19112 – WEMov). It serves as reference for subsequent research based on data from this Register, for which data collection is continuing. The RMWLE registers landmarks, such as monuments, plaques, streets and other toponymic infrastructures named after women with a significant history of migration. It honours aspects rarely prioritized in memorialization agendas, which are skewed towards men’s stories, and towards the more linear biographies of sedentary figures whose European, national, and regional memorialization have remained uncomplicated by migration. This Deep Data study reveals recurring patterns at the level of Europe in the memorialization of these women migrants. The diversity of stories, the richness and the prominence of landmarks devoted to men compared to women is a subject well-covered in memorialization studies. This unbalance is compounded by the data from our register which shows landmarks on women migrants that are sometime tokenized, often marginalized, and which reproduce the bias towards nurture and care that have besieged the memorialization of women in general. It further shows that the memorialization process and the political and cultural mechanisms of official commemoration often work against the recognition of cross-border careers and stories. The intersectionality of the project, highlighting both gender and migration, uncovers a political landscape of landmarks – and we reflect on how this register can help combat cultural prejudice by recovering migration episodes. The RMWLE helps us reflect on the defining impact of migration episodes, a reality rarely underlined in the biographies of famous women. This article is based on a quantitative content analysis, focused on identifying measurable features and frequencies within the RMLWE dataset, and combines it with a storytelling approach at the interpretation stage, to counter dominant cultural narratives and knowledge practices.
Actions to strengthen climate resilience are gaining more traction. In order to ensure effective adaptation, it is important to monitor the outcomes and impacts of these actions. However, there are numerous challenges and a multitude of approaches when it comes to monitoring adaptation to climate change. This paper addresses challenges and lessons learned in setting up mechanisms for monitoring climate resilience and adaptation projects. Drawing from three EU Horizon 2020 projects under the EU Mission on Adaptation to Climate Change, it synthesizes insights to support future initiatives in their monitoring endeavors for other projects to learn from. Findings, acquired through workshops with experts, highlight four key challenges and the projects' learnings: the challenge of tailoring global frameworks to local needs, data availability and evaluation of data, interdisciplinary collaboration in monitoring, and stakeholder engagement for monitoring endeavors.
Early life sleep is important for neuronal development and maturation. Using the highly social prairie vole rodent model, we have previously reported that early-life sleep disruption (ELSD) during the pre-weaning period postnatal day (P)14 to 21 results in adult interference with social bonding and increases ethanol consumption following a stressor. Furthermore, we have reported increased parvalbumin expression and reduced glutamatergic neurotransmission in cortical regions in adult prairie voles that experienced this paradigm. To understand the impact of ELSD on the lifespan, examination of an earlier time in life is necessary. Thus, the aim of the present study was to examine the behavioral outcomes of ELSD on adolescent prairie voles. Here we hypothesized that anxiety and reward related behaviors, as measured by light/dark box, 2-bottle choice and social interactions, would be negatively impacted by ELSD in adolescent male and female prairie voles. Male ELSD voles were no different from control voles in measures of anxiety and ethanol preference or consumption, but affiliative social interactions were significantly reduced. ELSD differentially impacted female prairie voles, with increased anxiety-like behavior and reductions in ethanol consumption compared to Controls, but no impact on ethanol preference or social interactions. Together, these results suggest both male and female prairie voles experience differential changes to reward seeking behaviors, but only female prairie voles showed increases in anxiety-like behavior. These results further suggest that early-life sleep is critically important for neurotypical behaviors in adolescence, a time where reward-seeking and risky behaviors are adaptive for learning and promoting survival.
Galectins are a family of mammalian glycan-binding proteins that have been implicated as regulators of myriad cellular processes including cell migration, apoptosis, and immune modulation. Several members of this family, such as galectin-1, exhibit both cell-surface and intracellular functions. Interestingly, galectin-1 can be found in the endomembrane system, nucleus, or cytosol, as well as on the cell surface. The mechanisms by which galectin-1 traffics between cellular compartments, including its unconventional secretion and internalization processes, are poorly understood. Here, we determined the pathways by which exogenous galectin-1 enters cells and explored its capacity as a delivery vehicle for protein and siRNA therapeutics. We used a galectin-1-toxin conjugate, modelled on antibody-drug conjugates, as a selection tool in a genome-wide CRISPR screen. We discovered that galectin-1 interacts with the endosome-lysosome trafficking receptor sortilin in a glycan-dependent manner, which regulates galectin-1 trafficking to the lysosome. Further, we show that this pathway can be exploited for delivery of a functional siRNA. This study sheds light on the mechanisms by which galectin-1 is internalized by cells and suggests a new strategy for intracellular drug delivery via galectin-1 conjugation.
Many bacterial pathogens, including the human exclusive pathogen Salmonella Typhi, express capsular polysaccharides as a crucial virulence factor. Here, through S. Typhi whole genome sequence analyses and functional studies, we found a list of single point mutations that make S. Typhi hypervirulent. We discovered a single point mutation in the Vi biosynthesis enzymes that control Vi polymerization or acetylation is enough to result in different capsule variants of S. Typhi. All variant strains are pathogenic, but the hyper Vi capsule variants are particularly hypervirulent, as demonstrated by the high morbidity and mortality rates observed in infected mice. The hypo Vi capsule variants have primarily been identified in Africa, whereas the hyper Vi capsule variants are distributed worldwide. Collectively, these studies increase awareness about the existence of different capsule variants of S. Typhi, establish a solid foundation for numerous future studies on S. Typhi capsule variants, and offer valuable insights into strategies to combat capsulated bacteria.
Cerebrovascular accidents, also known as strokes, are the leading cause of permanent disability in society, presenting significant socioeconomic and healthcare costs. They can be caused by ischemic factors or hemorrhages, with ischemic strokes being the most common among the population. Therapies for patients suffering from this condition are limited and primarily focus on acute-phase treatment. In recent years, there has been an increase in cellular therapies, employing Stem Cells to mitigate or eliminate the consequences arising from this disease. Mesenchymal Stem Cells (MSCs) hold substantial therapeutic potential in Nervous System pathologies due to their low antigenicity and capacity to differentiate into various human tissues, such as adipogenic, chondrogenic, and osteogenic tissues. This study conducts a literature review using the “clinical trials” and “Pubmed” database, summarizing all ongoing clinical trials for ischemic strokes that utilize MSCs as treatment.
Knowing the genes involved in quantitative traits provides an entry point to understanding the biological bases of behavior, but there are very few examples where the pathway from genetic locus to behavioral change is known. To explore the role of specific genes in fear behavior, we mapped three fear-related traits, tested fourteen genes at six quantitative trait loci (QTLs) by quantitative complementation, and identified six genes. Four genes, Lamp, Ptprd, Nptx2, and Sh3gl, have known roles in synapse function; the fifth, Psip1, was not previously implicated in behavior; and the sixth is a long non-coding RNA, 4933413L06Rik, of unknown function. Variation in transcriptome and epigenetic modalities occurred preferentially in excitatory neurons, suggesting that genetic variation is more permissible in excitatory than inhibitory neuronal circuits. Our results relieve a bottleneck in using genetic mapping of QTLs to uncover biology underlying behavior and prompt a reconsideration of expected relationships between genetic and functional variation.
Sensory neurons sense pathogenic infiltration, serving to inform immune coordination of host defense. However, sensory neuron-immune interactions have been predominantly shown to drive innate immune responses. Humoral memory, whether protective or destructive, is acquired early in life - as demonstrated by both early exposure to streptococci and allergic disease onset. Our study further defines the role of sensory neuron influence on humoral immunity in the lung. Using a murine model of Streptococcus pneumonia pre-exposure and infection and a model of allergic asthma, we show that sensory neurons are required for B-cell and plasma cell recruitment and antibody production. In response to S. pneumoniae , sensory neuron depletion resulted in a larger bacterial burden, reduced B-cell populations, IgG release and neutrophil stimulation. Conversely, sensory neuron depletion reduced B-cell populations, IgE and asthmatic characteristics during allergen-induced airway inflammation. The sensory neuron neuropeptide released within each model differed. With bacterial infection, vasoactive intestinal polypeptide (VIP) was preferentially released, whereas substance P was released in response to asthma. Administration of VIP into sensory neuron-depleted mice suppressed bacterial burden and increased IgG levels, while VIP1R deficiency increased susceptibility to bacterial infection. Sensory neuron-depleted mice treated with substance P increased IgE and asthma, while substance P genetic ablation resulted in blunted IgE, similar to sensory neuron-depleted asthmatic mice. These data demonstrate that the immunogen differentially stimulates sensory neurons to release specific neuropeptides which specifically target B-cells. Targeting sensory neurons may provide an alternate treatment pathway for diseases involved with insufficient and/or aggravated humoral immunity.
G protein-coupled receptors (GPCRs) are the largest family of druggable proteins encoded in the human genome, but progress in understanding and targeting them is hindered by the lack of tools to reliably measure their nuanced behavior in physiologically relevant contexts. Here, we developed a collection of compact ONE vector G-protein Optical (ONE-GO) biosensor constructs as a scalable platform that can be conveniently deployed to measure G-protein activation by virtually any GPCR with high fidelity even when expressed endogenously in primary cells. By characterizing dozens of GPCRs across many cell types like primary cardiovascular cells or neurons, we revealed insights into the molecular basis for G-protein coupling selectivity of GPCRs, pharmacogenomic profiles of anti-psychotics on naturally occurring GPCR variants, and G-protein subtype signaling bias by endogenous GPCRs depending on cell type or upon inducing disease-like states. In summary, this open-source platform makes the direct interrogation of context-dependent GPCR activity broadly accessible.
Background: Lung cancer is the most common cause of death among all types of cancer in Germany, with an annual death rate of 45 000 patients. Over the past 15 years, innovations in diagnosis and treatment have prolonged the survival of patients with non-small-cell lung cancer in all tumor stages.Methods: This review of the diagnosis and treatment of lung cancer is based on current national and international guidelines, and on prospective trials with the highest possible level of evidence that were retrieved by a selective search of the literature.Results: Improved outcomes in patients with non-small-cell lung cancer (85% of new diagnoses) were achieved with the aid of precise diagnostic techniques, including functional imaging and endobronchial procedures for localized disease stage. Contemporary surgical and radio-oncological technologies reduce the morbidity and expand the boundaries of local therapy. Molecular pathology, including the assessment of predictive biomarkers, is an integral part of the diagnostic evaluation of non-small-cell lung cancer in all tumor stages; it enables stratified cytotoxic/molecularly targeted treatments and immunotherapies and improves patient-reported outcomes. The percentage of long-term survivors in the metastatic stage has doubled by the introduction of immunotherapy. In contrast, there has been no major improvement in the survival of patients with small-cell lung cancer (15% of new diagnoses).Conclusion: In addition to the implementation of lung cancer screening in high-risk populations, the further development and consistent implementation of personalized diagnosis and treatment in certified lung cancer centers can be expected to prolong survival and improve the patients' quality of life.
Does neuroinflammation promote neurodegeneration? Does neurodegeneration promote neuroinflammation? Or, is the answer to both questions, yes? These questions have proven challenging to answer in patients with typical age-related neurodegenerative diseases in whom the onset of neuroinflammation and neurodegeneration are largely unknown. Patients recovering from diseases associated with abrupt-onset neuroinflammation, including rare forms of antibody-mediated encephalitis (AME) and common complications of novel coronavirus disease 2019 (COVID-19), provide a unique opportunity to untangle the relationship between neuroinflammation and neurodegeneration. This review explores the lessons learned from patients with AME and COVID-19.Persistent cognitive impairment is increasingly recognized in patients recovering from AME or COVID-19, yet the drivers of impairment remain largely unknown. Clinical observations, neuroimaging and biofluid biomarkers, and pathological studies imply a link between the severity of acute neuroinflammation, subsequent neurodegeneration, and disease-associated morbidity.Data from patients with AME and COVID-19 inform key hypotheses that may be evaluated through future studies incorporating longitudinal biomarkers of neuroinflammation and neurodegeneration in larger numbers of recovering patients. The results of these studies may inform the contributors to cognitive impairment in patients with AME and COVID-19, with potential diagnostic and therapeutic applications in patients with age-related neurodegenerative diseases.
Macrophages have emerged at the forefront of research in immunology and transplantation because of recent advances in basic science. New findings have illuminated macrophage populations not identified previously, expanded upon traditional macrophage phenotypes, and overhauled macrophage ontogeny. These advances have major implications for the field of transplant immunology. Macrophages are known to prime adaptive immune responses, perpetuate T-cell-mediated rejection and antibody-mediated rejection, and promote allograft fibrosis. In this review, macrophage phenotypes and their role in allograft injury of solid organ transplants will be discussed with an emphasis on kidney transplantation. Additionally, consideration will be given to the prospect of manipulating macrophage phenotypes as cell-based therapy. Innate immunity and macrophages represent important players in allograft injury and a promising target to improve transplant outcomes.
OBJECTIVE:This research reports on the health status, including chronic disease risk factors, among Maine loggers. METHODS:Loggers completed a survey and health screenings were held across Maine, collecting data on a variety of health endpoints. RESULTS:Seventy-five loggers participated. The majority were men (97.1%) with a median age of 46, and a mean BMI of 30.6 kg/m2 (SD 4.9). Nearly half of those screened (45.9%) had blood pressure at the level of stage II hypertension. Loggers with at least a single joint abnormality were 38.4%. The health screening cohort was similar to the non-health screening cohort for many attributes. CONCLUSIONS:Future research should focus on tailored interventions to improve cardiovascular and musculoskeletal risk factors among loggers.
Oxygen supplementation in preterm infants disrupts alveolar epithelial type 2 (AT2) cell proliferation through poorly understood mechanisms. Here, newborn mice are used to understand how hyperoxia stimulates an early aberrant wave of AT2 cell proliferation that occurs between Postnatal Days (PNDs) 0 and 4. RNA-sequencing analysis of AT2 cells isolated from PND4 mice revealed hyperoxia stimulates expression of mitochondrial-specific methylenetetrahydrofolate dehydrogenase 2 and other genes involved in mitochondrial one-carbon coupled folate metabolism and serine synthesis. The same genes are induced when AT2 cells normally proliferate on PND7 and when they proliferate in response to the mitogen fibroblast growth factor 7. However, hyperoxia selectively stimulated their expression via the stress-responsive activating transcription factor 4 (ATF4). Administration of the mitochondrial superoxide scavenger mitoTEMPO during hyperoxia suppressed ATF4 and thus early AT2 cell proliferation, but it had no effect on normative AT2 cell proliferation seen on PND7. Because ATF4 and methylenetetrahydrofolate dehydrogenase are detected in hyperplastic AT2 cells of preterm infant humans and baboons with bronchopulmonary dysplasia, dampening mitochondrial oxidative stress and ATF4 activation may provide new opportunities for controlling excess AT2 cell proliferation in neonatal lung disease.
Purpose: To explore the condition of fellow eyes of patients with macular neovascularization Type 3 (MNV3) and to verify whether the retinal-choroidal anastomosis (RCA) develops equally in all MNV types. Methods: The contralateral eyes of 94 patients with MNV3, 96 patients with MNV1, and 96 patients with MNV2 were included. Multimodal imaging was performed. The MNV3 stage including the development of fibrosis and RCA over 24 months was determined. Results: In the contralateral eyes of patients of the solitary (one lesion) MNV3 group, 32 eyes (42.1%) showed early/intermediate age-related macular degeneration, 25 eyes (33%) showed MNV3, and 11 eyes (14.5%) experienced fibrosis, of which 4 eyes (5.2%) had a RCA, 7 eyes (9.2%) had atrophy after resolved MNV3, and 1 eye (1.3%) developed MNV1. In the multifocal (more than one lesion) MNV3 group, 2 eyes (11.1%) showed early/intermediate age-related macular degeneration, 9 eyes (50%) showed 15 MNV3 lesions, and 4 eyes (22.2%) showed fibrosis, of which 2 eyes (11.1%) manifested with a RCA and 3 eyes (16.7%) showed atrophy after resolved MNV3. The number of eyes with a RCA accounted for 40% of all eyes with fibrosis. The count of simultaneous bilateral multifocal MNV3 was 5 (55.6%). In the MNV1 and MNV2 groups, no eye developed a RCA. The incidence of RCAs in the scarred eyes in MNV3 was significantly higher (P < 0.0001). Conclusion: Retinal-choroidal anastomosis is an exclusive clinical feature of MNV3. The development of the multifocal MNV3 is usually bilateral and simultaneous. The occurrence of fibrosis in MNV3 has decreased dramatically after the introduction of the antiangiogenic therapy.
INTRODUCTION:The pandemic of coronavirus disease 2019 (COVID-19) stands as a major global health and social burden. As cases are growing, several other symptoms, besides the typical respiratory ones, are emerging. The involvement of the nervous system is increasingly recognized with manifestations ranging from hyposmia to meningoencephalitis and cranial neuropathies.CASE REPORT:We report the case of a 41-year-old female patient who presented to the emergency department complaining of diplopia and headache over the last 2 days. She denied any medical history, as well as any other neurological or respiratory symptom. A detailed neurological and ophthalmological examination revealed a limitation to the abduction of the right eye due to palsy of the right lateral rectus muscle causing painless, horizontal diplopia in the right gaze. The computed tomography of the brain was normal. Based on the detected lymphopenia, she was tested for COVID-19 and was positive. The cerebrospinal fluid analysis showed no abnormalities, while also a repeated head computed tomography was similarly normal. The patient received no specialized medical treatment, and after 6 days, she was discharged home having a minimal degree of persistent diplopia. Two weeks later, brain magnetic resonance imaging was performed that was similarly unrevealing.CONCLUSIONS:Isolated abducens nerve palsy can be the only presenting symptom in COVID-19. Although several pathophysiological mechanisms have been proposed, the exact nature of this manifestation has not been clarified yet. Vigilance is required by neurologists to detect and manage patients with such subtle clinical presentations.
The development of ventilator-associated pneumonia (VAP) (1) in ICU patients with severe COVID-19 is common and associated with higher VAP rates compared with non-COVID-19 patients in several retrospective studies (2–6). Additionally, there is an increased risk of shock and blood stream infections associated with VAP in COVID-19 (5). A challenge in understanding the reason for this increased rate is the lack of a clear definition of VAP in COVID-19. Due to the frequent concomitant presence of fever, leukocytosis, and lung infiltrates due to the viral infection, differentiating bacterial colonization from a new bacterial secondary infection is challenging in the presence of these symptoms and imaging findings of an acute viral pneumonia. In part due to these challenges, the term ventilator-associated lower respiratory tract infection (VA-LRTI) has been used: the rate of VA-LRTI has also been found to be higher in ICU patients with COVID-19 compared with ICU patients with influenza and those without viral infection (7). A key remaining question is why VAP and VA-LRTI occur at higher rates in COVID-19 patients. Proposed reasons for increased rate of VAP and VA-LRTI in COVID-19 include viral immunomodulation, prolonged mechanical ventilation and hospital stay, steroids use, acute respiratory distress syndrome (ARDS), prone positioning, sedating and neuromuscular blocking agents, vasopressor use, extracorporeal mechanical oxygenation utilization, and increased demands of the healthcare system including patient volume, healthcare worker shortages, and use of personal protective equipment (8). Prior studies have not systematically evaluated how VA-LRTI has changed throughout the pandemic. In this issue of Critical Care Medicine, Hedberg et al (9) expand on the epidemiology of VA-LRTIs in COVID-19 using a retrospective analysis of ventilated adults in a large Swedish ICU from January 2011 to December 2020. Their primary goal was to evaluate changes in rate of VA-LRTI in COVID-19 compared with non-COVID-19 patients over time. Specifically, they compared COVID-19 patients with non-COVID-19 patients (including influenza and the 10 most common International Classification of Diseases, 10th Edition ICU diagnoses during and prior to the pandemic) and then performed a second analysis comparing the first wave of the COVID-19 pandemic (March–July 2020) with the second wave (October–December 2020). The cohort included 479 COVID-19 ICU episodes and 19,744 non-COVID-19 ICU episodes. Patients with COVID-19 were younger and had more comorbidities but were less likely to be immunosuppressed or have cancer. The median ICU length of stay was significantly longer for COVID-19 patients (14 vs 2 d; p < 0.001) with a higher 30-day mortality (24% vs 15%; p < 0.001). Markedly, the longest median duration of ventilation in non-COVID-19 diagnoses was 5 days for ARDS but reached 10 days in COVID-19. The proportion of VA-LRTI in ICU patients with COVID-19 was higher at 30% compared with 18% in patients without COVID-19. However, this difference was likely due to the longer duration of ventilation in COVID-19, a known risk factor for VAP (1). When adjusted for number of ventilator days at risk, the rate of VA-LRTI for patients with COVID-19 (31/1,000 ventilator-days) compared similarly to patients without COVID-19 (34/1,000 ventilator-days). Interestingly, this rate of VA-LRTI was higher in COVID-19 patients than that in other infectious causes of ICU stay (11/1,000 ventilator-days), namely, bacterial pneumonia, influenza, and severe sepsis. Comparing the first wave of the pandemic with the second wave, the second wave included older patients with more comorbidities, steroid use, and prone positioning, although a shorter length of mechanical ventilation. The VA-LRTI proportion in the COVID-19 group increased from 29% (99/381) to 38% (30/93) from the first to the second wave with a minimal change of 19% (37/567) to 21% (28/324) in the non-COVID-19 group. After multivariable analyses, the second wave had a significantly higher adjusted cause-specific hazard ratio (1.86 [95% CI, 1.15–3.01]) and adjusted subdistribution hazard ratio (1.81 [95% CI, 1.17–2.79]) compared with the first wave. How do we reconcile the various previous studies that have reported a significant increase in VAP rates in patients with COVID-19 (2–8,10–14) with this finding of no increase from Hedberg et al (9)? The first explanation may be related to the very high rate of VA-LRTI in the control arm of Hedberg et al (9) study: 34 per 1,000 ventilation-days, compared with lower control arm rates from previous studies: 13 per 1,000 ventilation-days (3) and 15 per 1,000 ventilation-days (2), which indicates that Hedberg et al (9) reported more than double the control baseline rate of other studies; thus, if patients without COVID-19 were already at such a high risk for VAP (9), it might have become not feasible to detect any VAP rate difference compared with patients with COVID-19. A second explanation is that the infection definitions (e.g., VAP and VA-LRTI) used in these studies were different and not amenable to comparison. Another surveillance definition, ventilator-associated events (VAEs), has also been evaluated and shown higher VAEs per 100 episodes of ventilation, but similar VAEs rates per 1,000 ventilator-days in patients with COVID-19 versus those without COVID-19 (15). A third explanation is regarding the multiple limitations associated with all these studies done during the pandemic: no reporting and analysis accounting for standardized infection control measures, no collection of local baseline rates of VAP, no data on availability and turnover of hospital and ICU beds, adequacy of the number of healthcare providers needed for each hospital and ICU size, access to and training of personal protective equipment, and use of concomitant medications that may cause further immunosuppression (e.g. steroids), thus increasing the risk of VAP or antivirals that may limit further progression of the viral disease and reduce the length of hospital stay (e.g., remdesivir), thus decreasing the risk of VAP. All of the above variables, individually or combined, may have biased these studies either way, that is, increasing or decreasing the detection of any potential differences in the VAP rates between patients with and without COVID-19. A fourth explanation may stem from the use of absolute versus relative rates of VAP, both of which can produce discrepant interpretations even though reflecting the same actual frequency of infection; for example, although the absolute rate of VAP may be increased with COVID-19, the rate relative to baseline disease severity, age, comorbidities, and hospital length of stay may not show the same increase. Finally, the different methods for statistical adjustment (linear, logistic, Cox, Fine-Gray, and subdistribution regression models) may produce different VAP rates. One thing we can say with certainty: patients hospitalized with COVID-19 are undoubtedly requiring longer hospital/ICU stay and prolonged mechanical ventilation duration, are more frequently proned, and are receiving more immunosuppressive drugs than any other respiratory viral infection ever before. These three variables above have been well-known risk factors for VAP for a long time, even before the COVID-19 pandemic. Thus, it should come as no surprise that we are actually seeing an increased absolute rate of VAP during this pandemic; however, the question that remains is after adjusting for all relevant variables, whether the relative rate of VAP is increased. Until we have prospective cohort studies with more granular and systematic data collection regarding infection control measures, baseline hospital rates of VAP/VA-LRTI/VAE, hospital and ICU capacity, noninvasive and invasive respiratory support availability and utilization, baseline disease severity, concomitant use of antiviral and immunosuppressive drugs, and statistical methods for the appropriate adjustments, the “relative rate puzzle” remains unknown, but the “absolute rate puzzle” is already known.
