ObjectivesWe evaluated whether implementation of lockdown orders in South Africa affected ambulatory clinic visitation in rural Kwa-Zulu Natal (KZN).DesignObservational cohortSettingData were analysed from 11 primary healthcare clinics in northern KZN.ParticipantsA total of 46 523 individuals made 89 476 clinic visits during the observation period.Exposure of interestWe conducted an interrupted time series analysis to estimate changes in clinic visitation with a focus on transitions from the prelockdown to the level 5, 4 and 3 lockdown periods.Outcome measuresDaily clinic visitation at ambulatory clinics. In stratified analyses, we assessed visitation for the following subcategories: child health, perinatal care and family planning, HIV services, non-communicable diseases and by age and sex strata.ResultsWe found no change in total clinic visits/clinic/day at the time of implementation of the level 5 lockdown (change from 90.3 to 84.6 mean visits/clinic/day, 95% CI −16.5 to 3.1), or at the transitions to less stringent level 4 and 3 lockdown levels. We did detect a >50% reduction in child healthcare visits at the start of the level 5 lockdown from 11.9 to 4.7 visits/day (−7.1 visits/clinic/day, 95% CI −8.9 to 5.3), both for children aged <1 year and 1–5 years, with a gradual return to prelockdown within 3 months after the first lockdown measure. In contrast, we found no drop in clinic visitation in adults at the start of the level 5 lockdown, or related to HIV care (from 37.5 to 45.6, 8.0 visits/clinic/day, 95% CI 2.1 to 13.8).ConclusionsIn rural KZN, we identified a significant, although temporary, reduction in child healthcare visitation but general resilience of adult ambulatory care provision during the first 4 months of the lockdown. Future work should explore the impacts of the circulating epidemic on primary care provision and long-term impacts of reduced child visitation on outcomes in the region.

Exposure to oxidant air pollution is associated with increased respiratory morbidities and susceptibility to infections. Ozone is a commonly encountered oxidant air pollutant, yet its effects on influenza infections in humans are not known. The greater Mexico City area was the primary site for the spring 2009 influenza A H1N1 pandemic, which also coincided with high levels of environmental ozone. Proteolytic cleavage of the viral membrane protein hemagglutinin (HA) is essential for influenza virus infectivity. Recent studies suggest that HA cleavage might be cell-associated and facilitated by the type II transmembrane serine proteases (TTSPs) human airway trypsin-like protease (HAT) and transmembrane protease, serine 2 (TMPRSS2), whose activities are regulated by antiproteases, such as secretory leukocyte protease inhibitor (SLPI). Based on these observations, we sought to determine how acute exposure to ozone may modulate cellular protease/antiprotease expression and function, and to define their roles in a viral infection. We utilized our in vitro model of differentiated human nasal epithelial cells (NECs) to determine the effects of ozone on influenza cleavage, entry, and replication. We show that ozone exposure disrupts the protease/antiprotease balance within the airway liquid. We also determined that functional forms of HAT, TMPRSS2, and SLPI are secreted from human airway epithelium, and acute exposure to ozone inversely alters their expression levels. We also show that addition of antioxidants significantly reduces virus replication through the induction of SLPI. In addition, we determined that ozone-induced cleavage of the viral HA protein is not cell-associated and that secreted endogenous proteases are sufficient to activate HA leading to a significant increase in viral replication. Our data indicate that pre-exposure to ozone disrupts the protease/antiprotease balance found in the human airway, leading to increased influenza susceptibility.

Summary Medical and public health research increasingly involves the collection of complex and high dimensional data. In particular, functional data—where the unit of observation is a curve or set of curves that are finely sampled over a grid—is frequently obtained. Moreover, researchers often sample multiple curves per person resulting in repeated functional measures. A common question is how to analyze the relationship between two functional variables. We propose a general function-on-function regression model for repeatedly sampled functional data on a fine grid, presenting a simple model as well as a more extensive mixed model framework, and introducing various functional Bayesian inferential procedures that account for multiple testing. We examine these models via simulation and a data analysis with data from a study that used event-related potentials to examine how the brain processes various types of images.

OIRD is an important, albeit mostly preventable, complication of opioid therapy in children. Naloxone use can be used as a measure to track opioid safety in children, identify contributing factors, and formulate preventive strategies to reduce the risk for OIRD.

The respiratory epithelium functions as a central orchestrator to initiate and organize responses to inhaled stimuli. Proteases and antiproteases are secreted from the respiratory epithelium and are involved in respiratory homeostasis. Modifications to the protease/antiprotease balance can lead to the development of lung diseases such as emphysema or chronic obstructive pulmonary disease. Furthermore, altered protease/antiprotease balance, in favor for increased protease activity, is associated with increased susceptibility to respiratory viral infections such as influenza virus. However, nutritional antioxidants induce antiprotease expression/secretion and decrease protease expression/activity, to protect against viral infection. As such, this review will elucidate the impact of this balance in the context of respiratory viral infection and lung disease, to further highlight the role epithelial cell-derived proteases and antiproteases contribute to respiratory immune function. Furthermore, this review will offer the use of nutritional antioxidants as possible therapeutics to boost respiratory mucosal responses and/or protect against infection.

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Rationale: Diesel exhaust enhances allergic inflammation, and pollutants are associated with heightened susceptibility to viral respiratory infections. The effects of combined diesel and virus exposure in humans are unknown. Objectives: Test whether acute exposure to diesel modifies inflammatory responses to influenza virus in normal humans and those with allergies. Methods: We conducted a double-blind, randomized, placebocontrolled study of nasal responses to live attenuated influenza virus in normal volunteers and those with allergic rhinitis exposed to diesel (100 mg/m 3 ) or clean air for 2 hours, followed by standard dose of virus and serial nasal lavages. Endpoints were inflammatory mediators (ELISA) and virus quantity (quantitative reverse-transcriptase polymerase chain reaction). To test for exposure effect, we used multiple regression with exposure group (diesel vs. air) as the main explanatory variable and allergic status as an additional factor. Measurements and Main Results: Baseline levels of mediators did not differ among groups. For most postvirus nasal cytokine responses, there was no significant diesel effect, and no significant interaction with allergy. However, diesel was associated with significantly increased IFN-g responses (P ¼ 0.02), with no interaction with allergy in the regression model. Eotaxin-1 (P ¼ 0.01), eosinophil cationic protein (P , 0.01), and influenza RNA sequences in nasal cells (P ¼ 0.03) were significantly increased with diesel exposure, linked to allergy. Conclusions: Short-term exposure to diesel exhaust leads to increased eosinophil activation and increased virus quantity after virus inoculation in those with allergic rhinitis. This is consistent with previous literature suggesting a diesel "adjuvant" effect promoting allergic inflammation, and our data further suggest this change may be associated with reduced virus clearance. Clinical trial registered with www.clinicaltrials.gov (NCT00617110).

Objectives Public health interventions designed to interrupt COVID-19 transmission could have deleterious impacts on primary healthcare access. We sought to identify whether implementation of the nationwide lockdown (shelter-in-place) order in South Africa affected ambulatory clinic visitation in rural Kwa-Zulu Natal (KZN). Design Prospective, longitudinal cohort study Setting Data were analyzed from the Africa Health Research Institute Health and Demographic Surveillance System, which includes prospective data capture of clinic visits at eleven primary healthcare clinics in northern KwaZulu-Natal Participants A total of 36,291 individuals made 55,545 clinic visits during the observation period. Exposure of Interest We conducted an interrupted time series analysis with regression discontinuity methods to estimate changes in outpatient clinic visitation from 60 days before through 35 days after the lockdown period. Outcome Measures Daily clinic visitation at ambulatory clinics. In stratified analyses we assessed visitation for the following sub-categories: child health, perinatal care and family planning, HIV services, non-communicable diseases, and by age and sex strata. Results We found no change in total clinic visits/clinic/day from prior to and during the lockdown (-6.9 visits/clinic/day, 95%CI -17.4, 3.7) or trends in clinic visitation over time during the lockdown period (-0.2, 95%CI -3.4, 3.1). We did detect a reduction in child healthcare visits at the lockdown (-7.2 visits/clinic/day, 95%CI -9.2, -5.3), which was seen in both children <1 and children 1-5. In contrast, we found a significant increase in HIV visits immediately after the lockdown (8.4 visits/clinic/day, 95%CI 2.4, 14.4). No other differences in clinic visitation were found for perinatal care and family planning, non-communicable diseases, or among adult men and women. Conclusions In rural KZN, the ambulatory healthcare system was largely resilient during the national-wide lockdown order. A major exception was child healthcare visitation, which declined immediately after the lockdown but began to normalize in the weeks thereafter. Future work should explore efforts to decentralize chronic care for high-risk populations and whether catch-up vaccination programs might be required in the wake of these findings.