Antibiotic resistance of urinary tract infection recurrences in a large U.S. integrated health care system.

BACKGROUND: Data on antibiotic resistance of uropathogens for UTI recurrences are lacking. METHODS: In a retrospective cohort of adults at Kaiser Permanente Southern California with culture-confirmed index uncomplicated UTI (uUTI) between 01/2016 and 12/2020, we examined the number and characteristics of subsequent culture-confirmed UTIs through 2021. RESULTS: We identified 148,994 individuals with a culture-confirmed index uUTI (88% female, 44% Hispanic, mean age 51 years [s.d. 19]), of whom 19% developed a subsequent culture-confirmed UTI after a median 300 days (IQR: 126-627). The proportion of UTI due to E. coli was highest for index uUTI (79%) and decreased to 73% for sixth UTI (UTI 6) (p-for trend <0.001), while the proportion due to Klebsiella spp increased from index UTI (7%) to UTI 6 (11%) (p-for-trend <0.001). Non-susceptibility to ≥1 and ≥3 antibiotic classes was observed in 57% and 13% of index uUTIs, respectively, and was higher for subsequent UTIs (65% and 20%, respectively, for UTI 6). Most commonly observed antibiotic non-susceptibility patterns included penicillins alone (12%), and penicillins, trimethoprim-sulfamethoxazole plus ≥1 additional antibiotic class (9%). CONCLUSIONS: Antibiotic non-susceptibility is common in UTIs and increases with subsequent UTIs. Continuous monitoring of UTI recurrences and susceptibility patterns are needed to guide treatment decisions.

Immune escape and attenuated severity associated with the SARS-CoV-2 BA.2.86/JN.1 lineage.

The SARS-CoV-2 BA.2.86 lineage, and its sublineage JN.1 in particular, achieved widespread transmission in the US during winter 2023-24. However, the increase in infections was not accompanied by increases in COVID-19 hospitalizations and mortality commensurate with prior waves. To understand shifts in COVID-19 epidemiology associated with JN.1 emergence, we compared characteristics and clinical outcomes of time-matched cases infected with BA.2.86- derived lineages (predominantly representing JN.1) versus co-circulating XBB-derived lineages in December, 2023 and January, 2024. Cases infected with BA.2.86-derived lineages received greater numbers of COVID-19 vaccine doses, including XBB.1.5-targeted and BA.4/BA.5-targeted boosters, in comparison to cases infected with XBB-derived lineages. Additionally, cases infected with BA.2.86-derived lineages experienced greater numbers of documented prior SARS-CoV-2 infections. These associations of BA.2.86-derived lineages with immune escape were confirmed when comparing cases diagnosed during periods when JN.1 was the predominant circulating lineage to cases diagnosed during November, 2023. Cases infected with BA.2.86-derived lineages, or during periods when JN.1 was the predominant circulating lineage, also experienced lower risk of progression to severe clinical outcomes requiring emergency department consultations or hospital admission. Sensitivity analyses suggested under-ascertainment of prior infections, even if differential between cases infected with BA.2.86-derived lineages and non-BA.2.86 lineages, could not explain this apparent attenuation of severity. Our findings implicate escape from immunity acquired from prior vaccination or infection in the emergence of the JN.1 lineage and suggest infections with this lineage are less likely to experience clinically-severe disease. Monitoring of immune escape and clinical severity in emerging SARS-CoV-2 variants remains a priority to inform responses.

Effectiveness and durability of mRNA-1273 BA.4/BA.5 bivalent vaccine (mRNA-1273.222) against SARS-CoV-2 BA.4/BA.5 and XBB sublineages.

Emerging SARS-CoV-2 sublineages continue to cause serious COVID-19 disease, but most individuals have not received any COVID-19 vaccine for >1 year. Assessment of long-term effectiveness of bivalent COVID-19 vaccines against circulating sublineages is important to inform the potential need for vaccination with updated vaccines. In this test-negative study at Kaiser Permanente Southern California, sequencing-confirmed BA.4/BA.5- or XBB-related SARS-CoV-2-positive cases (September 1, 2022 to June 30, 2023), were matched 1:3 to SARS-CoV-2-negative controls. We assessed mRNA-1273 bivalent relative (rVE) and absolute vaccine effectiveness (VE) compared to ≥2 or 0 doses of original monovalent vaccine, respectively. The rVE analysis included 20,966 cases and 62,898 controls. rVE (95%CI) against BA.4/BA.5 at 14-60 days and 121-180 days was 52.7% (46.9-57.8%) and 35.5% (-2.8-59.5%) for infection, and 59.3% (49.7-67.0%) and 33.2% (-28.2-68.0%) for Emergency Department/Urgent Care (ED/UC) encounters. For BA.4/BA.5-related hospitalizations, rVE was 71.3% (44.9-85.1%) and 52.0% (-1.2-77.3%) at 14-60 days and 61-120 days, respectively. rVE against XBB at 14-60 days and 121-180 days was 48.8% (33.4-60.7%) and -3.9% (-18.1-11.3%) for infection, 70.7% (52.4-82.0%) and 15.7% (-6.0-33.2%) for ED/UC encounters, and 87.9% (43.8-97.4%) and 57.1% (17.0-77.8%) for hospitalization. VE and subgroup analyses (age, immunocompromised status, previous SARS-CoV-2 infection) results were similar to rVE analyses. rVE of mRNA-1273 bivalent vaccine against BA.4/BA.5 and XBB infections, ED/UC encounters, and hospitalizations waned over time. Periodic revaccination with vaccines targeting emerging variants may be important in reducing COVID-19 morbidity and mortality.

Real-world effectiveness of recombinant zoster vaccine in self-identified Chinese individuals aged ≥50 years in the United States.

We evaluated the vaccine effectiveness (VE) of two doses of recombinant zoster vaccine (RZV) against herpes zoster (HZ) and postherpetic neuralgia (PHN) in Chinese adults at Kaiser Permanente Southern California (KPSC). Chinese KPSC members were identified based on self-reported ethnicity or self-reported preferred spoken/written language. Those aged ≥50 years who received two doses of RZV 4 weeks to ≤ 6 months apart were matched 1:4 to RZV unvaccinated Chinese members and followed through June 2022; second doses were accrued 6/1/2018-12/31/2020. We estimated incidence and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) comparing outcomes (HZ and PHN). Adjusted VE (%) was calculated as (1-aHR)×100. 3978 RZV vaccinated Chinese members were matched to 15,912 RZV unvaccinated Chinese members. The incidence per 1000 person-years (95% CI) of HZ in the vaccinated group was 1.5 (0.9-2.5) and 10.9 (9.8-12.1) in the unvaccinated group; aHR (95% CI) was 0.12 (0.07-0.21). Adjusted VE (95% CI) was 87.6% (78.9-92.7) against HZ. We identified 0 PHN cases in the vaccinated group and 19 in the unvaccinated group. Among Chinese adults aged ≥50 years, two doses of RZV provided substantial protection against HZ and PHN supporting the real-world effectiveness of the vaccine in this population.

Predictors of nirmatrelvir-ritonavir receipt among COVID-19 patients in a large US health system.

A clear understanding of real-world uptake of nirmatrelvir-ritonavir for treatment of SARS-CoV-2 can inform treatment allocation strategies and improve interpretation of effectiveness studies. We used data from a large US healthcare system to describe nirmatrelvir-ritonavir dispenses among all SARS-CoV-2 positive patients aged ≥ 12 years meeting recommended National Institutes of Health treatment eligibility criteria for the study period between 1 January and 31 December, 2022. Overall, 10.9% (N = 34,791/319,900) of treatment eligible patients with SARS-CoV-2 infections received nirmatrelvir-ritonavir over the study period. Although uptake of nirmatrelvir-ritonavir increased over time, by the end of 2022, less than a quarter of treatment eligible patients with SARS-CoV-2 infections had received nirmatrelvir-ritonavir. Across patient demographics, treatment was generally consistent with tiered treatment guidelines, with dispenses concentrated among patients aged ≥ 65 years (14,706/63,921; 23.0%), and with multiple comorbidities (10,989/54,431; 20.1%). However, neighborhoods of lower socioeconomic status (upper third of neighborhood deprivation index [NDI]) had between 12% (95% CI: 7-18%) and 28% (25-32%) lower odds of treatment dispense over the time periods studied compared to the lower third of NDI distribution, even after accounting for demographic and clinical characteristics. A limited chart review (N = 40) confirmed that in some cases a decision not to treat was appropriate and aligned with national guidelines to use clinical judgement on a case-by-case basis. There is a need to enhance patient and provider awareness on the availability and benefits of nirmatrelvir-ritonavir for the treatment of COVID-19 illness.

Incidence and imaging characteristics of difficult to detect retrospectively identified brain metastases in patients receiving repeat courses of stereotactic radiosurgery.

PURPOSE: During stereotactic radiosurgery (SRS) planning for brain metastases (BM), brain MRIs are reviewed to select appropriate targets based on radiographic characteristics. Some BM are difficult to detect and/or definitively identify and may go untreated initially, only to become apparent on future imaging. We hypothesized that in patients receiving multiple courses of SRS, reviewing the initial planning MRI would reveal early evidence of lesions that developed into metastases requiring SRS. METHODS: Patients undergoing two or more courses of SRS to BM within 6 months between 2016 and 2018 were included in this single-institution, retrospective study. Brain MRIs from the initial course were reviewed for lesions at the same location as subsequently treated metastases; if present, this lesion was classified as a "retrospectively identified metastasis" or RIM. RIMs were subcategorized as meeting or not meeting diagnostic imaging criteria for BM (+ DC or -DC, respectively). RESULTS: Among 683 patients undergoing 923 SRS courses, 98 patients met inclusion criteria. There were 115 repeat courses of SRS, with 345 treated metastases in the subsequent course, 128 of which were associated with RIMs found in a prior MRI. 58% of RIMs were + DC. 17 (15%) of subsequent courses consisted solely of metastases associated with + DC RIMs. CONCLUSION: Radiographic evidence of brain metastases requiring future treatment was occasionally present on brain MRIs from prior SRS treatments. Most RIMs were + DC, and some subsequent SRS courses treated only + DC RIMs. These findings suggest enhanced BM detection might enable earlier treatment and reduce the need for additional SRS.

Development of a multi-feature-combined model: proof-of-concept with application to local failure prediction of post-SBRT or surgery early-stage NSCLC patients.

Objective: To develop a Multi-Feature-Combined (MFC) model for proof-of-concept in predicting local failure (LR) in NSCLC patients after surgery or SBRT using pre-treatment CT images. This MFC model combines handcrafted radiomic features, deep radiomic features, and patient demographic information in an integrated machine learning workflow. Methods: The MFC model comprised three key steps. (1) Extraction of 92 handcrafted radiomic features from the GTV segmented on pre-treatment CT images. (2) Extraction of 512 deep radiomic features from pre-trained U-Net encoder. (3) The extracted handcrafted radiomic features, deep radiomic features, along with 4 patient demographic information (i.e., gender, age, tumor volume, and Charlson comorbidity index), were concatenated as a multi-dimensional input to the classifiers for LR prediction. Two NSCLC patient cohorts from our institution were investigated: (1) the surgery cohort includes 83 patients with segmentectomy or wedge resection (7 LR), and (2) the SBRT cohort includes 84 patients with lung SBRT (9 LR). The MFC model was developed and evaluated independently for both cohorts, and was subsequently compared against the prediction models based on only handcrafted radiomic features (R models), patient demographic information (PI models), and deep learning modeling (DL models). ROC with AUC was adopted to evaluate model performance with leave-one-out cross-validation (LOOCV) and 100-fold Monte Carlo random validation (MCRV). The t-test was performed to identify the statistically significant differences. Results: In LOOCV, the AUC range (surgery/SBRT) of the MFC model was 0.858-0.895/0.868-0.913, which was higher than the three other models: 0.356-0.480/0.322-0.650 for PI models, 0.559-0.618/0.639-0.682 for R models, and 0.809/0.843 for DL models. In 100-fold MCRV, the MFC model again showed the highest AUC results (surgery/SBRT): 0.742-0.825/0.888-0.920, which were significantly higher than PI models: 0.464-0.564/0.538-0.628, R models: 0.557-0.652/0.551-0.732, and DL models: 0.702/0.791. Conclusion: We successfully developed an MFC model that combines feature information from multiple sources for proof-of-concept prediction of LR in patients with surgical and SBRT early-stage NSCLC. Initial results suggested that incorporating pre-treatment patient information from multiple sources improves the ability to predict the risk of local failure.

Effectiveness of BNT162b2 BA.4/5 bivalent mRNA vaccine against a range of COVID-19 outcomes in a large health system in the USA: a test-negative case-control study.

BACKGROUND: XBB-related omicron sublineages have recently replaced BA.4/5 as the predominant omicron sublineages in the USA and other regions globally. Despite preliminary signs of immune evasion of XBB sublineages, few data exist describing the real-world effectiveness of bivalent COVID-19 vaccines, especially against XBB-related illness. We aimed to investigate the effectiveness of the Pfizer--BioNTech BNT162b2 BA.4/5 bivalent vaccine against both BA.4/5-related and XBB-related disease in adults aged 18 years or older. METHODS: In this test-negative case-control study, we estimated the effectiveness of the BNT162b2 BA.4/5 bivalent vaccine using data from electronic health records of Kaiser Permanente Southern California health system members aged 18 years or older who received at least two doses of the wild-type COVID-19 mRNA vaccines. Participants sought care for acute respiratory infection between Aug 31, 2022, and April 15, 2023, and were tested for SARS-CoV-2 via PCR tests. Relative vaccine effectiveness (≥2 doses of wild-type mRNA vaccine plus a BNT162b2 BA.4/5 bivalent booster vs ≥2 doses of a wild-type mRNA vaccine alone) and absolute vaccine effectiveness (vs unvaccinated individuals) was estimated against critical illness related to acute respiratory infection (intensive care unit [ICU] admission, mechanical ventilation, or inpatient death), hospital admission, emergency department or urgent care visits, and in-person outpatient encounters with odds ratios from logistic regression models adjusted for demographic and clinical factors. We stratified vaccine effectiveness estimates for hospital admission, emergency department or urgent care visits, and outpatient encounters by omicron sublineage (ie, likely BA.4/5-related vs likely XBB-related), time since bivalent booster receipt, age group, number of wild-type doses received, and immunocompromised status. This study is registered with ClinicalTrials.gov (NCT04848584). FINDINGS: Analyses were conducted for 123 419 encounters (24 246 COVID-19 cases and 99 173 test-negative controls), including 4131 episode of critical illness (a subset of hospital admissions), 14 529 hospital admissions, 63 566 emergency department or urgent care visits, and 45 324 outpatient visits. 20 555 infections were BA.4/5 related and 3691 were XBB related. In adjusted analyses, relative vaccine effectiveness for those who received the BNT162b2 BA.4/5 bivalent booster compared with those who received at least two doses of a wild-type mRNA vaccine alone was an additional 50% (95% CI 23-68) against critical illness, an additional 39% (28-49) against hospital admission, an additional 35% (30-40) against emergency department or urgent care visits, and an additional 28% (22-33) against outpatient encounters. Waning of the bivalent booster from 0-3 months to 4-7 months after vaccination was evident for outpatient outcomes but was not detected for critical illness, hospital admission, and emergency department or urgent care outcomes. The relative effectiveness of the BNT162b2 BA.4/5 bivalent booster for XBB-related infections compared with BA.4/5-related infections was 56% (95% CI 12-78) versus 40% (27-50) for hospital admission; 34% (21-45) versus 36% (30-41) against emergency department or urgent care visits; and 29% (19-38) versus 27% (20-33) for outpatient encounters. INTERPRETATION: By mid-April, 2023, individuals previously vaccinated only with wild-type vaccines had little protection against COVID-19-including hospital admission. A BNT162b2 BA.4/5 bivalent booster restored protection against a range of COVID-19 outcomes, including against XBB-related sublineages, with the most substantial protection observed against hospital admission and critical illness. FUNDING: Pfizer.

Receipt of BNT162b2 Vaccine and COVID-19 Ambulatory Visits in US Children Younger Than 5 Years.

This study examines the association of the receipt of wild-type BNT162b2 vaccine with medically attended COVID-19 outcomes among children younger than 5 years in the US.

mRNA-1273 bivalent (original and Omicron) COVID-19 vaccine effectiveness against COVID-19 outcomes in the United States.

The bivalent (original and Omicron BA.4/BA.5) mRNA-1273 COVID-19 vaccine was authorized to offer broader protection against COVID-19. We conducted a matched cohort study to evaluate the effectiveness of the bivalent vaccine in preventing hospitalization for COVID-19 (primary outcome) and medically attended SARS-CoV-2 infection and hospital death (secondary outcomes). Compared to individuals who did not receive bivalent mRNA vaccination but received ≥2 doses of any monovalent mRNA vaccine, the relative vaccine effectiveness (rVE) against hospitalization for COVID-19 was 70.3% (95% confidence interval, 64.0%-75.4%). rVE was consistent across subgroups and not modified by time since last monovalent dose or number of monovalent doses received. Protection was durable ≥3 months after the bivalent booster. rVE against SARS-CoV-2 infection requiring emergency department/urgent care and against COVID-19 hospital death was 55.0% (50.8%-58.8%) and 82.7% (63.7%-91.7%), respectively. The mRNA-1273 bivalent booster provides additional protection against hospitalization for COVID-19, medically attended SARS-CoV-2 infection, and COVID-19 hospital death.

Real-World Evidence to Supplement Randomized Clinical Trials: Tocilizumab for Severe COVID-19 Pneumonia vs. a Cohort Receiving Standard of Care.

Randomized controlled trials (RCTs) remain the gold standard for evaluating treatment efficacy, but real-world evidence can supplement RCT results. Tocilizumab was not found to reduce 28-day mortality in a phase III, double-blind, placebo-controlled trial (COVACTA) among hospitalized patients with severe coronavirus disease 2019 (COVID-19) pneumonia. We created a real-world external comparator arm mirroring the COVACTA trial to confirm findings and assess the feasibility of using an external comparator arm to supplement an RCT. Eligible COVACTA participants in both the tocilizumab treatment and placebo arms were matched 1:1 using propensity score matching to persons without tocilizumab exposure in an external comparator arm. Adjusted Cox proportional hazard models estimated differences in 28-day mortality comparing COVACTA participants to matched external comparator arm participants. Patients in the COVACTA tocilizumab treatment arm had a similar risk of death compared with patients in the external comparator arm (hazard ratio (HR): 1.09, 95% confidence interval (CI): 0.64-1.84) with similar estimated 28-day mortality in the COVACTA tocilizumab treatment arm compared with the external comparator arm (18%, 95% CI: 13-24 vs. 19%, 95% CI: 13-24, P > 0.9). COVACTA placebo treatment arm participants had a similar risk of mortality (adjusted HR: 0.69, 95% CI: 0.32-1.46) compared with the external comparator arm. Using an external comparator arm has the potential to supplement RCT data and support results of primary RCT analyses.

Timely Prenatal and Infant Pertussis Vaccine Uptake in an Integrated Health System.

BACKGROUND: Hispanic infants bear the burden of pertussis infection. We examined pertussis protection from vaccination in infants with US-born and foreign-born Hispanic mothers. METHODS: Retrospective cohort study of infants up to 1 year of age. Secondary data of mothers with continuous membership since the 27th week of pregnancy with infants born 1/1/2012-12/31/2017 in an integrated health care delivery organization, which broadly represent the Southern California population. RESULTS: Foreign-born Hispanic mothers had higher prenatal tetanus, diphtheria, acellular pertussis (Tdap) uptake compared to US-born white mothers [adjusted risk ratio (aRR): 1.04, 95% confidence interval (CI): 1.03, 1.05]. Infants with mothers on Medicaid insurance disproportionately did not enroll in the health plan by the time they were eligible for their first dose of the DTaP vaccine (68.4%). Once initiating the infant vaccine series, foreign-born Hispanic mothers more likely adhered than US-born white mothers (aRR: 1.05, CI: 1.02, 1.08). DISCUSSION: In an integrated health system, disparities in vaccine uptake can be minimized. Infants who are born to mothers with Medicaid insurance and are not enrolled in the health plan after birth may be under-protected from pertussis.

Effectiveness of a fourth dose of mRNA-1273 against COVID-19 among older adults in the United States: Interim results from an observational cohort study.

We evaluated relative vaccine effectiveness (rVE) of 4- vs. 3-dose mRNA-1273 against SARS-CoV-2 infection, and COVID-19 hospitalization and death in immunocompetent adults aged ≥50 years at Kaiser Permanente Southern California. We included 178,492 individuals who received a fourth dose of mRNA-1273, and 178,492 randomly selected 3-dose recipients who were matched to 4-dose recipients by age, sex, race/ethnicity, and third dose date. Adjusted 4- vs. 3-dose rVE against SARS-CoV-2 infection, COVID-19 hospitalization, and COVID-19 hospitalization death were 25.9 % (23.5 %, 28.2 %), 67.3 % (58.7 %, 74.1 %), and 72.5 % (-35.9 %, 95.2 %), respectively. Adjusted rVE against SARS-CoV-2 infection ranged between 19.8 % and 39.1 % across subgroups. Adjusted rVE against SARS-CoV-2 infection and COVID-19 hospitalization decreased 2-4 months after the fourth dose. Four mRNA-1273 doses provided significant protection against COVID-19 outcomes compared with 3 doses, consistent in various subgroups of demographic and clinical characteristics, although rVE varied and waned over time.

Post-licensure safety study of new-onset immune-mediated diseases, herpes zoster, and anaphylaxis in adult recipients of HepB-CpG vaccine versus HepB-alum vaccine.

BACKGROUND: HepB-CpG (Heplisav-B) is a licensed hepatitis B vaccine with a novel adjuvant that requires 2 doses (0, 1 month) compared to HepB-alum (Engerix-B) which requires 3 doses (0, 1, 6 months). Monitoring safety outcomes following receipt of vaccines with novel adjuvants outside trial settings is important. Hence, as part of a post-marketing commitment, we compared the incidence of new-onset immune-mediated diseases, herpes zoster (HZ), and anaphylaxis among recipients of HepB-CpG versus HepB-alum. METHODS: This cohort study included adults not on dialysis who received ≥1 dose of hepatitis B vaccine from 8/7/2018 to 10/31/2019, during which HepB-CpG was routinely administered in 7 of 15 Kaiser Permanente Southern California medical centers while HepB-alum was administered in the other 8 centers. Recipients of HepB-CpG or HepB-alum were followed through electronic health records for 13 months for occurrence of pre-specified new-onset immune-mediated diseases, HZ, and anaphylaxis identified using diagnosis codes. Incidence rates were compared using Poisson regression with inverse probability of treatment weighting when there was ≥80 % power to detect a relative risk (RR) of 5 for anaphylaxis and RR of 3 for other outcomes. Chart review to confirm new-onset diagnosis was conducted for outcomes with statistically significant elevated risk. RESULTS: There were 31,183 HepB-CpG and 38,442 HepB-alum recipients (overall 49.0 % female, 48.5 % age ≥50 years, and 49.6 % Hispanic). Among immune-mediated events that occurred frequently enough for formal comparison, rates among HepB-CpG versus Hep-B-alum recipients were similar except for rheumatoid arthritis (RA) (adjusted RR 1.53 [95 % CI: 1.07, 2.18]). After chart confirmation of new-onset RA, the adjusted RR was 0.93 (0.34, 2.49). The adjusted RR for HZ was 1.06 (0.89, 1.27). Anaphylaxis occurred in 0 HepB-CpG and 2 HepB-alum recipients. CONCLUSIONS: This large post-licensure study did not identify evidence of safety concerns for HepB-CpG compared to HepB-alum for immune-mediated diseases, HZ, or anaphylaxis.

Vaccine effectiveness of the mRNA-1273 3-dose primary series against COVID-19 in an immunocompromised population: A prospective observational cohort study.

BACKGROUND: Data on the effectiveness of the 3-dose mRNA-1273 primary series are limited, particularly in comparison to 2 doses. Given suboptimal COVID-19 vaccine uptake among immunocompromised populations, it is important to monitor the effectiveness of fewer than the recommended doses in this population. METHODS: We conducted a matched cohort study at Kaiser Permanente Southern California to evaluate the relative vaccine effectiveness (rVE) of the 3-dose series vs 2 doses of mRNA-1273 in preventing SARS-CoV-2 infection and severe COVID-19 outcomes among immunocompromised individuals. RESULTS: We included 21,942 3-dose recipients who were 1:1 matched with randomly selected 2-dose recipients (third doses accrued 08/12/2021-12/31/2021, with follow-up through 01/31/2022). Adjusted rVE of 3 vs 2 doses of mRNA-1273 against SARS-CoV-2 infection, COVID-19 hospitalization, and COVID-19 hospital death were 55.0 % (95 % CI: 50.8-58.9 %), 83.0 % (75.4-88.3 %), and 87.1 % (30.6-97.6 %), respectively. CONCLUSION: Three doses of mRNA-1273 were associated with a significantly higher rVE against SARS-CoV-2 infection and severe outcomes, compared to 2 doses. These findings were consistent across subgroups of demographic and clinical characteristics, and mostly consistent across subgroups of immunocompromising conditions. Our study highlights the importance of completing the 3-dose series for immunocompromised populations.

Effectiveness of nirmatrelvir-ritonavir in preventing hospital admissions and deaths in people with COVID-19: a cohort study in a large US health-care system.

BACKGROUND: In the USA, oral nirmatrelvir-ritonavir is authorised for use in patients aged 12 years or older with mild-to-moderate COVID-19 who are at risk of progression to severe disease and hospitalisation. We aimed to establish the effectiveness of nirmatrelvir-ritonavir in preventing hospital admissions and death in people with COVID-19 in an outpatient prescribing context in the USA. METHODS: In this matched observational outpatient cohort study in the Kaiser Permanente Southern California (CA, USA) health-care system, data were extracted from electronic health records of non-hospitalised patients aged 12 years or older who received a positive SARS-CoV-2 PCR test result (their index test) between April 8 and Oct 7, 2022, and had not received another positive test result within the preceding 90 days. We compared outcomes between people who received nirmatrelvir-ritonavir and those who did not receive nirmatrelvir-ritonavir by matching cases by date, age, sex, clinical status (including care received, the presence or absence of acute COVID-19 symptoms at testing, and time from symptom onset to testing), vaccination history, comorbidities, health-care seeking during the previous year, and BMI. Our primary endpoint was the estimated effectiveness of nirmatrelvir-ritonavir in preventing hospital admissions or death within 30 days of a positive test for SARS-CoV-2. FINDINGS: 7274 nirmatrelvir-ritonavir recipients and 126 152 non-recipients with positive SARS-CoV-2 tests were included in our study. 5472 (75·2%) treatment recipients and 84 657 (67·1%) non-recipients were tested within 5 days of symptom onset. Nirmatrelvir-ritonavir had an overall estimated effectiveness of 53·6% (95% CI 6·6-77·0) in preventing hospital admission or death within 30 days of a positive test for SARS-CoV-2, which increased to 79·6% (33·9-93·8) when nirmatrelvir-ritonavir was dispensed within 5 days of symptom onset. Within the subgroup of patients tested within 5 days of symptom onset and whose treatment was dispensed on the day of their test, the estimated effectiveness of nirmatrelvir-ritonavir was 89·6% (50·2-97·8). INTERPRETATION: In a setting with high levels of COVID-19 vaccine uptake, nirmatrelvir-ritonavir effectively reduced the risk of hospital admission or death within 30 days of a positive outpatient SARS-CoV-2 test. FUNDING: US Centers for Disease Control and Prevention and US National Institutes of Health.

Uncertainties in the dosimetric heterogeneity correction and its potential effect on local control in lung SBRT.

Objective. Dose calculation in lung stereotactic body radiation therapy (SBRT) is challenging due to the low density of the lungs and small volumes. Here we assess uncertainties associated with tissue heterogeneities using different dose calculation algorithms and quantify potential associations with local failure for lung SBRT.Approach. 164 lung SBRT plans were used. The original plans were prepared using Pencil Beam Convolution (PBC, n = 8) or Anisotropic Analytical Algorithm (AAA, n = 156). Each plan was recalculated with AcurosXB (AXB) leaving all plan parameters unchanged. A subset (n = 89) was calculated with Monte Carlo to verify accuracy. Differences were calculated for the planning target volume (PTV) and internal target volume (ITV) Dmean[Gy], D99%[Gy], D95%[Gy], D1%[Gy], and V100%[%]. Dose metrics were converted to biologically effective doses (BED) usingα/ß= 10Gy. Regression analysis was performed for AAA plans investigating the effects of various parameters on the extent of the dosimetric differences. Associations between the magnitude of the differences for all plans and outcome were investigated using sub-distribution hazards analysis.Main results. For AAA cases, higher energies increased the magnitude of the difference (ΔDmean of -3.6%, -5.9%, and -9.1% for 6X, 10X, and 15X, respectively), as did lung volume (ΔD99% of -1.6% per 500cc). Regarding outcome, significant hazard ratios (HR) were observed for the change in the PTV and ITV D1% BEDs upon univariate analysis (p = 0.042, 0.023, respectively). When adjusting for PTV volume and prescription, the HRs for the change in the ITV D1% BED remained significant (p = 0.039, 0.037, respectively).Significance. Large differences in dosimetric indices for lung SBRT can occur when transitioning to advanced algorithms. The majority of the differences were not associated with local failure, although differences in PTV and ITV D1% BEDs were associated upon univariate analysis. This shows uncertainty in near maximal tumor dose to potentially be predictive of treatment outcome.

Effectiveness of mRNA-1273 vaccination against SARS-CoV-2 omicron subvariants BA.1, BA.2, BA.2.12.1, BA.4, and BA.5.

Studies have reported reduced natural SARS-CoV-2 infection- and vaccine-induced neutralization against omicron BA.4/BA.5 compared with earlier omicron subvariants. This test-negative case-control study evaluates mRNA-1273 vaccine effectiveness (VE) against infection and hospitalization with omicron subvariants. The study includes 30,809 SARS-CoV-2 positive and 92,427 SARS-CoV-2 negative individuals aged ≥18 years tested during 1/1/2022-6/30/2022. While 3-dose VE against BA.1 infection is high and wanes slowly, VE against BA.2, BA.2.12.1, BA.4, and BA.5 infection is initially moderate to high (61.0%-90.6% 14-30 days post third dose) and wanes rapidly. The 4-dose VE against infection with BA.2, BA.2.12.1, and BA.4 ranges between 64.3%-75.7%, and is low (30.8%) against BA.5 14-30 days post fourth dose, disappearing beyond 90 days for all subvariants. The 3-dose VE against hospitalization for BA.1, BA.2, and BA.4/BA.5 is 97.5%, 82.0%, and 72.4%, respectively; 4-dose VE against hospitalization for BA.4/BA.5 is 88.5%. Evaluation of the updated bivalent booster is warranted.

Analysis of mRNA COVID-19 Vaccine Uptake Among Immunocompromised Individuals in a Large US Health System.

Importance: Immunocompromised individuals are at increased risk for severe outcomes due to SARS-CoV-2 infection. Given the varying and complex nature of COVID-19 vaccination recommendations, it is important to understand COVID-19 vaccine uptake in this vulnerable population. Objective: To assess mRNA COVID-19 vaccine uptake and factors associated with uptake among immunocompromised individuals from December 14, 2020, through August 6, 2022. Design, Setting, and Participants: This cohort study was conducted with patients of Kaiser Permanente Southern California (KPSC), an integrated health care system in the US. The study included patients aged 18 years or older who were immunocompromised (individuals with an immunocompromising condition or patients who received immunosuppressive medications in the year prior to December 14, 2020) and still met criteria for being immunocompromised 1 year later. Exposures: Age, sex, self-identified race and ethnicity, prior positive COVID-19 test result, immunocompromising condition, immunomodulating medication, comorbidities, health care utilization, and neighborhood median income. Main Outcomes and Measures: Outcomes were the number of doses of mRNA COVID-19 vaccine received and the factors associated with receipt of at least 4 doses, estimated by hazard ratios (HRs) and 95% Wald CIs via Cox proportional hazards regression. Statistical analyses were conducted between August 9 and 23, 2022. Results: Overall, 42 697 immunocompromised individuals met the study eligibility criteria. Among these, 18 789 (44.0%) were aged 65 years or older; 20 061 (47.0%) were women and 22 635 (53.0%) were men. With regard to race and ethnicity, 4295 participants (10.1%) identified as Asian or Pacific Islander, 5174 (12.1%) as Black, 14 289 (33.5%) as Hispanic, and 17 902 (41.9%) as White. As of the end of the study period and after accounting for participant censoring due to death or disenrollment from the KPSC health plan, 78.0% of immunocompromised individuals had received a third dose of mRNA COVID-19 vaccine. Only 41.0% had received a fourth dose, which corresponds to a primary series and a monovalent booster dose for immunocompromised individuals. Uptake of a fifth dose was only 0.9% following the US Centers for Disease Control and Prevention (CDC) recommendation to receive a second monovalent booster (ie, fifth dose). Adults aged 65 years or older (HR, 3.95 [95% CI, 3.70-4.22]) were more likely to receive at least 4 doses compared with those aged 18 to 44 years or 45 to 64 years (2.52 [2.36-2.69]). Hispanic and non-Hispanic Black adults (HR, 0.77 [95% CI, 0.74-0.80] and 0.82 [0.78-0.87], respectively, compared with non-Hispanic White adults), individuals with prior documented SARS-CoV-2 infection (0.71 [0.62-0.81] compared with those without), and individuals receiving high-dose corticosteroids (0.88 [0.81-0.95] compared with those who were not) were less likely to receive at least 4 doses. Conclusions and Relevance: These findings suggest that adherence to CDC mRNA monovalent COVID-19 booster dose recommendations among immunocompromised individuals was low. Given the increased risk for severe COVID-19 in this vulnerable population and the well-established additional protection afforded by booster doses, targeted and tailored efforts to ensure that immunocompromised individuals remain up to date with COVID-19 booster dose recommendations are warranted.

BNT162b2 Against COVID-19-Associated Emergency Department and Urgent Care Visits Among Children 5-11 Years of Age: A Test Negative Design.

In a 1:1 matched test-negative design among 5- to 11-year-olds in the Kaiser Permanente Southern California health system (n = 3984), BNT162b2 effectiveness against the omicron-related emergency department or urgent care encounters was 60% [95%CI: 47-69] <3 months post-dose-two and 28% [8-43] after ≥3 months. A booster improved protection to 77% [53-88].