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, this surge in infections was not accompanied by 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 lineages (predominantly representing JN.1) versus co-circulating XBB-derived lineages in December, 2023 and January, 2024. Cases infected with BA.2.86 lineages received greater numbers of COVID-19 vaccine doses, including XBB.1.5-targeted boosters, in comparison to cases infected with XBB-derived lineages. Additionally, cases infected with BA.2.86 lineages experienced greater numbers of documented prior SARS-CoV-2 infections. Cases infected with BA.2.86 lineages 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 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.

Post-marketing safety study to evaluate pregnancy outcomes among recipients of hepatitis B vaccines.

HepB-CpG is a licensed adjuvanted two-dose hepatitis B vaccine for adults, with limited data on exposure during pregnancy. We assessed the risk of pregnancy outcomes among individuals who received HepB-CpG or the 3-dose HepB-alum vaccine ≤28 d prior to conception or during pregnancy at Kaiser Permanente Southern California (KPSC). The pregnancy cohort included KPSC members aged ≥18 y who received ≥1 dose of hepatitis B vaccine (HepB-CpG or HepB-alum) at KPSC outpatient family or internal medicine departments from August 2018 to November 2020. We followed these individuals through electronic health records from the vaccination date until the end of pregnancy, KPSC health plan disenrollment, or death, whichever came first. Among 81 and 125 eligible individuals who received HepB-CpG and HepB-alum, respectively, live births occurred in 84% and 74%, spontaneous abortion occurred in 7% and 17% (adjusted relative risk [aRR] 0.40, 95% CI: 0.16-1.00), and preterm birth occurred in 15% and 14% of liveborn infants (aRR 0.97, 95% CI 0.47-1.99). No major birth defects were identified through 6 months of age. The study found no evidence of adverse pregnancy outcomes for recipients of HepB-CpG in comparison to HepB-alum.

Performance of pulse oximeters as a function of race compared to skin pigmentation: a single center retrospective study.

Pulse oximetry (SpO2) is a critical monitor for assessing oxygenation status and guiding therapy in critically ill patients. Race has been identified as a potential source of SpO2 error, with consequent bias and inequities in healthcare. This study was designed to evaluate the incidence of occult hypoxemia and accuracy of pulse oximetry associated with the Massey-Martin scale and characterize the relationship between Massey scores and self-identified race. This retrospective single institute study utilized the Massey-Martin scale as a quantitative assessment of skin pigmentation. These values were recorded peri-operatively in patients enrolled in unrelated clinical trials. The electronic medical record was utilized to obtain demographics, arterial blood gas values, and time matched SpO2 values for each PaO2 ≤ 125 mmHg recorded throughout their hospitalizations. Differences between SaO2 and SpO2 were compared as a function of both Massey score and self-reported race. 4030 paired SaO2-SpO2 values were available from 579 patients. The average error (SaO2-SpO2) ± SD was 0.23 ± 2.6%. Statistically significant differences were observed within Massey scores and among races, with average errors that ranged from - 0.39 ± 2.3 to 0.53 ± 2.5 and - 0.55 ± 2.1 to 0.37 ± 2.7, respectively. Skin color varied widely within each self-identified race category. There was no clinically significant association between error rates and Massey-Martin scale grades and no clinically significant difference in accuracy observed between self-reported Black and White patients. In addition, self-reported race is not an appropriate surrogate for skin color.

Association of pneumococcal conjugate vaccination with SARS-CoV-2 infection among older adult recipients of COVID-19 vaccines: a longitudinal cohort study.

BACKGROUND: Pneumococcal carriage is associated with increased acquisition and duration of SARS-CoV-2 infection among adults. While pneumococcal conjugate vaccines (PCVs) prevent carriage of vaccine-serotype pneumococci, their potential impact on COVID-19 related outcomes remains poorly understood in populations with prevalent immunity against SARS-CoV-2. METHODS: We undertook a retrospective cohort study of adults aged ≥65 years in the Kaiser Permanente Southern California (KPSC) healthcare system who had received ≥2 COVID-19 vaccine doses, comparing risk of SARS-CoV-2 infection between 1 January, 2021 and 31 December, 2022 among recipients and non-recipients of PCV13. We estimated adjusted hazard ratios via Cox proportional hazards models, employing multiple strategies to mitigate bias from differential test-seeking behavior. RESULTS: The adjusted hazard ratio (aHR) of confirmed SARS-CoV-2 infection comparing PCV13 recipients to non-recipients was 0.92 (95% confidence interval: 0.90-0.95), corresponding to prevention of 3.9 (2.6-5.3) infections per 100 person-years. Following receipt of 2, 3, and ≥4 COVID-19 vaccine doses, aHRs were 0.85 (0.81-0.89), 0.94 (0.90-0.97), and 0.99 (0.93-1.04), respectively. The aHR for persons who had not received COVID-19 vaccination in the preceding 6 months was 0.90 (0.86-0.93), versus 0.94 (0.91-0.98) within 6 months after receipt of any dose. Similarly, the aHR was 0.92 (0.89-0.94) for persons without history of documented SARS-CoV-2 infection, versus 1.00 (0.90-1.12) for persons with documented prior infection. CONCLUSIONS: Among older adults who had received ≥2 COVID-19 vaccine doses, PCV13 was associated with modest protection against SARS-CoV-2 infection. Protective effects of PCV13 were greater among individuals expected to have weaker immune protection against SARS-CoV-2 infection.

Comparative Effectiveness of Licensed Influenza Vaccines in Preventing Influenza-related Medical Encounters and Hospitalizations in the 2022-2023 Influenza Season Among Adults ≥65 Years of Age.

BACKGROUND: Influenza causes substantial morbidity, particularly among older individuals. Updated data on the effectiveness of currently licensed vaccines in this population are needed. METHODS: At Kaiser Permanente Southern California, we conducted a retrospective cohort study to evaluate comparative vaccine effectiveness (cVE) of high-dose (HD), adjuvanted, and standard-dose (SD) cell-based influenza vaccines, relative to the SD egg-based vaccine. We included adults aged ≥65 years who received an influenza vaccine between 1 August 2022 and 31 December 2022, with follow-up up to 20 May 2023. Primary outcomes were: (1) influenza-related medical encounters and (2) polymerase chain reaction (PCR)-confirmed influenza-related hospitalization. Adjusted hazard ratios (aHR) were estimated by Cox proportional hazards regression, adjusting for confounders using inverse probability of treatment weighting (IPTW). cVE (%) was calculated as (1-aHR) × 100 when aHR ≤1, and ([1/aHR]-1) × 100 when aHR >1. RESULTS: Our study population (n = 495 119) was 54.9% female, 46.3% non-Hispanic White, with a median age of 73 years (interquartile range [IQR] 69-79). Characteristics of all groups were well balanced after IPTW. Adjusted cVEs against influenza-related medical encounters in the HD, adjuvanted, and SD cell-based vaccine groups were 9.1% (95% confidence interval [CI]: .9, 16.7), 16.9% (95% CI: 1.7, 29.8), and -6.3 (95% CI: -18.3, 6.9), respectively. Adjusted cVEs against PCR-confirmed hospitalization in the HD, adjuvanted, and SD cell-based groups were 25.1% (95% CI: .2, 43.8), 61.6% (95% CI: 18.1, 82.0), and 26.4% (95% CI: -18.3, 55.7), respectively. CONCLUSIONS: Compared to the SD egg-based vaccine, HD and adjuvanted vaccines conferred additional protection against influenza-related outcomes in the 2022-2023 season in adults ≥65 years. Our results provide real-world evidence of the comparative effectiveness of currently licensed vaccines.

Leveraging Natural Ecosystems to Reoptimize Education and Training for Great Power Competition in the Air Force Medical Service.

Organizations today are complex, hyperdimensional, and continuously changing in response to the environment. Over the past decade, the Military Health System has seen continuous organizational change to transform healthcare delivery, and the Air Force Medical Service (AFMS) is currently transitioning to an Air Force Medical Command (AFMEDCOM) structure to best prepare for Great Power Competition and other challenges ahead. The current state of the enterprise involves decision making, resourcing, and execution of education and training that is largely decentralized in nature. To support these efforts, in February 2024, a team of diverse AFMS stakeholders gathered in Washington, D.C. to examine the future of medical education and training for the U.S. Air Force in a new way: through systems theory and ecosystem mapping. This ecosystem approach enables development of an organizational structure and process for change that considers how all stakeholders relate, what external factors threaten the desired transformation, and how the resulting enterprise could become more resilient with future uncertainty and change. This paper discusses the theory behind the ecosystem approach and how it was used to develop a transformed model for the AFMS to organize its education and training. Additionally, a dialogue is presented on how this unique methodology to understanding stakeholder relationships can be leveraged in the re-optimization efforts for Great Power Competition.

Neuropeptide Y Y2 Receptors in Sensory Neurons Tonically Suppress Nociception and Itch but Facilitate Postsurgical and Neuropathic Pain Hypersensitivity.

BACKGROUND: Neuropeptide Y (NPY) Y2 receptor (Y2) antagonist BIIE0246 can both inhibit and facilitate nociception. The authors hypothesized that Y2 function depends on inflammation or nerve injury status. METHODS: The authors implemented a battery of behavioral tests in mice of both sexes that received (1) no injury; (2) an incision model of postoperative pain; (3) a spared nerve injury model of neuropathic pain; and (4) a latent sensitization model of chronic postsurgical pain. In addition to Y2 gene expression assays, spinal Y2 G-protein coupling was studied with guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding assays. RESULTS: The authors report that intrathecal BIIE0246 increased mechanical and cold hypersensitivity, produced behavioral signs of spontaneous nociception and itch, and produced conditioned place aversion and preference in normal, uninjured mice. BIIE0246 did not change heat hypersensitivity or motor coordination. Conditional (sensory neuron-specific) Y2 deletion prevented BIIE0246-induced mechanical and cold hypersensitivity, nocifensive behaviors, and aversion. Both conditional deletion and pharmacologic blockade of Y2 reduced mechanical and thermal hypersensitivity after incision or nerve injury. SNI did not change the sensitivity of Y2 G-protein coupling with the Y2 agonist peptide YY (3-36) (PYY3-36), but increased the population of Y2 that effectively coupled G-proteins. Intrathecal PYY3-36 failed to reduce spared nerve injury- or incision-induced hypersensitivity in C57BL/6N mice. Incision did not change Npy2r gene expression in dorsal root ganglion. CONCLUSIONS: The authors conclude that Y2 at central terminals of primary afferent neurons provides tonic inhibition of mechanical and cold nociception and itch. This switches to the promotion of mechanical and thermal hyperalgesia in models of acute and chronic postsurgical and neuropathic pain, perhaps due to an increase in the population of Y2 that effectively couples to G-proteins. These results support the development of Y2 antagonists for the treatment of chronic postsurgical and neuropathic pain.

Diversity and selection analyses identify transmission-blocking antigens as the optimal vaccine candidates in Plasmodium falciparum.

BACKGROUND: A highly effective vaccine for malaria remains an elusive target, at least in part due to the under-appreciated natural parasite variation. This study aimed to investigate genetic and structural variation, and immune selection of leading malaria vaccine candidates across the Plasmodium falciparum's life cycle. METHODS: We analysed 325 P. falciparum whole genome sequences from Zambia, in addition to 791 genomes from five other African countries available in the MalariaGEN Pf3k Database. Ten vaccine antigens spanning three life-history stages were examined for genetic and structural variations, using population genetics measures, haplotype network analysis, and 3D structure selection analysis. FINDINGS: Among the ten antigens analysed, only three in the transmission-blocking vaccine category display P. falciparum 3D7 as the dominant haplotype. The antigens AMA1, CSP, MSP119 and CelTOS, are much more diverse than the other antigens, and their epitope regions are under moderate to strong balancing selection. In contrast, Rh5, a blood stage antigen, displays low diversity yet slightly stronger immune selection in the merozoite-blocking epitope region. Except for CelTOS, the transmission-blocking antigens Pfs25, Pfs48/45, Pfs230, Pfs47, and Pfs28 exhibit minimal diversity and no immune selection in epitopes that induce strain-transcending antibodies, suggesting potential effectiveness of 3D7-based vaccines in blocking transmission. INTERPRETATION: These findings offer valuable insights into the selection of optimal vaccine candidates against P. falciparum. Based on our results, we recommend prioritising conserved merozoite antigens and transmission-blocking antigens. Combining these antigens in multi-stage approaches may be particularly promising for malaria vaccine development initiatives. FUNDING: Purdue Department of Biological Sciences; Puskas Memorial Fellowship; National Institute of Allergy and Infectious Diseases (U19AI089680).

Effectiveness of BNT162b2 XBB Vaccine Against XBB and JN.1 Sublineages.

We provide updated results (11 October 2023 through 29 February 2024) from our previously conducted test-negative case-control study in Kaiser Permanente Southern California to evaluate sublineage-specific effectiveness of the BNT162b2 XBB1.5-adapted vaccine. Results suggest that XBB1.5-adapted vaccines may have reduced effectiveness against JN.1 versus XBB sublineages.

Estimated Effectiveness of the BNT162b2 XBB Vaccine Against COVID-19.

Importance: Data describing the early additional protection afforded by the recently recommended BNT162b2 XBB vaccine (Pfizer-BioNTech; 2023-2024 formulation) are limited. Objective: To estimate the association between receipt of the BNT162b2 XBB vaccine and medically attended COVID-19 outcomes among US adults 18 years and older. Design, Setting, and Participants: This test-negative case-control study was performed to estimate the effectiveness of the BNT162b2 XBB vaccine against COVID-19-associated hospitalization and emergency department (ED) or urgent care (UC) encounters among adults in the Kaiser Permanente Southern California health system between October 10, 2023, and December 10, 2023. Cases were those presenting with an acute respiratory illness and who had a positive SARS-CoV-2 polymerase chain reaction test; controls had an acute respiratory illness but tested negative for SARS-CoV-2. Exposure: The primary exposure was receipt of the BNT162b2 XBB vaccine compared with not receiving an XBB vaccine of any kind, regardless of prior COVID-19 vaccination or SARS-CoV-2 infection history. Receipt of prior (non-XBB) versions of COVID-19 vaccines was also compared with being unvaccinated to estimate remaining protection from older vaccines. Main Outcomes and Measures: Analyses for cases and controls were conducted separately for COVID-19 hospital admissions and ED/UC encounters. Adjusted odds ratios and 95% CIs were estimated from multivariable logistic regression models that were adjusted for patient demographic and clinical characteristics. Estimation of vaccine effectiveness was calculated as 1 - odds ratio × 100%. Results: Among 2854 cases and 15 345 controls (median [IQR] age, 56 [37-72] years; 10 658 [58.6%] female), adjusted estimation of effectiveness of the BNT162b2 XBB vaccine received a median of 34 days prior vs not having received an XBB vaccine of any kind was 62% (95% CI, 32%-79%) against COVID-19 hospitalization and 58% (95% CI, 48%-67%) for ED/UC visits. Compared with being unvaccinated, those who had received only older versions of COVID-19 vaccines did not show statistically significant reduced risk of COVID-19 outcomes, including hospital admission. Conclusions and Relevance: Findings of this case-control study reaffirm current recommendations for broad age-based use of annually updated COVID-19 vaccines given that (1) the BNT162b2 XBB vaccine provided statistically significant additional protection against a range of COVID-19 outcomes and (2) older versions of COVID-19 vaccines offered little, if any, long-term protection, including against hospital admission, regardless of the number or type of prior doses received.

Risk factors for recurrent urinary tract infections among women in a large integrated health care organization in the United States.

BACKGROUND: Urinary tract infections (UTIs) occur commonly and often recur. However, recent data on the epidemiology of recurrent UTI (rUTI) are scarce. METHODS: Between 01/01/2016-31/12/2020, index uncomplicated UTIs (uUTI) from office, emergency department (ED), hospital, and virtual care settings were identified from electronic health records of women at Kaiser Permanente Southern California. We defined rUTI as ≥3 UTI within 365 days or ≥2 UTI within 180 days. We determined the proportion of women with cystitis index uUTI who had rUTI and examined factors associated with rUTIs using modified multivariable Poisson regression. RESULTS: Among 374,171 women with cystitis index uUTI, 54,318 (14.5%) had rUTI. A higher proportion of women with rUTI compared to those without rUTI were age 18-27 or ≥78 years at index uUTI (19.7% vs 18.7% and 9.0% vs 6.0%, respectively), were immunocompromised, or had a positive urine culture at index uUTI. In multivariable analyses, characteristics associated with rUTI included younger or older age (48-57 vs 18-27 years aRR=0.83 [95% CI: 0.80-0.85]; ≥78 vs 18-27 years aRR=1.07 [95%CI=1.03-1.11]), Charlson Comorbidity Index (≥3 vs 0, aRR=1.12 [95%CI:1.08-1.17]), and diabetes mellitus (aRR=1.07 [95%CI:1.04-1.10]). More frequent prior year outpatient and ED encounters, oral antibiotic prescriptions, oral contraceptive prescriptions, positive culture at index uUTI, and antibiotic resistant organisms were also associated with increased risk of rUTI. CONCLUSIONS: The high risk of rUTI among women with cystitis is concerning, especially given previous reports of increasing UTI incidence. Current assessment of the epidemiology of rUTI may guide the development of preventive interventions against UTI.

Diversity and selection analyses identify transmission-blocking antigens as the optimal vaccine candidates in Plasmodium falciparum.

Background: A highly effective vaccine for malaria remains an elusive target, at least in part due to the under-appreciated natural parasite variation. This study aimed to investigate genetic and structural variation, and immune selection of leading malaria vaccine candidates across the Plasmodium falciparum's life cycle. Methods: We analyzed 325 P. falciparum whole genome sequences from Zambia, in addition to 791 genomes from five other African countries available in the MalariaGEN Pf3k Rdatabase. Ten vaccine antigens spanning three life-history stages were examined for genetic and structural variations, using population genetics measures, haplotype network analysis, and 3D structure selection analysis. Findings: Among the ten antigens analyzed, only three in the transmission-blocking vaccine category display P. falciparum 3D7 as the dominant haplotype. The antigens AMA1, CSP, MSP119 and CelTOS, are much more diverse than the other antigens, and their epitope regions are under moderate to strong balancing selection. In contrast, Rh5, a blood stage antigen, displays low diversity yet slightly stronger immune selection in the merozoite-blocking epitope region. Except for CelTOS, the transmission-blocking antigens Pfs25, Pfs48/45, Pfs230, Pfs47, and Pfs28 exhibit minimal diversity and no immune selection in epitopes that induce strain-transcending antibodies, suggesting potential effectiveness of 3D7-based vaccines in blocking transmission. Interpretations: These findings offer valuable insights into the selection of optimal vaccine candidates against P. falciparum. Based on our results, we recommend prioritizing conserved merozoite antigens and transmission-blocking antigens. Combining these antigens in multi-stage approaches may be particularly promising for malaria vaccine development initiatives. Funding: Purdue Department of Biological Sciences; Puskas Memorial Fellowship; National Institute of Allergy and Infectious Diseases (U19AI089680).

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.

Predicting transcriptional activation domain function using Graph Neural Networks.

Analysis of factors that lead to the functionality of transcriptional activation domains remains a crucial and yet challenging task owing to the significant diversity in their sequences and their intrinsically disordered nature. Almost all existing methods that have aimed to predict activation domains have involved traditional machine learning approaches, such as logistic regression, that are unable to capture complex patterns in data or plain convolutional neural networks and have been limited in exploration of structural features. However, there is a tremendous potential in the inspection of the structural properties of activation domains, and an opportunity to investigate complex relationships between features of residues in the sequence. To address these, we have utilized the power of graph neural networks which can represent structural data in the form of nodes and edges, allowing nodes to exchange information among themselves. We have experimented with two kinds of graph formulations, one involving residues as nodes and the other assigning atoms to be the nodes. A logistic regression model was also developed to analyze feature importance. For all the models, several feature combinations were experimented with. The residue-level GNN model with amino acid type, residue position, acidic/basic/aromatic property and secondary structure feature combination gave the best performing model with accuracy, F1 score and AUROC of 97.9%, 71% and 97.1% respectively which outperformed other existing methods in the literature when applied on the dataset we used. Among the other structure-based features that were analyzed, the amphipathic property of helices also proved to be an important feature for classification. Logistic regression results showed that the most dominant feature that makes a sequence functional is the frequency of different types of amino acids in the sequence. Our results consistent have shown that functional sequences have more acidic and aromatic residues whereas basic residues are seen more in non-functional sequences.

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.

Nanoscale Three-Dimensional Imaging of Integrated Circuits Using a Scanning Electron Microscope and Transition-Edge Sensor Spectrometer.

X-ray nanotomography is a powerful tool for the characterization of nanoscale materials and structures, but it is difficult to implement due to the competing requirements of X-ray flux and spot size. Due to this constraint, state-of-the-art nanotomography is predominantly performed at large synchrotron facilities. We present a laboratory-scale nanotomography instrument that achieves nanoscale spatial resolution while addressing the limitations of conventional tomography tools. The instrument combines the electron beam of a scanning electron microscope (SEM) with the precise, broadband X-ray detection of a superconducting transition-edge sensor (TES) microcalorimeter. The electron beam generates a highly focused X-ray spot on a metal target held micrometers away from the sample of interest, while the TES spectrometer isolates target photons with a high signal-to-noise ratio. This combination of a focused X-ray spot, energy-resolved X-ray detection, and unique system geometry enables nanoscale, element-specific X-ray imaging in a compact footprint. The proof of concept for this approach to X-ray nanotomography is demonstrated by imaging 160 nm features in three dimensions in six layers of a Cu-SiO2 integrated circuit, and a path toward finer resolution and enhanced imaging capabilities is discussed.

Publication Rates of Podium Presentations at an Annual Orthopedic Surgery Resident and Fellow Research Symposium.

Introduction Research is an important aspect of residency and fellowship programs across the country. Developing strategies to foster research productivity is worthwhile. An annual research project is one strategy that some programs implement. Methods All resident and fellow (Sports Medicine, Adult Reconstruction, Spine) presentations at an orthopedic surgery department's annual research symposium from June 2016 through June 2021 were identified. Abstract titles, title keywords, and author names were searched in PubMed and Google Scholar to identify the presence of a peer-reviewed publication. Using the total number of research symposium presentations given, the publication rate was calculated for each year, as well as collectively for 2016 to 2021. In addition to publication rate, first author percent, number of citations, Altmetric score, and journal impact factor were recorded. Current PGY-2 through PGY-5 residents completed a survey to assess the perceived value of the annual research symposium. Results Ninety-eight research symposium presentations were reviewed (69 residents, 29 fellows). Forty (58%) resident studies were published and 28 were first-author publications (70%). Thirteen (45%) fellow studies were published and seven were first-author publications (54%). Combining residents and fellows, the overall publication rate was 54% (53/98), and 66% of these (35/53) were first-author publications. There was a wide range of published manuscript journal impact factors, Altmetric scores, and number of citations. All residents surveyed reported finding value in the research symposium. Conclusion The overall publication rate of presentations at an annual orthopedic surgery department research symposium between 2016 and 2021 was 54%, consistent with publication rates reported at National Orthopedic Surgery Society meetings. All residents reported finding value in the annual research symposium. The results of this study support the academic value of implementing a required annual research project and may provide a useful gauge to inform residency and fellowship curricula at other institutions.

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.

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.

AKAP12 Upregulation Associates With PDE8A to Accelerate Cardiac Dysfunction.

BACKGROUND: In heart failure, signaling downstream the ß2-adrenergic receptor is critical. Sympathetic stimulation of ß2-adrenergic receptor alters cAMP (cyclic adenosine 3',5'-monophosphate) and triggers PKA (protein kinase A)-dependent phosphorylation of proteins that regulate cardiac function. cAMP levels are regulated in part by PDEs (phosphodiesterases). Several AKAPs (A kinase anchoring proteins) regulate cardiac function and are proposed as targets for precise pharmacology. AKAP12 is expressed in the heart and has been reported to directly bind ß2-adrenergic receptor, PKA, and PDE4D. However, its roles in cardiac function are unclear. METHODS: cAMP accumulation in real time downstream of the ß2-adrenergic receptor was detected for 60 minutes in live cells using the luciferase-based biosensor (GloSensor) in AC16 human-derived cardiomyocyte cell lines overexpressing AKAP12 versus controls. Cardiomyocyte intracellular calcium and contractility were studied in adult primary cardiomyocytes from male and female mice overexpressing cardiac AKAP12 (AKAP12OX) and wild-type littermates post acute treatment with 100-nM isoproterenol (ISO). Systolic cardiac function was assessed in mice after 14 days of subcutaneous ISO administration (60 mg/kg per day). AKAP12 gene and protein expression levels were evaluated in left ventricular samples from patients with end-stage heart failure. RESULTS: AKAP12 upregulation significantly reduced total intracellular cAMP levels in AC16 cells through PDE8. Adult primary cardiomyocytes from AKAP12OX mice had significantly reduced contractility and impaired calcium handling in response to ISO, which was reversed in the presence of the selective PDE8 inhibitor (PF-04957325). AKAP12OX mice had deteriorated systolic cardiac function and enlarged left ventricles. Patients with end-stage heart failure had upregulated gene and protein levels of AKAP12. CONCLUSIONS: AKAP12 upregulation in cardiac tissue is associated with accelerated cardiac dysfunction through the AKAP12-PDE8 axis.