COVID-19 Vaccination Coverage Among People Experiencing Homelessness in a Highly Vaccinated Midwest County-Dane County, Wisconsin, 2021.

People experiencing homelessness (PEH) are at increased risk for coronavirus disease 2019 (COVID-19) infection. This study assessed COVID-19 vaccination coverage among vaccine-eligible PEH (5 years and older) stratified by demographic characteristics. PEH were less likely to complete a primary vaccination series than the Dane County population (32.0%; 95% confidence interval [CI], 30.3%-33.8% vs 82.4%; 95% CI, 82.3%-82.5%) and were less likely to have received a booster when eligible (30.8%; 95% CI, 27.8%-33.9% vs 67.2%; 95% CI, 67.1%-67.4%). Vaccination rates were lowest among young PEH and PEH of color.

In-Home COVID-19 Testing for Children With Medical Complexity: Feasibility and Association With School Attendance and Safety Perceptions.

The REstarting Safe Education and Testing program for children with medical complexity was implemented in May 2021 at the University of Wisconsin to evaluate the feasibility of in-home rapid antigen COVID-19 testing among neurocognitively affected children. Parents or guardians administered BinaxNOW rapid antigen self-tests twice weekly for three months and changed to symptom and exposure testing or continued surveillance. In-home testing was feasible: nearly all (92.5%) expected tests were conducted. Symptomatic testing identified seven of nine COVID-19 cases. School safety perceptions were higher among those opting for symptom testing. Clinical Trials.gov identifier: NCT04895085. (Am J Public Health. 2022;112(S9):S878-S882. https://doi.org/10.2105/AJPH.2022.306971).

Clinical Manifestations and Outcomes in Immunocompetent and Immunocompromised Patients With Blastomycosis.

BACKGROUND: Blastomyces is a dimorphic fungus that infects persons with or without underlying immunocompromise. To date, no study has compared the clinical features and outcomes of blastomycosis between immunocompromised and immunocompetent persons. METHODS: A retrospective study of adult patients with proven blastomycosis from 2004-2016 was conducted at the University of Wisconsin. Epidemiology, clinical features, and outcomes were analyzed among solid-organ transplantation (SOT) recipients, persons with non-SOT immunocompromise (non-SOT IC), and persons with no immunocompromise (NIC). RESULTS: A total of 106 cases met the inclusion criteria including 74 NIC, 19 SOT, and 13 non-SOT IC (malignancy, HIV/AIDS, idiopathic CD4+ lymphopenia). The majority of patients (61.3%) had at least 1 epidemiologic risk factor for acquisition of Blastomyces. Pneumonia was the most common manifestation in all groups; however, immunocompromised patients had higher rates of acute pulmonary disease (P = .03), more severe infection (P = .007), respiratory failure (P = .010), and increased mortality (P = .02). Receipt of SOT primarily accounted for increased severity, respiratory failure, and mortality in immunosuppressed patients. SOT recipients had an 18-fold higher annual incidence of blastomycosis than the general population. The rate of disseminated blastomycosis was similar among NIC, SOT, and non-SOT IC. Relapse rates were low (5.3-7.7%). CONCLUSIONS: Immunosuppression had implications regarding the acuity, severity, and respiratory failure. The rate of dissemination was similar across the immunologic spectrum, which is in sharp contrast to other endemic fungi. This suggests that pathogen-related factors have a greater influence on dissemination for blastomycosis than immune defense.

Urine Antigen Testing is Equally Sensitive to B. dermatitidis and B. gilchristii Infections.

INTRODUCTION: Blastomycosis is endemic in Wisconsin with Blastomyces dermatitidis and B. gilchristii responsible for infections. Urine antigen testing is a non-invasive diagnostic method for blastomycosis with up to 93% test sensitivity. However, the test's sensitivity has not been evaluated with relationship to B. gilchristii infections. METHODS: We aimed to assess physician use of the urine antigen assay and its sensitivity to B. gilchristii and B. dermatitidis infections in a retrospective study. Culture confirmed clinical cases of blastomycosis from 2008-2016 were identified within Marshfield Clinic Health System (MCHS) and UW Hospital and Clinics (UWHC) medical records. Clinical data were abstracted from each medical record and included the following: patient demographics, presence of immune compromising and underlying medical conditions, treatment drugs, presence of isolated pulmonary or disseminated disease, death, urine antigen testing, timeframe of testing, and quantitative test values (EIA units or ng/mL). RESULTS: A total of 140 blastomycosis cases were included in this study, with MCHS contributing 114 cases to the study and UWHC contributing 26 cases. The majority of UWHC cases (n=22; 85%) were caused by B. dermatitidis and the majority of MCHS cases (n=73; 64%) were caused by B. gilchristii. UWHC physicians were significantly more likely to treat with multiple drugs during the course of infection and were more likely to prescribe amphotericin B and voriconazole. Urine antigen testing was more frequently used at UWHC (n=24; 92%) than MCHS (n=51; 45%; P < 0.00001). In this study, the urine antigen assay demonstrated 79% sensitivity. Sensitivity was significantly associated with the timeframe of testing (P < 0.05), with most true positive urine antigen tests (83%) being performed ≤ 7 days from diagnosis. In this study, the urine antigen assay was capable of detecting both B. dermatitidis and B. gilchristii at about equal sensitivity. Urine antigen concentration (ng/mL) trended higher in B. dermatitidis infections. CONCLUSION: This study found that the urine antigen assay is capable of detecting both species of Blastomyces at about the same sensitivity. We recommend continued use of the urine antigen assay for diagnosis of blastomycosis and recommend that the assay be used early in the diagnostic process to minimize the chance of false negative results.

First described case of prosthetic joint infection with Clostridium disporicum.

An orthopedic hardware infection with Clostridium disporicum is described. C. disporicum is a gram positive anaerobic bacillus which can contain two subterminal spores. C. disporicum had not previously been reported in musculoskeletal infections. Gram stains demonstrating gram positive bacilli with two subterminal spores should alert practitioners to the possibility of C. disporicum infection.

Retrievable inferior vena cava filters can be placed and removed with a high degree of success: Initial experience.

OBJECTIVES: Evaluate the success rate of retrievable inferior vena cava filter (IVC) removal in a tertiary care practice. BACKGROUND: Retrievable IVC filters became readily available in the United States following Food and Drug Administration approval in 2003, and their use has increased dramatically. They represent an attractive option for patients with contraindications to anticoagulation who may only need short-term protection against pulmonary embolism. METHODS: All patients who had undergone placement of a retrievable IVC filter at Mayo Clinic between 2003 and 2005 were retrospectively reviewed to evaluate our initial experience with retrievable inferior vena cava filters at a large tertiary care center. RESULTS: During a three-year-period of time, Mayo Clinic, Rochester, MN placed 892 IVC filters of which 460 were retrievable. Of the 460 retrievable filters placed (249 Günther Tulip®, 207 Recovery®, and 4 OptEase®), retrieval was attempted in 223 (48.5%). Of 223 initial attempts, 196 (87.9%) were initially successful and 27 (12.1%) were unsuccessful. Of the 27 unsuccessful initial retrieval attempts, 23 (85.2%) were because of the presence of significant thrombus within the filter and 4 (14.8%) were because of tilting and strut perforation. Of the 23 filters containing significant thrombus, 9 (39.1%) were later retrieved after a period of anticoagulation and resolution of the thrombus. CONCLUSIONS: Retrievable IVC filters can be removed with a high degree of success. Approximately one in ten retrievable IVC filter removal attempts may fail initially, usually because of significant thrombus within the filter. This does not preclude possible removal at a later date.

Different Components of Sexual Narcissism Are Differentially Associated With Specific Sexual Aggression Strategies: An Exploratory Study Among Male and Female College Students.

Objectives: This study investigated whether components of sexual narcissism are associated with different types of sexual aggression (e.g., verbal pressure or force) among students because this is a prevalent problem on college campuses. Methods: College students (N = 508) were recruited for a cross-sectional online study. Results: Results showed that components of sexual narcissism were related to different strategies of sexual aggression, with sexual entitlement being associated with not providing the victim an opportunity to object and exploiting intoxication. Gender moderated some of the associations, with women showing a stronger relationship than men. Conclusions: These findings suggest that sexual narcissism represents a risk factor for sexual aggression in men and women and highlight the need for gender-inclusive and tailored interventions to prevent sexual aggression.

Performance characteristics of "lollipop" swabs for the diagnosis of infection with SARS-CoV-2.

BACKGROUND: Common biologic samples used to diagnose COVID-19 include nasopharyngeal, nasal, or oropharyngeal swabs, and salivary samples. The performance characteristics of a sucked "lollipop" swab to detect SARS-CoV-2 virus is assessed in four small sub-studies. METHODS: In each sub-study, a flocked swab was sucked for 20 s and submitted for PCR detection of SARS-CoV-2 virus. RESULTS: Across all studies, 52 of 69 (75.4%) COVID-19 positive participants had positive "lollipop" swabs. Twelve of the 17 COVID-19 positive participants with negative "lollipop" swabs had known corresponding cycle threshold values of >37 from their nasal/nasopharyngeal swabs, an indication of low viral load at time of sampling. In a paired samples sub-study, the sensitivity and specificity of the "lollipop" swabs were 100% and 98%. CONCLUSIONS: "Lollipop" swabs performed satisfactorily especially in individuals with acute infection of COVID-19. "Lollipop" swabs are a simple method of sample collection for detecting SARS-CoV-2 virus and warrants additional consideration.

Validation of Thermal Imaging and the ALT-70 Prediction Model to Differentiate Cellulitis From Pseudocellulitis.

Importance: Cellulitis is misdiagnosed in up to 30% of cases due to mimic conditions termed pseudocellulitis. The resulting overuse of antibiotics is a threat to patient safety and public health. Surface thermal imaging and the ALT-70 (asymmetry, leukocytosis, tachycardia, and age ≥70 years) prediction model have been proposed as tools to help differentiate cellulitis from pseudocellulitis. Objectives: To validate differences in skin surface temperatures between patients with cellulitis and patients with pseudocellulitis, assess the optimal temperature measure and cut point for differentiating cellulitis from pseudocellulitis, and compare the performance of skin surface temperature and the ALT-70 prediction model in differentiating cellulitis from pseudocellulitis. Design, Setting, and Participants: This prospective diagnostic validation study was conducted among patients who presented to the emergency department with acute dermatologic lower extremity symptoms from October 11, 2018, through March 11, 2020. Statistical analysis was performed from July 2020 to March 2021 with additional work conducted in September 2023. Main Outcomes and Measures: Temperature measures for affected and unaffected skin were obtained. Cellulitis vs pseudocellulitis was assessed by a 6-physician, independent consensus review. Differences in temperature measures were compared using the t test. Logistic regression was used to identify the temperature measure and associated cut point with the optimal performance for discriminating between cellulitis and pseudocellulitis. Diagnostic performance characteristics for the ALT-70 prediction model, surface skin temperature, and both combined were also assessed. Results: The final sample included 204 participants (mean [SD] age, 56.6 [16.5] years; 121 men [59.3%]), 92 (45.1%) of whom had a consensus diagnosis of cellulitis. There were statistically significant differences in all skin surface temperature measures (mean temperature, maximum temperature, and gradients) between cellulitis and pseudocellulitis. The maximum temperature of the affected limb for patients with cellulitis was 33.2 °C compared with 31.2 °C for those with pseudocellulitis (difference, 2.0 °C [95% CI, 1.3-2.7 °C]; P < .001). The maximum temperature was the optimal temperature measure with a cut point of 31.2 °C in the affected skin, yielding a mean (SD) negative predictive value of 93.5% (4.7%) and a sensitivity of 96.8% (2.3%). The sensitivity of all 3 measures remained above 90%, while specificity varied considerably (ALT-70, 22.0% [95% CI, 15.8%-28.1%]; maximum temperature of the affected limb, 38.4% [95% CI, 31.7%-45.1%]; combination measure, 53.9% [95% CI, 46.5%-61.2%]). Conclusions and Relevance: In this large diagnostic validation study, significant differences in skin surface temperature measures were observed between cases of cellulitis and cases of pseudocellulitis. Thermal imaging and the ALT-70 both demonstrated high sensitivity, but specificity was improved by combining the 2 measures. These findings support the potential of thermal imaging, alone or in combination with the ALT-70 prediction model, as a diagnostic adjunct that may reduce overdiagnosis of cellulitis.

Recommendations for SARS-CoV-2 Testing in Children With Disabilities and Medical Complexity.

Schools provide important services that cannot be provided virtually to children with medical complexity and children with intellectual and developmental disabilities, yet these children are among the most at risk from coronavirus disease 2019 (COVID-19). To keep schools open for children with medical complexity and/or intellectual and developmental disabilities during the COVID-19 pandemic, we implemented severe acute respiratory syndrome coronavirus 2 testing at 3 sites across the United States. We evaluated testing strategies for staff and students at each site, including specimen source (nasopharyngeal or saliva), test type (polymerase chain reaction or rapid antigen), and frequency and type (screening versus exposure/symptomatic) of testing provided. Among the greatest barriers to severe acute respiratory syndrome coronavirus 2 testing in these schools was the engagement of caregivers and challenges navigating legal guardianship for consenting adult students. Additionally, variability in testing strategies nationally and in the community, as well as surges in viral transmission across the United States during the course of the pandemic, led to testing hesitancy and variable participation rates. Essential to the successful implementation of testing programs is building a trusted relationship with school administrators and guardians. Leveraging our experiences with COVID-19 and forming lasting school partnerships can help keep schools for vulnerable children safe in future pandemics.

Comparing skin surface temperature to clinical documentation of skin warmth in emergency department patients diagnosed with cellulitis.

Objective: To compare clinical documentation of skin warmth to patient report and quantitative skin surface temperatures of patients diagnosed with cellulitis in the emergency department (ED). Methods: Adult patients (≥18 years) presenting to the ED with an acute complaint involving visible erythema of the lower extremity were prospectively enrolled. Those diagnosed with cellulitis were included in this analysis. Participant report of skin warmth was recorded and skin surface temperature values were obtained from the affected and corresponding unaffected area of skin using thermal cameras. Average temperature (Tavg) was extracted from each image and the difference in Tavg between the affected and unaffected limb was calculated (Tgradient). Clinical documentation of skin warmth was compared to patient report and measured skin warmth (Tgradient >0°C). Results: Among 126 participants diagnosed with cellulitis, 110 (87%) exhibited objective warmth (Tgradient >0°C) and 58 (53%) of these cases had warmth documented in the physical examination. Of those with objective warmth, 86 (78%) self-reported warmth and 7 (6%) had warmth documented in their history of present illness (HPI) (difference = 72%, 95% confidence interval [CI]: 62%-82%; P < 0.001). A significant difference was observed for Tavg affected when warmth was documented (32.1°C) versus not documented (31.0°C) in the physical examination (difference = 1.1°C, 95% CI: 0.29-1.94; P = 0.0083). No association was found between Tgradient and patient-reported or HPI-documented warmth. Conclusions: The majority of ED-diagnosed cellulitis exhibited objective warmth, yet significant discordance was observed between patient-reported, clinician-documented, and measured warmth. This raises concerns over inadequate documentation practices and/or the poor sensitivity of touch as a reliable means to assess skin surface temperature. Introduction of objective temperature measurement tools could reduce subjectivity in the assessment of warmth in patients with suspected cellulitis.

COVID-19 Vaccination Intentions for Children With Medical Complexity.

OBJECTIVES: The chronic conditions and functional limitations experienced by children with medical complexity (CMC) place them at disproportionate risk for COVID-19 transmission and poor outcomes. To promote robust vaccination uptake, specific constructs associated with vaccine hesitancy must be understood. Our objective was to describe demographic, clinical, and vaccine perception variables associated with CMC parents' intention to vaccinate their child against COVID-19. METHODS: We conducted a cross-sectional survey (June-August 2021) for primary caregivers of CMC between ages 5 to 17 at an academic medical center in the Midwest. Multivariable logistic regression examined associations between vaccination intent and selected covariates. RESULTS: Among 1330 families, 65.8% indicated vaccination intent. In multivariable models, demographics had minimal associations with vaccination intent; however, parents of younger children (<12 years) had significantly lower adjusted odds of vaccination intent (adjusted odds ratio [95% confidence interval]: 0.26 [0.17-0.3]) compared to parents of older children (≥12 years). CMC with higher severity of illness, ie, those with ≥1 hospitalization in the previous year (versus none) or >1 complex chronic condition (vs 1), had higher adjusted odds of vaccination intent (1.82 [1.14-2.92] and 1.77 [1.16-2.71], respectively). Vaccine perceptions associated with vaccine intention included "My doctor told me to get my child a COVID-19 vaccine" (2.82 [1.74-4.55]); and "I'm concerned about my child's side effects from the vaccine" (0.18 [0.12-0.26]). CONCLUSIONS: One-third of CMC families expressed vaccine hesitation; however, constructs strongly associated with vaccination intent are potentially modifiable. Pediatrician endorsement of COVID-19 vaccination and careful counseling on side effects might be promising strategies to encourage uptake.

Ensemble machine learning classification of daily living abilities among older people with HIV.

BACKGROUND: clinically relevant methods to identify individuals at risk for impaired daily living abilities secondary to neurocognitive impairment (ADLs) remain elusive. This is especially true for complex clinical conditions such as HIV-Associated Neurocognitive Disorders (HAND). The aim of this study was to identify novel and modifiable factors that have potential to improve diagnostic accuracy of ADL risk, with the long-term goal of guiding future interventions to minimize ADL disruption. METHODS: study participants included 79 people with HIV (PWH; mean age = 63; range = 55-80) enrolled in neuroHIV studies at University California San Francisco (UCSF) between 2016 and 2019. All participants were virally suppressed and exhibited objective evidence of neurocognitive impairment. ADL status was defined as either normative (n = 39) or at risk (n = 40) based on a task-based protocol. Gradient boosted multivariate regression (GBM) was employed to identify the combination of variables that differentiated ADL subgroup classification. Predictor variables included demographic factors, HIV disease severity indices, brain white matter integrity quantified using diffusion tensor imaging, cognitive test performance, and health co-morbidities. Model performance was examined using average Area Under the Curve (AUC) with repeated five-fold cross validation. FINDINGS: the univariate GBM yielded an average AUC of 83% using Wide Range Achievement test 4 (WRAT-4) reading score, self-reported thought confusion and difficulty reading, radial diffusivity (RD) in the left external capsule, fractional anisotropy (FA) in the left cingulate gyrus, and Stroop performance. The model allowing for two-way interactions modestly improved classification performance (AUC of 88%) and revealed synergies between race, reading ability, cognitive performance, and neuroimaging metrics in the genu and uncinate fasciculus. Conversion of Neuropsychological Assessment Battery Daily Living Module (NAB-DLM) performance from raw scores into T scores amplified differences between White and non-White study participants. INTERPRETATION: demographic and sociocultural factors are critical determinants of ADL risk status among older PWH who meet diagnostic criteria for neurocognitive impairment. Task-based ADL assessment that relies heavily on reading proficiency may artificially inflate the frequency/severity of ADL impairment among diverse clinical populations. Culturally relevant measures of ADL status are needed for individuals with acquired neurocognitive disorders, including HAND.

Neurocognitive Trajectories After 72 Weeks of First-Line Anti-retroviral Therapy in Vietnamese Adults With HIV-HCV Co-infection.

Background: Long-term neurocognitive outcomes following first-line suppressive anti-retroviral therapy (ART) remain uncertain for individuals with HIV and hepatitis C (HCV) co-infection. The study examined neurocognitive performance before and after 72 weeks of ART using repeated multivariate analyses and latent trajectory models. Methods: One hundred and sixty adults with chronic, untreated HIV infection (n = 80 with HCV co-infection and n = 80 HIV mono-infected) and 80 demographically similar healthy controls were recruited from the Hospital for Tropical Diseases in Ho Chi Minh City and the surrounding community, respectively. Neurocognitive measures (adapted for use in Vietnam) and liver enzyme tests were compared across groups at baseline. Repeated multivariate and group-based trajectory analyses (GBTA) examined neurocognitive subgroup profiles of the co-infected individuals after 72 weeks of de novo efavirenz- (n = 41) or raltegravir-based (n = 39) ART. Results: Baseline analyses revealed worse motor function in HIV-HCV co-infected individuals compared to both comparison groups. Longitudinal analyses revealed improved neurocognitive performance by week 48 for most participants regardless of treatment arm. GBTA identified a subgroup (35% of HIV-HCV sample) with persistent motor impairment despite otherwise successful ART. Higher HIV viral load and lower CD4+ T cell count at baseline predicted persistent motor dysfunction. Liver indices and ART regimen did not predict neurocognitive outcomes in HIV-HCV co-infected individuals. Conclusions: Most HIV-HCV co-infected individuals achieve normative neurocognitive performance after 48 weeks of de novo suppressive ART. However, individuals with more severe HIV disease prior to ART exhibited motor impairment at baseline and 72 weeks after otherwise successful treatment. Interventions aimed at improving motor symptoms at the time of HIV treatment onset may improve long-term clinical outcomes in HIV-HCV co-infected adults.

Percutaneous blunt dissection technique for retrieval of over-the-wire Greenfield filters.

Although the over-the-wire Greenfield filter was designed as a permanent filter, the present report describes two patients who had Greenfield filters percutaneously removed. One was removed at approximately 2,250 days after placement. This patient had developed severe abdominal pain believed to be caused by the filter that resolved after percutaneous filter removal. The second patient had the filter removed 8 months after placement at her request. The technique of filter removal involves the use of large telescoping sheaths to facilitate separation of the filter from the vena caval wall.

Pharmacology of nonsteroidal antiinflammatory drugs and opioids.

Chronic pain affects up to 50 million Americans every day. Traditional treatment has included acetaminophen, nonsteroidal antiinflammatory drugs (NSAIDs), or opioids. The combination of NSAIDs and opioids can provide effective treatment for up to 90% of patients with chronic pain, but the NSAIDs have the potential for significant, even life-threatening side effects. Additionally, the nonselective cyclooxygenase inhibitors with 16,000 deaths per year in the United States might not be any safer. The opioids are great for short-term pain, but may need to be adjusted or changed frequently due to the development of tolerance. Understanding of the mechanism of opioids and NSAIDs has improved greatly over the past decade, but is still incomplete.

Impact of COVID-19 Quarantine and School Cancelation on Other Common Infectious Diseases.

Coronavirus disease 2019 lead to wide-spread quarantines and cancelations. The impact of these measures on other, noncoronavirus disease 2019, infectious diseases was analyzed within Dane County, Wisconsin. The incidence of streptococcal pharyngitis and acute otitis media decreased during quarantine while gonorrhea increased. Quarantine had the expected result for infections spread via the respiratory route but a different effect from those transmitted through sexual activity.

Immune recovery in HIV-1 infected patients with sustained viral suppression under long-term antiretroviral therapy in Ethiopia.

BACKGROUND: There is very little data on long-term immune recovery responses in patients on suppressive antiretroviral therapy (ART) in the setting of sub-Saharan Africa (SSA). Thus, we sought to determine CD4+ T-cell, CD8+ T-cell and CD4/CD8 ratio responses in a cohort of HIV infected individuals on sustained suppressive ART followed up for more than a decade. METHODS: The cohort comprised adult patients who started ART between 2001 and 2007 and followed for up to 14 years. Trends in median CD4+ T-cells, CD8+ T-cells and CD4/CD8 ratio were reviewed retrospectively. Poisson regression models were used to identify factors associated with achieving normalized T-cell biomarkers. Kaplan-Meier curves were used to estimate the probability of attaining normalized counts while on suppressive ART. RESULTS: A total of 227 patients with a median duration of follow-up on ART of 12 (IQR: 10.5-13.0) years were included. CD4 cell count increased from baseline median of 138 cells (IQR: 70-202) to 555 cells (IQR: 417-830). CD4 cell increased continuously up until 5 years, after which it plateaued up until 14 years of follow up. Only 69.6% normalized their CD4 cell count within a median of 6.5 (IQR: 3.0-10.5) years. In addition, only 15.9% of the cohort were able to achieve the median reference CD4+ T-cell threshold count in Ethiopians (≈760 cells/µL). CD8+ T-cell counts increased initially until year 1, after which continuous decrease was ascertained. CD4/CD8 ratio trend revealed continuous increase throughout the course of ART, and increased from a median baseline of 0.14 (IQR: 0.09-0.22) to a median of 0.70 (IQR: 0.42-0.95). However, only 12.3% normalized their ratio (≥ 1.0) after a median of 11.5 years. In addition, only 8.8% of the cohort were able to achieve the median reference ratio of healthy Ethiopians. CONCLUSION: Determination of both CD4+ and CD8+ T-cells, along with CD4/CD8 ratio is highly relevant in long-term follow-up of patients to assess immune recovery. Monitoring ratio levels may serve as a better biomarker risk for disease progression among patients on long-term ART. In addition, the findings emphasize the relevance of initiation of ART at the early stage of HIV-1 infection.