Lessons Learned from the Connecticut Response to COVID-19 in Nursing Homes during the First 2 Years of the Pandemic.

Nearly half of all SARS-CoV-2-related deaths in the United States occurred in long-term care facilities during the early pandemic. In Connecticut, statewide mitigation of this impact involved a collaboration between the Connecticut Department of Public Health and the Yale School of Public Health, alongside existing relationships with the long-term care industry and individual facilities. This close government-academic-industry collaboration facilitated the creation of a robust COVID-19 surveillance system that allowed for real-time analysis and identification of nursing homes where outbreak support was needed. The collaboration further facilitated vaccine and booster deployment to Connecticut nursing homes at a speed that outpaced much of the country. The impact of these interventions is demonstrated through COVID-19 case and death burdens among nursing home residents and the greater Connecticut population during each wave of the pandemic. We outline the evolution and impact of these alliances and how they enabled us to prioritize facilities, interventions, and the distribution of limited resources and training throughout the pandemic. We further detail lessons learned over the first 2 years of the pandemic. Such partnerships strengthen our ability to respond effectively to public health crises and should be created and/or maintained in the face of continued pandemic threats.

Rapid, selective and homogeneous brain cooling with transnasal flow of ambient air for pediatric resuscitation.

Neurologic outcome from out-of-hospital pediatric cardiac arrest remains poor. Although therapeutic hypothermia has been attempted in this patient population, a beneficial effect has yet to be demonstrated, possibly because of the delay in achieving target temperature. To minimize this delay, we developed a simple technique of transnasal cooling. Air at ambient temperature is passed through standard nasal cannula with an open mouth to produce evaporative cooling of the nasal passages. We evaluated efficacy of brain cooling with different airflows in different size piglets. Brain temperature decreased by 3°C within 25 minutes with nasal airflow rates of 16, 32, and 16 L/min in 1.8-, 4-, and 15-kg piglets, respectively, whereas rectal temperature lagged brain temperature. No substantial spatial temperature gradients were seen along the neuroaxis, suggesting that heat transfer is via blood convection. The evaporative cooling did not reduce nasal turbinate blood flow or sagittal sinus oxygenation. The rapid and selective brain cooling indicates a high humidifying capacity of the nasal turbinates is present early in life. Because of its simplicity, portability, and low cost, transnasal cooling potentially could be deployed in the field for early initiation of brain cooling prior to maintenance with standard surface cooling after pediatric cardiac arrest.

Clinical characteristics of Plasmodium falciparum infection among symptomatic patients presenting to a major urban military hospital in Cameroon.

BACKGROUND: Urban malaria has received insufficient attention in the literature. The prevalence and clinical characteristics of Plasmodium falciparum infection amongst patients presenting with suspected malaria were investigated at a major urban hospital in Douala, Cameroon with a particular focus on anaemia. METHODS: A cross-sectional, 18-week demographic and clinical survey was conducted of patients presenting to the Emergency Department of Douala Military Hospital with suspected malaria, largely defined by the presence or recent history of fever. Venous samples were tested for P. falciparum using rapid diagnostic tests and PCR, and anaemia was defined by haemoglobin level according to WHO definitions. Likelihood ratios (LR), odds ratios (OR), and population attributable risk percent (PARP) were calculated. RESULTS: Participants were ages 8 months to 86 years, 51% were women (257/503), and all districts of Douala were represented. Overall, 38.0% (n = 189/497) were anaemic, including 5.2% (n = 26/497) with severe anaemia. Anaemia prevalence was significantly higher (OR: 2.20, 95% CI 1.41-3.45) among children < 15 years (53.1%, n = 52/98) compared to adults (34%, n = 133/392). Plasmodium falciparum was detected in 37.2% by nested PCR. Among all participants, several factors were associated with clinically significant LR for P. falciparum infection, including age 10-14 years (positive LR: 3.73), living in the island district of Douala VI (positive LR: 3.41), travel to any of three northern regions (positive LR: 5.11), and high fever > 40 °C at presentation (positive LR: 4.83). Among all participants, 8.7% of anaemia was associated with P. falciparum infection, while the PARP was 33.2% among those < 15 years of age and 81.0% among 10-14-year-olds. CONCLUSIONS: The prevalence of P. falciparum infection in the urban hospital was high. Mirroring trends in many rural African settings, older children had the highest positivity rate for P. falciparum infection. Anaemia was also common in all age groups, and for those 10-14 years of age, 80% of the risk for anaemia was associated with P. falciparum infection. Malaria rates in major urban population centres can be high, and more research into the multifactorial causes of anaemia across the age spectrum are needed.

Towards rainbow portable Cytophone with laser diodes for global disease diagnostics.

In vivo, Cytophone has demonstrated the capability for the early diagnosis of cancer, infection, and cardiovascular disorders through photoacoustic detection of circulating disease markers directly in the bloodstream with an unprecedented 1,000-fold improvement in sensitivity. Nevertheless, a Cytophone with higher specificity and portability is urgently needed. Here, we introduce a novel Cytophone platform that integrates a miniature multispectral laser diode array, time-color coding, and high-speed time-resolved signal processing. Using two-color (808 nm/915 nm) laser diodes, we demonstrated spectral identification of white and red clots, melanoma cells, and hemozoin in malaria-infected erythrocytes against a blood background and artifacts. Data from a Plasmodium yoelii murine model and cultured human P. falciparum were verified in vitro with confocal photothermal and fluorescent microscopy. With these techniques, we detected infected cells within 4 h after invasion, which makes hemozoin promising as a spectrally selective marker at the earliest stages of malaria progression. Along with the findings from our previous application of Cytophone with conventional lasers for the diagnosis of melanoma, bacteremia, sickle anemia, thrombosis, stroke, and abnormal hemoglobin forms, this current finding suggests the potential for the development of a portable rainbow Cytophone with multispectral laser diodes for the identification of these and other diseases.

Repeatability and reproducibility of a handheld quantitative G6PD diagnostic.

BACKGROUND: The introduction of novel short course treatment regimens for the radical cure of Plasmodium vivax requires reliable point-of-care diagnosis that can identify glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. While deficient males can be identified using a qualitative diagnostic test, the genetic make-up of females requires a quantitative measurement. SD Biosensor (Republic of Korea) has developed a handheld quantitative G6PD diagnostic (STANDARD G6PD test), that has approximately 90% accuracy in field studies for identifying individuals with intermediate or severe deficiency. The device can only be considered for routine care if precision of the assay is high. METHODS AND FINDINGS: Commercial lyophilised controls (ACS Analytics, USA) with high, intermediate, and low G6PD activities were assessed 20 times on 10 Biosensor devices and compared to spectrophotometry (Pointe Scientific, USA). Each device was then dispatched to one of 10 different laboratories with a standard set of the controls. Each control was tested 40 times at each laboratory by a single user and compared to spectrophotometry results. When tested at one site, the mean coefficient of variation (CV) was 0.111, 0.172 and 0.260 for high, intermediate, and low controls across all devices respectively; combined G6PD Biosensor readings correlated well with spectrophotometry (rs = 0.859, p<0.001). When tested in different laboratories, correlation was lower (rs = 0.604, p<0.001) and G6PD activity determined by Biosensor for the low and intermediate controls overlapped. The use of lyophilised human blood samples rather than fresh blood may have affected these findings. Biosensor G6PD readings between sites did not differ significantly (p = 0.436), whereas spectrophotometry readings differed markedly between sites (p<0.001). CONCLUSIONS: Repeatability and inter-laboratory reproducibility of the Biosensor were good; though the device did not reliably discriminate between intermediate and low G6PD activities of the lyophilized specimens. Clinical studies are now required to assess the devices performance in practice.

Repeat positive SARS-CoV-2 RNA testing in nursing home residents during the initial 9 months of the COVID-19 pandemic: an observational retrospective analysis.

BACKGROUND: Nursing homes are high-risk COVID-19 settings with residents who are typically older and have multiple comorbidities. SARS-CoV-2 testing occurs frequently in nursing homes, with public health guidance suggesting that repeat testing is generally not warranted in the 90 days following initial positive test results. Interpretation of repeat positive tests beyond 90 days is challenging and the consequences of decisions following these tests are significant. METHODS: We utilized a surveillance system for COVID-19 to identify Connecticut nursing home residents who tested positive for SARS-CoV-2 by RNA-based testing ≥ 90 days after initial positive results. We analyzed statewide nursing home testing data over a 9-month period, from the first Connecticut nursing home case identified on March 15 through December 15, 2020, when nursing home COVID-19 vaccinations began in Connecticut. FINDINGS: We identified 156 residents (median age 75 years) with positive RNA-based PCR tests occurring ≥90 days after an initial positive test. Residents with repeat positives tests represented approximately 2.6% (156/6,079) of nursing home residents surviving beyond 90 days of their initial SARS-CoV-2 diagnosis statewide since the start of the pandemic, with a median time to repeat positivity of 135 days (range 90-245 days). Deaths were reported in 12.8% (20/156) of residents following the repeat positive test, with 80% (16/20) having one or more intervening negative RT-PCR tests prior to the repeat positive test. INTERPRETATION: Our analysis suggests that repeat positive testing in nursing home populations may exceed those reported in younger age groups. Repeat positive tests beyond 90 days may accompany severe outcomes, and should be prospectively investigated with genomic, virologic and additional data, when feasible. Data shed light on the duration of protective immunity following natural infection in this subset of largely elderly and medically frail individuals. FUNDING: This work was conducted in the context of the Connecticut DPH COVID-19 response and not supported by specific funding.

Effectiveness of the Pfizer-BioNTech COVID-19 Vaccine Among Residents of Two Skilled Nursing Facilities Experiencing COVID-19 Outbreaks - Connecticut, December 2020-February 2021.

Residents of long-term care facilities (LTCFs), particularly those in skilled nursing facilities (SNFs), have experienced disproportionately high levels of COVID-19-associated morbidity and mortality and were prioritized for early COVID-19 vaccination (1,2). However, this group was not included in COVID-19 vaccine clinical trials, and limited postauthorization vaccine effectiveness (VE) data are available for this critical population (3). It is not known how well COVID-19 vaccines protect SNF residents, who typically are more medically frail, are older, and have more underlying medical conditions than the general population (1). In addition, immunogenicity of the Pfizer-BioNTech vaccine was found to be lower in adults aged 65-85 years than in younger adults (4). Through the CDC Pharmacy Partnership for Long-Term Care Program, SNF residents and staff members in Connecticut began receiving the Pfizer-BioNTech COVID-19 vaccine on December 18, 2020 (5). Administration of the vaccine was conducted during several on-site pharmacy clinics. In late January 2021, the Connecticut Department of Public Health (CT DPH) identified two SNFs experiencing COVID-19 outbreaks among residents and staff members that occurred after each facility's first vaccination clinic. CT DPH, in partnership with CDC, performed electronic chart review in these facilities to obtain information on resident vaccination status and infection with SARS-CoV-2, the virus that causes COVID-19. Partial vaccination, defined as the period from >14 days after the first dose through 7 days after the second dose, had an estimated effectiveness of 63% (95% confidence interval [CI] = 33%-79%) against SARS-CoV-2 infection (regardless of symptoms) among residents within these SNFs. This is similar to estimated effectiveness for a single dose of the Pfizer-BioNTech COVID-19 vaccine in adults across a range of age groups in noncongregate settings (6) and suggests that to optimize vaccine impact among this population, high coverage with the complete 2-dose series should be recommended for SNF residents and staff members.

Soluble epoxide hydrolase inhibition decreases reperfusion injury after focal cerebral ischemia.

Epoxyeicosatrienoic acids (EETs) are produced by cytochrome P450 epoxygenases from arachidonic acid, and their rapid metabolism is mainly through soluble epoxide hydrolase (sEH). EETs exert vasodilatory, anti-inflammatory, anti-apoptotic, and pro-angiogenic effects. Administration of sEH inhibitors before or at the onset of stroke is protective, but the effects of post-treatment at reperfusion, when inflammation is augmented, has not been as well studied. We tested the hypothesis that 1-Trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), a potent and highly selective sEH inhibitor, suppresses inflammation and protects the brain when administered at reperfusion. Vehicle or 1 mg/kg TPPU was administered at reperfusion after 90 minutes of focal ischemia and again 24 hours later. Protein expression and activity of sEH increased after reperfusion and activity was decreased by TPPU administration. TPPU decreased infarct volume by 50%, reduced neurologic deficits and improved performance on sensorimotor tasks. Furthermore, TPPU significantly lowered the mRNA expression of interleukin-1beta by 3.5-fold and tumor necrosis factor-alpha by 2.2-fold, increased transforming growth factor-beta mRNA by 1.8-fold, and augmented immunostaining of vascular endothelial growth factor in peri-infarct cortex. Thus, inhibition of sEH at reperfusion significantly reduces infarction and improves sensorimotor function, possibly by suppressing early proinflammatory cytokines and promoting reparative cytokines and growth factors.

End-Tidal CO2-Guided Chest Compression Delivery Improves Survival in a Neonatal Asphyxial Cardiac Arrest Model.

OBJECTIVES: To determine whether end-tidal CO2-guided chest compression delivery improves survival over standard cardiopulmonary resuscitation after prolonged asphyxial arrest. DESIGN: Preclinical randomized controlled study. SETTING: University animal research laboratory. SUBJECTS: 1-2-week-old swine. INTERVENTIONS: After undergoing a 20-minute asphyxial arrest, animals received either standard or end-tidal CO2-guided cardiopulmonary resuscitation. In the standard group, chest compression delivery was optimized by video and verbal feedback to maintain the rate, depth, and release within published guidelines. In the end-tidal CO2-guided group, chest compression rate and depth were adjusted to obtain a maximal end-tidal CO2 level without other feedback. Cardiopulmonary resuscitation included 10 minutes of basic life support followed by advanced life support for 10 minutes or until return of spontaneous circulation. MEASUREMENTS AND MAIN RESULTS: Mean end-tidal CO2 at 10 minutes of cardiopulmonary resuscitation was 34 ± 8 torr in the end-tidal CO2 group (n = 14) and 19 ± 9 torr in the standard group (n = 14; p = 0.0001). The return of spontaneous circulation rate was 7 of 14 (50%) in the end-tidal CO2 group and 2 of 14 (14%) in the standard group (p = 0.04). The chest compression rate averaged 143 ± 10/min in the end-tidal CO2 group and 102 ± 2/min in the standard group (p < 0.0001). Neither asphyxia-related hypercarbia nor epinephrine administration confounded the use of end-tidal CO2-guided chest compression delivery. The response of the relaxation arterial pressure and cerebral perfusion pressure to the initial epinephrine administration was greater in the end-tidal CO2 group than in the standard group (p = 0.01 and p = 0.03, respectively). The prevalence of resuscitation-related injuries was similar between groups. CONCLUSIONS: End-tidal CO2-guided chest compression delivery is an effective resuscitation method that improves early survival after prolonged asphyxial arrest in this neonatal piglet model. Optimizing end-tidal CO2 levels during cardiopulmonary resuscitation required that chest compression delivery rate exceed current guidelines. The use of physiologic feedback during cardiopulmonary resuscitation has the potential to provide optimized and individualized resuscitative efforts.

Sex-specific associations between cerebrovascular blood pressure autoregulation and cardiopulmonary injury in neonatal encephalopathy and therapeutic hypothermia.

BACKGROUND: Cardiopulmonary injury is common in neonatal encephalopathy, but the link with cerebrovascular dysfunction is unknown. We hypothesized that alterations of cerebral autoregulation are associated with cardiopulmonary injury in neonates treated with therapeutic hypothermia (TH) for neonatal encephalopathy. METHODS: The cerebral hemoglobin volume index (HVx) from near-infrared spectroscopy was used to identify the mean arterial blood pressure (MAP) with optimal autoregulatory vasoreactivity (MAPOPT). We measured associations between MAP relative to MAPOPT and indicators of cardiopulmonary injury (duration of mechanical respiratory support and administration of inhaled nitric oxide (iNO), milrinone, or steroids). RESULTS: We identified associations between cerebrovascular autoregulation and cardiopulmonary injury that were often sex-specific. Greater MAP deviation above MAPOPT was associated with shorter duration of intubation in boys but longer ventilatory support in girls. Greater MAP deviation below MAPOPT related to longer intensive care stay in boys. Milrinone was associated with greater MAP deviation below MAPOPT in girls. CONCLUSION: MAP deviation from MAPOPT may relate to cardiopulmonary injury after neonatal encephalopathy, and sex may modulate this relationship. Whereas MAP above MAPOPT may protect the brain and lungs in boys, it may be related to cardiopulmonary injury in girls. Future studies are needed to characterize the role of sex in these associations.

Optimizing Cerebral Autoregulation May Decrease Neonatal Regional Hypoxic-Ischemic Brain Injury.

BACKGROUND: Therapeutic hypothermia provides incomplete neuroprotection for neonatal hypoxic-ischemic encephalopathy (HIE). We examined whether hemodynamic goals that support autoregulation are associated with decreased brain injury and whether these relationships are affected by birth asphyxia or vary by anatomic region. METHODS: Neonates cooled for HIE received near-infrared spectroscopy autoregulation monitoring to identify the mean arterial blood pressure with optimized autoregulatory function (MAPOPT). Blood pressure deviation from MAPOPT was correlated with brain injury on MRI after adjusting for the effects of arterial carbon dioxide, vasopressors, seizures, and birth asphyxia severity. RESULTS: Blood pressure deviation from MAPOPT related to neurologic injury in several regions independent of birth asphyxia severity. Greater duration and deviation of blood pressure below MAPOPT were associated with greater injury in the paracentral gyri and white matter. Blood pressure within MAPOPT related to lesser injury in the white matter, putamen and globus pallidus, and brain stem. Finally, blood pressures that exceeded MAPOPT were associated with reduced injury in the paracentral gyri. CONCLUSIONS: Blood pressure deviation from optimal autoregulatory vasoreactivity was associated with MRI markers of brain injury that, in many regions, were independent of the initial birth asphyxia. Targeting hemodynamic ranges to optimize autoregulation has potential as an adjunctive therapy to hypothermia for HIE.

Hypothermia and Rewarming Activate a Macroglial Unfolded Protein Response Independent of Hypoxic-Ischemic Brain Injury in Neonatal Piglets.

Therapeutic hypothermia provides incomplete neuroprotection after hypoxia-ischemia (HI)-induced brain injury in neonates. We previously showed that cortical neuron and white matter apoptosis are promoted by hypothermia and early rewarming in a piglet model of HI. The unfolded protein response (UPR) may be one of the potential mediators of this cell death. Here, neonatal piglets underwent HI or sham surgery followed by 29 h of normothermia, 2 h of normothermia + 27 h of hypothermia or 18 h of hypothermia + rewarming. Piglets recovered for 29 h. Immunohistochemistry for endoplasmic reticulum to nucleus signaling-1 protein (ERN1), a marker of UPR activation, was used to determine the ratios of ERN1+ macroglia and neurons in the motor subcortical white matter and cerebral cortex. The ERN1+ macroglia were immunophenotyped as oligodendrocytes and astrocytes by immunofluorescent colabeling. Temperature (p = 0.046) and HI (p < 0.001) independently affected the ratio of ERN1+ macroglia. In sham piglets, sustained hypothermia (p = 0.011) and rewarming (p = 0.004) increased the ERN1+ macroglia ratio above that in normothermia. HI prior to hypothermia diminished the UPR. Ratios of ERN1+ macroglia correlated with white matter apoptotic profile counts in shams (r = 0.472; p = 0.026), thereby associating UPR activation with white matter apoptosis during hypothermia and rewarming. Accordingly, macroglial cell counts decreased in shams that received sustained hypothermia (p = 0.009) or rewarming (p = 0.007) compared to those in normothermic shams. HI prior to hypothermia neutralized the macroglial cell loss. Neither HI nor temperature affected ERN1+ neuron ratios. In summary, delayed hypothermia and rewarming activate the macroglial UPR, which is associated with white matter apoptosis. HI may decrease the macroglial endoplasmic reticulum stress response after hypothermia and rewarming.

Additive Neuroprotection of a 20-HETE Inhibitor with Delayed Therapeutic Hypothermia after Hypoxia-Ischemia in Neonatal Piglets.

The severity of perinatal hypoxia-ischemia and the delay in initiating therapeutic hypothermia limit the efficacy of hypothermia. After hypoxia-ischemia in neonatal piglets, the arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) has been found to contribute to oxidative stress at 3 h of reoxygenation and to eventual neurodegeneration. We tested whether early administration of a 20-HETE synthesis inhibitor after reoxygenation augments neuroprotection with 3-hour delayed hypothermia. In two hypothermic groups, whole body cooling from 38.5 to 34°C was initiated 3 h after hypoxia-ischemia. Rewarming occurred from 20 to 24 h; then anesthesia was discontinued. One hypothermic group received a 20-HETE inhibitor at 5 min after reoxygenation. A sham-operated group and another hypoxia-ischemia group remained normothermic. At 10 days of recovery, resuscitated piglets with delayed hypothermia alone had significantly greater viable neuronal density in the putamen, caudate nucleus, sensorimotor cortex, CA3 hippocampus, and thalamus than did piglets with normothermic recovery, but the values remained less than those in the sham-operated group. In piglets administered the 20-HETE inhibitor before hypothermia, the density of viable neurons in the putamen, cortex and thalamus was significantly greater than in the group with hypothermia alone. Cytochrome P450 4A, which can synthesize 20-HETE, was expressed in piglet neurons in these regions. We conclude that early treatment with a 20-HETE inhibitor enhances the therapeutic benefit of delayed hypothermia in protecting neurons in brain regions known to be particularly vulnerable to hypoxia-ischemia in term newborns.

Rewarming from therapeutic hypothermia induces cortical neuron apoptosis in a swine model of neonatal hypoxic-ischemic encephalopathy.

The consequences of therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy are poorly understood. Adverse effects from suboptimal rewarming could diminish neuroprotection from hypothermia. Therefore, we tested whether rewarming is associated with apoptosis. Piglets underwent hypoxia-asphyxia followed by normothermic or hypothermic recovery at 2 hours. Hypothermic groups were divided into those with no rewarming, rewarming at 0.5 °C/hour, or rewarming at 4 °C/hour. Neurodegeneration at 29 hours was assessed by hematoxylin and eosin staining, TUNEL assay, and immunoblotting for cleaved caspase-3. Rewarmed piglets had more apoptosis in motor cortex than did those that remained hypothermic after hypoxia-asphyxia. Apoptosis in piriform cortex was greater in hypoxic-asphyxic, rewarmed piglets than in naive/sham piglets. Caspase-3 inhibitor suppressed apoptosis with rewarming. Rapidly rewarmed piglets had more caspase-3 cleavage in cerebral cortex than did piglets that remained hypothermic or piglets that were rewarmed slowly. We conclude that rewarming from therapeutic hypothermia can adversely affect the newborn brain by inducing apoptosis through caspase mechanisms.