Prehospital Time Following Traumatic Injury Is Independently Associated With the Need for In-Hospital Blood and Early Mortality for Specific Injury Types.

OBJECTIVE: Treating traumatic hemorrhage is time sensitive. Prehospital care and transport modes (eg, helicopter and ground) may influence in-hospital events. We hypothesized that prehospital time (on-scene time [OST] and total prehospital time [TPT]) and transport mode are associated with same-day transfusion and mortality. Furthermore, we sought to identify regions of anatomic injury that modify the relationship between prehospital time and outcomes in strata corresponding to transport types. METHODS: We obtained prehospital, in-hospital, and trauma registry data from an 8-center cohort of adult nonburn trauma patients from 2017 to 2022 directly transported from the scene to the hospital and having an Injury Severity Score (ISS) > 9 for the Task Order 1 project of the Linking Investigators in Trauma and Emergency Services research network. We excluded patients missing prehospital times, patients < 18 years of age, patients from interfacility transfers, and recipients of prehospital blood. Our same-day outcomes were in-hospital transfusions within 4 hours and 24-hour mortality. Each outcome was adjusted using multivariable logistic regression for covariates of prehospital phases (OST and TPT), mode of transport (helicopter and ground), age, sex, ISS, Glasgow Coma Scale motor subscale score < 6, and field hypotension (systolic blood pressure < 90 mm Hg). We evaluated the association of prehospital time on outcomes for scene missions by transport mode across severe injury patterns defined by Abbreviated Injury Scale > 2 body regions. RESULTS: Of 78,198 subjects, 34,504 were eligible for the study with a mean age of 47.6 ± 20.3 years, ISS of 18 ± 11, OST of 15.9 ± 9.5 minutes, and TPT of 48.7 ± 20.3 minutes. Adjusted for injury severity and demographic factors, transport type significantly modified the relationship between prehospital time and outcomes. The association of OST and TPT with the odds of 4-hour transfusion was absent for the ground emergency medical services (GEMS) cohort and present for the helicopter emergency medical services (HEMS) ambulance cohort, whereas these times were associated with decreased 24-hour mortality for both transport types. When stratifying by injury to most anatomic regions, OST and TPT were associated with a decreased need for 4-hour transfusions in the GEMS cohort. However, OST was associated with increased early transfusion only among patients with severe injuries of the thorax, and this association persisted after adjusting additionally for injury type (odds ratio [OR] = 1.03; 95% confidence interval [CI], 1.00-1.05; P = .02). The presence of polytrauma supported an association between prehospital time and decreased 24-hour mortality for the GEMS cohort (OST: OR = 0.97; 95% CI, 0.95-0.99; P < .01; TPT: OR = 0.99; 95% CI, 0.98-0.99; P = .02), whereas no injuries showed significant association of helicopter prehospital time on mortality after adjustment. CONCLUSION: We determined that transport type affects the relationship between prehospital time and hospital outcomes (4-hour transfusion: positive relationship for HEMS and negative for GEMS, 24-hour mortality: negative for both transport types). Furthermore, we identified regions of anatomic injury that modify the relationship between prehospital time and outcomes in strata corresponding to transport types. Of these regions, most notable were severe isolated injuries to the thorax that supported a positive relationship between HEMS OST and 4-hour transfusions and polytrauma that showed a negative relationship between GEMS OST or TPT and 24-hour mortality after adjustment.

Symptoms of Liver Disease During Tenofovir Therapy With or Without Peginterferon: Results from the Hepatitis B Research Network Immune Active Trial.

AIMS: Evaluate patient-reported liver symptoms during treatment for chronic hepatitis B viral (HBV) infection and associations between changes in symptoms and levels of alanine aminotransferase (ALT) and viral markers. METHODS: Data from 200 participants in the Hepatitis B Research Network Immune Active Trial who completed symptom assessments were analyzed. Patients were treated with tenofovir, with or without peginterferon (TDF + PegIFN vs. TDF alone) for 192 weeks. Participants completed a Symptom Checklist at baseline and every 4-12 weeks. A total symptom score was created, ranging from 0 (none) to 40 (severe). The SF-36 was completed every 48 weeks. Associations of symptom scores with ALT and viral markers were evaluated at baseline and end of treatment. RESULTS: Participants were 65% male, 83% Asian, with a mean age of 42. Baseline symptoms were mild (median = 2, range 0-25) and associated with baseline ALT, HBV DNA levels and HBeAg + status. Patients on TDF alone experienced a more rapid and greater improvement in symptoms, but by week 192, symptom improvement was similar in both groups (54% vs 36%). Symptom improvements correlated with ALT and HBV DNA, most markedly among those with symptoms at baseline. Most patients (4 out of 6) who achieved HBsAg loss experienced symptom improvements. Overall, SF-36 scores did not change with treatment. CONCLUSIONS: Reduction in ALT and HBV DNA levels with therapy are associated with significant improvement in liver symptoms such as fatigue and pain over the liver, especially among those with higher ALT, HBV DNA, symptoms and HBeAg + status prior to treatment.

Changes in serum hepatitis B surface and e antigen, interferon-inducible protein 10, and aminotransferase levels during combination therapy of immune-tolerant chronic hepatitis B.

BACKGROUND AND AIMS: Treatment of immune-tolerant (IT) children and adults with combined peginterferon alfa-2a and entecavir results in a decline in serum HBeAg and HBsAg concentrations but rarely results in loss of HBeAg or sustained off-treatment response. Factors associated with declines in these viral antigens during treatment remain unexplored. APPROACH AND RESULTS: We investigated the pattern of virologic and biochemical response in 86 participants (59 children, 27 adults) by serial quantitative measurement of HBsAg (qHBsAg), quantitative HBeAg (qHBeAg), HBV RNA, interferon-inducible protein (IP-10), IL-18, and alanine aminotransferase (ALT). Each individual had previously been treated with 8 weeks of entecavir followed by 40 weeks of combined peginteferon and entecavir. We defined the interrelationships between these parameters and virologic response measured as nadir declines from baseline for HBeAg and HBsAg. The patterns of HBsAg and HBeAg decline were similar in pediatric and adult participants. Higher levels of IP-10 were observed during treatment in participants with greater ALT elevations and greater reductions of qHBsAg and qHBeAg. Individuals with peak ALT values exceeding three times the upper limit of normal were significantly more likely to have >1 log10 decline in both viral antigens. HBV DNA became undetectable in 21 of 86 (24%) and HBV RNA in 4 of 77 (5%) during therapy, but both markers remained negative only in those who became HBsAg negative, all of whom also had ALT elevations. CONCLUSIONS: Induction of IP-10 during peginterferon treatment in adults and children in the IT phase of chronic HBV infection is associated with ALT elevations and decline in viral antigens, suggesting a degree of interferon-inducible viral control.

Liver disease symptoms are associated with higher risk of adverse clinical outcomes: A longitudinal study of North American adults with chronic Hepatitis B.

BACKGROUND: Symptoms of chronic hepatitis B (CHB) are not well characterized. AIMS: To evaluate CHB symptoms and associations with disease activity and clinical outcomes. METHODS: Longitudinal data from 1,576 participants in the Hepatitis B Research Network Cohort Study who completed symptom assessments were analyzed. A composite symptom score was calculated using a Symptom Checklist (0=none to 40=extreme). Multivariable mixed models assessed variables associated with symptom change over time. Latent class symptom trajectories were evaluated. The cumulative probability of long-term clinical outcomes (new onset cirrhosis, hepatic decompensation, hepatocellular carcinoma, liver transplantation, death) was examined by baseline symptom groups. RESULTS: Participants median age was 42 (range:18-80), 51% were male, 75% Asian, (68% of whom were born outside North America) with a median follow-up of 4.2 years. On average, symptoms did not significantly change over time. The multivariable model identified several variables associated with higher symptoms during follow-up: being female, non-Asian, born in the US/Canada, lower education, higher AST, lower platelets, and more comorbidities. Two patient subgroups were identified based on longitudinal symptom trajectories: a low symptom group (92%, n=1,451) with symptom scores averaging 2.4 over time and a moderate symptom group (8%, n=125) with symptom scores averaging 11.5. During follow-up, 7.3% in the moderate symptom group, but only 3.2% of the low symptom group, developed adverse outcomes (p=0.02). CONCLUSIONS: In this large cohort of CHB patients, symptoms were generally mild and stable over time. However, in some patients with moderate symptoms at baseline, deleterious clinical outcomes were more frequent in follow-up.

Chronic Hepatitis Is Common and Often Untreated Among Children with Hepatitis B Infection in the United States and Canada.

OBJECTIVE: To determine the outcomes of chronic hepatitis B virus (HBV) infection in a large, prospectively studied cohort of children in the US and Canada. STUDY DESIGN: This was a prospective, observational study of children with chronic HBV enrolled in 7 clinical centers and evaluated at baseline, weeks 24 and 48, and annually thereafter, with analysis of demographic, clinical, physical examination, and blood test data. RESULTS: Among 362 children followed for a median of 4.2 years, elevated alanine aminotransferase (ALT) levels (>1 upper limit of normal) were present in 72% at last evaluation, including in 60% of children with loss of hepatitis B e antigen during follow-up and 70% of those who were hepatitis B e antigen negative at baseline. Significant ALT flares (male patients ≥400 U/L, female patients ≥350 U/L) occurred in 13 children. Of 129 children who fulfilled the American Association for the Study of Liver Diseases treatment criteria during follow-up, anti-HBV treatment was initiated in only 25. One child died (unrelated to liver disease), 1 developed cirrhosis, but no episodes of cirrhotic decompensation or hepatocellular carcinoma were observed. Decline in platelet count was inversely associated with ALT elevations. CONCLUSIONS: In a cohort of children with chronic HBV infection in the US and Canada, many children remained at risk of progressive liver disease due to active hepatitis, but major clinical outcomes such as cirrhosis, cancer, and death were rare. Many children who met criteria for treatment remained untreated.

Maternal knowledge of the risk of vertical transmission and offspring acquisition of hepatitis B.

INTRODUCTION AND OBJECTIVES: Universal vaccination at birth and in infancy is key to the elimination of chronic hepatitis B infection. We aimed to assess hepatitis B immune-prophylaxis and perinatal transmission knowledge, in a large and ethnically diverse cohort of previously pregnant North American women, chronically infected with hepatitis B. MATERIALS AND METHODS: The Hepatitis B Research Network (HBRN) is comprised of 28 Clinical Centers in the United States and Canada. Female cohort participants were administered a questionnaire to assess: (1) their assertion of knowledge regarding HBV prophylaxis at birth, testing, and diagnosis of hepatitis B in their children, and (2) the percentage of affirmative to negative responses for each of the HBV-related interventions her child may have received. The relationship between asserted knowledge, actions taken and maternal demographics were assessed. RESULTS: A total of 351 mothers with 627 children born in or after 1992 were included. Median age at enrollment was 39.8 years. Mothers were mostly foreign-born with the largest percentage from Asia (73.4%) and Africa (11.7%). Of the 627 children, 94.5% had mothers who asserted that they knew whether their child had received HBIG or HBV vaccine at birth, for 88.8% of the children, their mothers indicated that they knew if their child was tested for HBV and for 84.5% of children, their mothers knew if the child was diagnosed with HBV infection. Among children whose mothers asserted knowledge of their HBV management, 95.3% were reported to have received HBIG or HBV vaccine, 83.4% of children were said to have been tested for HBV, and 4.8% of children were said to have been diagnosed with HBV. Younger maternal age was the only factor significantly associated with higher percentage of children for whom mothers reported knowledge of testing (p=0.02) or diagnosis of HBV (p=0.02). CONCLUSIONS: While high percentages of North American children had mothers asserting knowledge of HBV prophylaxis and testing, knowledge gaps remain, with mothers of 5.5-15.5% of children lacking knowledge of key components of the HBV prevention and diagnosis in the perinatal setting. Targeted education of HBsAg-positive mothers may aid in closing this gap and reducing vertical transmission.

Life-course impact of child maltreatment on midlife health-related quality of life in women: longitudinal mediation analysis for potential pathways.

PURPOSE: We examined (1) if child maltreatment (CM) is associated with lower health-related quality of life (HRQoL) and fewer quality-adjusted life years (QALY) over a 9-year follow-up of midlife women and (2) if adulthood psychosocial mediators could explain these associations. METHODS: Women (n = 342) completed the Childhood Trauma Questionnaire. Longitudinal HRQoL and QALY outcomes measured at five study visits include 36-item Short-Form Health Survey mental component score and physical component score and the Short Form-6 Dimension health index. Aims 1 and 2 were investigated by generalized estimating equations and sequential structural nested mean models, respectively. RESULTS: Twenty percent reported 2+ CM types. Compared with women without CM, women who experienced 2+ CM types reported 5- and 4-points lower scores in mental component score and physical component score, respectively, and 28 fewer healthy days per year in QALY. Low optimism, sleep problems, and low social support each explained greater than 10% of the relationship between 2+ CM and HRQoL and QALY over time. CONCLUSIONS: CM is a life-course social determinant of HRQoL and QALY throughout midlife, particularly in women who experienced 2+ CM types. Several mediators are modifiable and could be targets of interventions to mitigate the negative impact of CM on midlife HRQoL and QALY in women.

Patient-reported outcomes in a large North American cohort living with chronic hepatitis B virus: a cross-sectional analysis.

BACKGROUND: Patient-reported outcomes (PROs) such as health-related quality of life (HRQoL) and symptoms associated with chronic hepatitis B viral (HBV) infection have not been well-described in North American cohorts. AIMS: To evaluate several PROs and associations with HBV disease activity markers. METHODS: Cross-sectional analysis including 876 adults who completed PRO measures during the Hepatitis B Research Network Adult Cohort Study. Participants on HBV treatment were excluded. Outcomes included: HRQoL using the SF-36 mental component summary and physical component summary scores; symptom burden using a 10-item Total Symptom Checklist and fatigue using an instrument from the Patient-Reported Outcomes Measurement Information System®. Covariates included laboratory markers of disease severity, virological status, comorbidities and medications. RESULTS: Median age was 42 (range: 19-79), 51% were female, 73% Asian, 19% HBeAg (+), 2% had AST-platelet ratio index (APRI) ≥1.5 and 74% without comorbidities. Mean mental component summary T-score = 52, physical component summary T-score = 54 and PROMIS Fatigue T-score = 47. On a scale from 0 (none) to 40 (extreme), the mean Symptom Checklist score = 3 and 25% reported no symptoms. The most frequent symptoms were fatigue (60%), irritability (32%) and itching (32%). Most symptoms were 'a little bit' bothersome. In multivariable regressions, APRI ≥1.50 and more comorbidities were associated with worse patient-reported outcomes; virological markers were not. Adding the Total Symptom Checklist score to original regression models increased explanation of variation in the mental component summary score from 4% to 44% and the Physical Component Summary Score from 17% to 34%. CONCLUSIONS: Untreated North American HBV patients with mild liver disease report favourable health-related quality of life and minimal symptoms. HBV does not impact health-related quality of life unless advanced liver disease or comorbidities are present. High symptom burden explains substantial variation in health-related quality of life. (CT.gov identifier: NCT01263587).

Prevalence and Impact of Hepatitis E Virus Infection Among Persons With Chronic Hepatitis B Living in the US and Canada.

BACKGROUND: Patients with chronic hepatitis B virus (HBV) may experience spontaneous biochemical flares of liver disease activity. This study aimed to determine (i) the prevalence of prior and possible acute hepatitis E virus (HEV) infection among persons with chronic HBV and (ii) whether HEV infection is associated with liver disease flares among persons with chronic HBV. METHODS: Serum from a random sample of 600 adults in the Hepatitis B Research Network Cohort Study was tested for HEV RNA and anti-HEV IgM and IgG. Logistic regression models were used to estimate crude and adjusted odds ratios of anti-HEV prevalence for participant characteristics. RESULTS: Anti-HEV IgG and IgM seroprevalence was 28.5% and 1.7%, respectively. No participants had detectable HEV RNA. Of the 10 anti-HEV IgM+ participants, only 1 had elevated serum ALT at seroconversion. The odds of anti-HEV seropositivity (IgG+ or IgM+) were higher in older participants, males, Asians, less educated people, and those born outside the United States and Canada. CONCLUSIONS: Acute HEV infection is a rare cause of serum ALT flares among persons with chronic HBV. The high seroprevalence of anti-HEV IgG among the chronic HBV patients is strongly associated with various demographic factors in this largely Asian American cohort.

Combination of Entecavir/Peginterferon Alfa-2a in Children With Hepatitis B e Antigen-Positive Immune Tolerant Chronic Hepatitis B Virus Infection.

The optimal management strategy for children with immune-tolerant chronic hepatitis B virus (HBV) infection remains unknown. The purpose of this clinical trial was to determine the safety and efficacy of therapy with entecavir and peginterferon in a group of children in the immune-tolerant phase of HBV infection. Children with immune-tolerant features of chronic hepatitis B (CHB) received entecavir once-daily in a dose of 0.015 mg/kg (0.5 mg maximum) for 48 weeks; peginterferon alfa-2a (180 µg/1.73m2 subcutaneously) once-weekly was added at the end of week 8 and continued until week 48. The primary endpoint was lack of detectable hepatitis B e antigen (HBeAg) with HBV DNA levels ≤1,000 IU/mL 48 weeks after stopping therapy. Sixty children (75% female), median age 10.9 (range, 3.4-17.9) years, were enrolled. All were positive for hepatitis B surface antigen (HBsAg) and HBeAg and had high levels of HBV DNA with normal or minimally elevated levels of alanine aminotransferase (ALT). Fifty-five children completed the entire 48-week course of therapy. At 48 weeks after treatment ended (week 96), 2 children (3%) achieved the primary endpoint and were also HBsAg negative and anti-hepatitis B surface antigen antibody (anti-HBs) positive. One child was HBeAg positive but HBsAg negative at week 60; another was HBeAg negative but HBsAg positive at week 72, which were their last clinic visits. In the remaining children, serum ALT and HBV DNA levels at week 96 were similar to baseline. Thirty-seven children experienced adverse events (AEs), and 1 had a serious AE (SAE). Conclusion: The combination of entecavir and peginterferon for up to 48 weeks rarely led to loss of HBeAg with sustained suppression of HBV DNA levels in children in the immune-tolerant phase of HBV infection, and treatment was associated with frequent AEs.

Entecavir and Peginterferon Alfa-2a in Adults With Hepatitis B e Antigen-Positive Immune-Tolerant Chronic Hepatitis B Virus Infection.

Monotherapy with interferon or nucleoside analog is generally not recommended during the immune-tolerant (IT) phase of chronic hepatitis B virus (HBV) infection. Recognition that high HBV DNA levels are associated with hepatocellular carcinoma has increased interest in treating HBV in the IT phase. Small pediatric studies reported efficacy with combination nucleoside analog and interferon therapy. The aim of this study was to evaluate the safety and efficacy of the combination of entecavir and peginterferon in adults in the IT phase of chronic HBV infection. Hepatitis B e antigen (HBeAg)-positive adults with HBV DNA > 107 IU/mL and alanine aminotransferase (ALT) ≤ 1.5 times the upper limit of normal (ULN) (male: ≤ 45, female: ≤ 30 U/L) received entecavir 0.5 mg daily for 8 weeks followed by the addition of peginterferon alfa-2a 180 µg/week to entecavir for an additional 40 weeks. The primary endpoint was HBeAg loss and HBV DNA ≤ 1,000 IU/mL 48 weeks after end of treatment (EOT). Among 28 participants from 11 sites, the median age was 37.2 (range: 22-61) years, 54% were male, and 96% were Asian. Nearly all were infected with genotype C (64%) or B (32%). Median baseline HBV DNA was 8.2 log10 IU/mL, and ALT was 0.9 times the ULN. Although one (4%) participant cleared HBeAg, none met the primary endpoint of both HBeAg loss AND HBV DNA ≤ 1,000 IU/mL 48 weeks post-EOT. ALT elevations > 5 times the ULN occurred in eight (29%) participants, and none were associated with icterus. Forty-eight weeks posttreatment, HBV DNA rebounded to baseline levels in all participants, including the participant who lost HBeAg, and ALT values returned to near baseline levels in all but four participants. Conclusion: A lead-in strategy of 8 weeks of entecavir followed by combination peginterferon and entecavir therapy for 40 weeks had limited efficacy in adults in the IT phase of chronic HBV infection and cannot be recommended.

Child maltreatment as a social determinant of midlife health-related quality of life in women: do psychosocial factors explain this association?

PURPOSE: We examined if child maltreatment (CM) is associated with worse health-related quality of life (HRQoL) in midlife women and if the association is mediated by psychosocial factors. METHODS: A total of 443 women were enrolled in the Pittsburgh site of the longitudinal Study of Women's Health Across the Nation-Mental Health Study. The analytic sample included 338 women who completed the SF-36 and the Childhood Trauma Questionnaire. Generalized linear regression was used to assess the association between CM and two HRQoL component scores. Structural nested mean models were used to evaluate the contribution of each psychosocial mediator (lifetime psychiatric history, depressive symptoms, sleep problems, very upsetting life events, low social support) to the association. RESULTS: Thirty-eight percent of women reported CM. The mean mental (MCS) and physical (PCS) SF-36 component scores were 2.3 points (95% CI - 4.3, - 0.3) and 2.5 points (95% CI - 4.5, - 0.6) lower, respectively, in women with any CM than in those without. When number of CM types increased (0, 1, 2, 3+ types), group mean scores decreased in MCS (52, 51, 48, 47, respectively; p < .01) and PCS (52, 52, 49, 49, respectively; p = .03). In separate mediation analyses, depressive symptoms, very upsetting life events, or low social support, reduced these differences in MCS, but not PCS. CONCLUSIONS: CM is a social determinant of midlife HRQoL in women. The relationship between CM and MCS was partially explained by psychosocial mediators. It is important to increase awareness among health professionals that a woman's midlife well-being may be influenced by early-life adversity.

Health-related Quality of Life in Pediatric Patients With Chronic Hepatitis B Living in the United States and Canada.

OBJECTIVES: The aim of the study was to determine whether selected sociodemographic and hepatitis B virus (HBV)-specific clinical factors are associated with health-related quality of life (HRQoL) among pediatric patients chronically infected with HBV. METHODS: Children with chronic HBV enrolled in the Hepatitis B Research Network completed the Child Health Questionnaire at study entry. Caregivers of children 5 to <10 years completed the parent-reported form (CHQ-Parent Report Form); youth 10 to <18 years completed the child-reported CHQ-Child Report Form. We examined univariable associations of the Child Health Questionnaire scores with selected independent variables: sex, adoption status, maternal education, alanine aminotransferase (U/L), aspartate aminotransferase-to-platelet ratio index, and HBV-specific symptom count. RESULTS: A total of 244 participants (83 young children 5-<10 years, 161 youth 10-<18 years) were included, all HBV treatment-naïve. Among young children, increased alanine aminotransferase level was negatively associated with CHQ-Parent Report Form psychosocial summary t score (r = -0.28, P = 0.01). No other subscale comparisons for young children were statistically significant. Among youth, adoption was associated with better physical functioning and general health (P < 0.01). Higher maternal education was associated with better role/functioning-physical and -emotional scores (P < 0.05). Maternal education and adoption status were linked with adoption associated with higher maternal education. Increased symptom count in youth was associated with worse HRQoL in subscales measuring bodily pain, behavior, mental health, and self-esteem (P < 0.01). CONCLUSIONS: Although overall HRQoL is preserved in children with chronic HBV, some sociodemographic and HBV-related clinical factors were associated with impaired HRQoL in our pediatric patients at baseline. Measurement of HRQoL can focus resources on education and psychosocial support in children and families most in need.