Search

Objectives: We aimed to determine whether surgeon variation in management of intraductal papillary mucinous neoplasm (IPMN) is driven by differences in risk perception and quantify surgeons' risk threshold for changing their recommendations., Background: Surgeons vary widely in management of IPMN., Methods: We conducted a survey of members of the Americas HepatoPancreatoBiliary Association, presented participants with 2 detailed clinical vignettes and asked them to choose between surgical resection and surveillance. We also asked them to judge the likelihood that the IPMN harbors cancer and that the patient would have a serious complication if surgery was performed. Finally, we asked surgeons to rate the level of cancer risk at which they would change their treatment recommendation. We examined the association between surgeons' treatment recommendations and their risk perception and risk threshold., Results: One hundred fifty surgeons participated in the study. Surgeons varied in their recommendations for surgery [19% for vignette 1 (V1) and 12% for V2] and in their perception of the cancer risk (interquartile range: 2%-10% for V1 and V2) and risk of surgical complications (V1 interquartile range: 10%-20%, V2 20-30%). After adjusting for surgeon characteristics, surgeons who were above the median in cancer risk perception were 22 percentage points (27% vs 5%) more likely to recommend resection than those who were below the median (95% CI: 11%-4%; P <0.001). The median risk threshold at which surgeons would change their recommendation was 15% (V1 and V2). Surgeons who recommended surgery had a lower risk threshold for changing their recommendation than those who recommended surveillance (V1: 10.0 vs 15.0, P =0.06; V2: 7.0 vs 15.0, P =0.05)., Conclusions: The treatment that patients receive for IPMNs depends greatly on how their surgeons perceive the risk of cancer in the lesion. Efforts to improve cancer risk prediction for IPMNs may lead to decreased variations in care., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Chimeric antigen receptor (CAR) T cell therapy is a revolutionary form of immunotherapy that has proven to be efficacious in the treatment of many hematologic cancers. CARs are modified T lymphocytes that express an artificial receptor specific to a tumor-associated antigen. These engineered cells are then reintroduced to upregulate the host immune responses and eradicate malignant cells. While the use of CAR T cell therapy is rapidly expanding, little is known about how common side effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) present radiographically. Here we provide a comprehensive review of how side effects present in different organ systems and how they can be optimally imaged. Early and accurate recognition of the radiographic presentation of these side effects is critical to the practicing radiologist and their patients so that these side effects can be promptly identified and treated., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kathleen M. Capaccione reports a relationship with Cardinal Health that includes: consulting or advisory. Mary Salvatore reports a relationship with Genentech and Boehringer Ingelheim that includes: consulting or advisory, funding/grants, and speaking and lecture fees., (Copyright © 2023 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Introduction: Magnetic resonance imaging (MRI) research has advanced our understanding of neurodegeneration in sporadic early-onset Alzheimer's disease (EOAD) but studies include small samples, mostly amnestic EOAD, and have not focused on developing an MRI biomarker., Methods: We analyzed MRI scans to define the sporadic EOAD-signature atrophy in a small sample (n = 25) of Massachusetts General Hospital (MGH) EOAD patients, investigated its reproducibility in the large longitudinal early-onset Alzheimer's disease study (LEADS) sample (n = 211), and investigated the relationship of the magnitude of atrophy with cognitive impairment., Results: The EOAD-signature atrophy was replicated across the two cohorts, with prominent atrophy in the caudal lateral temporal cortex, inferior parietal lobule, and posterior cingulate and precuneus cortices, and with relative sparing of the medial temporal lobe. The magnitude of EOAD-signature atrophy was associated with the severity of cognitive impairment., Discussion: The EOAD-signature atrophy is a reliable and clinically valid biomarker of AD-related neurodegeneration that could be used in clinical trials for EOAD., Highlights: We developed an early-onset Alzheimer's disease (EOAD)-signature of atrophy based on magnetic resonance imaging (MRI) scans. EOAD signature was robustly reproducible across two independent patient cohorts. EOAD signature included prominent atrophy in parietal and posterior temporal cortex. The EOAD-signature atrophy was associated with the severity of cognitive impairment. EOAD signature is a reliable and clinically valid biomarker of neurodegeneration., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Medicaid expansion's (ME) impact on postoperative outcomes after abdominal surgery remains poorly defined. We aimed to evaluate ME's effect on surgical morbidity, mortality, and readmissions in a state that expanded Medicaid (Virginia) compared to a state that did not (Tennessee) over the same time period., Methods: Virginia Surgical Quality Collaborative (VSQC) American College of Surgeons National Surgical Quality Improvement Program data for Medicaid, uninsured, and private insurance patients undergoing abdominal procedures before Virginia's ME (3/22/18-12/31/18) were compared with post-ME (1/1/19-12/31/19), as were corresponding non-ME state Tennessee Surgical Quality Collaborative (TSQC) data for the same 2018 and 2019 time periods. Postexpansion odds ratios for 30-d morbidity, 30-d mortality, and 30-d unplanned readmission were estimated using propensity score-adjusted logistic regression models., Results: In Virginia, 4753 abdominal procedures, 2097 pre-ME were compared to 2656 post-ME. In Tennessee, 5956 procedures, 2484 in 2018 were compared to 3472 in 2019. VSQC's proportion of Medicaid population increased following ME (8.9% versus 18.8%, P < 0.001) while uninsured patients decreased (20.4% versus 6.4%, P < 0.001). Post-ME VSQC had fewer 30-d readmissions (12.2% versus 6.0%, P = 0.013). Post-ME VSQC Medicaid patients had significantly lower probability of morbidity (-8.18, 95% confidence interval: -15.52 ∼ -0.84, P = 0.029) and readmission (-6.92, 95% confidence interval: -12.56 ∼ -1.27, P = 0.016) compared to pre-ME. There were no differences in probability of morbidity or readmission in the TSQC Medicaid population between study periods (both P > 0.05); there were no differences in mortality between study periods in VSQC and TSQC patient populations (both P > 0.05)., Conclusions: ME was associated with decreased 30-d morbidity and unplanned readmissions in the VSQC. Data-driven policies accounting for ME benefits should be considered., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Remote, internet-based methods for recruitment, screening, and longitudinally assessing older adults have the potential to facilitate Alzheimer's disease (AD) clinical trials and observational studies., Methods: The Brain Health Registry (BHR) is an online registry that includes longitudinal assessments including self- and study partner-report questionnaires and neuropsychological tests. New initiatives aim to increase inclusion and engagement of commonly underincluded communities using digital, community-engaged research strategies. New features include multilingual support and biofluid collection capabilities., Results: BHR includes > 100,000 participants. BHR has made over 259,000 referrals resulting in 25,997 participants enrolled in 30 aging and AD studies. In addition, 28,278 participants are coenrolled in BHR and other studies with data linkage among studies. Data have been shared with 28 investigators. Recent efforts have facilitated the enrollment and engagement of underincluded ethnocultural communities., Discussion: The major advantages of the BHR approach are scalability and accessibility. Challenges include compliance, retention, cohort diversity, and generalizability., Highlights: Brain Health Registry (BHR) is an online, longitudinal platform of > 100,000 members. BHR made > 259,000 referrals, which enrolled 25,997 participants in 32 studies. New efforts increased enrollment and engagement of underincluded communities in BHR. The major advantages of the BHR approach are scalability and accessibility. BHR provides a unique adjunct for clinical neuroscience research., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: Investigation of learning slopes in early-onset dementias has been limited. The current study aimed to highlight the sensitivity of learning slopes to discriminate disease severity in cognitively normal participants and those diagnosed with early-onset dementia with and without β-amyloid positivity METHOD: Data from 310 participants in the Longitudinal Early-Onset Alzheimer's Disease Study (aged 41 to 65) were used to calculate learning slope metrics. Learning slopes among diagnostic groups were compared, and the relationships of slopes with standard memory measures were determined RESULTS: Worse learning slopes were associated with more severe disease states, even after controlling for demographics, total learning, and cognitive severity. A particular metric-the learning ratio (LR)-outperformed other learning slope calculations across analyses CONCLUSIONS: Learning slopes appear to be sensitive to early-onset dementias, even when controlling for the effect of total learning and cognitive severity. The LR may be the learning measure of choice for such analyses., Highlights: Learning is impaired in amyloid-positive EOAD, beyond cognitive severity scores alone. Amyloid-positive EOAD participants perform worse on learning slopes than amyloid-negative participants. Learning ratio appears to be the learning metric of choice for EOAD participants., (© 2023 the Alzheimer's Association.)

Introduction: One goal of the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is to investigate the genetic etiology of early onset (40-64 years) cognitive impairment. Toward this goal, LEADS participants are screened for known pathogenic variants., Methods: LEADS amyloid-positive early-onset Alzheimer's disease (EOAD) or negative early-onset non-AD (EOnonAD) cases were whole exome sequenced (N = 299). Pathogenic variant frequency in APP, PSEN1, PSEN2, GRN, MAPT, and C9ORF72 was assessed for EOAD and EOnonAD. Gene burden testing was performed in cases compared to similar-age cognitively normal controls in the Parkinson's Progression Markers Initiative (PPMI) study., Results: Previously reported pathogenic variants in the six genes were identified in 1.35% of EOAD (3/223) and 6.58% of EOnonAD (5/76). No genes showed enrichment for carriers of rare functional variants in LEADS cases., Discussion: Results suggest that LEADS is enriched for novel genetic causative variants, as previously reported variants are not observed in most cases., Highlights: Sequencing identified eight cognitively impaired pathogenic variant carriers. Pathogenic variants were identified in PSEN1, GRN, MAPT, and C9ORF72. Rare variants were not enriched in APP, PSEN1/2, GRN, and MAPT. The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is a key resource for early-onset Alzheimer's genetic research., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Disease of the aortic arch, descending thoracic, or thoracoabdominal aorta necessitates dedicated expertise across medical, endovascular, and surgical specialties. Cardiologists, cardiac surgeons, vascular surgeons, interventional radiologists, and others have expertise and skills that aid in the management of patients with complex aortic disease. No specialty is uniformly expert in all aspects of required care. Because of this dispersion of expertise across specialties, an aortic team model approach to decision-making and treatment is advocated. A nonhierarchical partnership across specialties within an interdisciplinary aortic clinic ensures that all treatment options are considered and promotes shared decision-making between the patient and all aortic experts. Furthermore, regionalization of care for aortic disease of increased complexity assures that the breadth of treatment options is available and that favourable volume-outcome ratios for high-risk procedures are maintained. An awareness of best practice care pathways for patient referrals for preventative management, acute care scenarios, chronic care scenarios, and pregnancy might facilitate a more organized management schema for aortic disease across Canada and improve lifelong surveillance initiatives., (Copyright © 2023 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objective: The Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) seeks to provide comprehensive understanding of early-onset Alzheimer's disease (EOAD; onset <65 years), with the current study profiling baseline clinical, cognitive, biomarker, and genetic characteristics of the cohort nearing the data-collection mid-point., Methods: Data from 371 LEADS participants were compared based on diagnostic group classification (cognitively normal [n = 89], amyloid-positive EOAD [n = 212], and amyloid-negative early-onset non-Alzheimer's disease [EOnonAD; n = 70])., Results: Cognitive performance was worse for EOAD than other groups, and EOAD participants were apolipoprotein E (APOE) ε4 homozygotes at higher rates. An amnestic presentation was common among impaired participants (81%), with several clinical phenotypes present. LEADS participants generally consented at high rates to optional trial procedures., Conclusions: We present the most comprehensive baseline characterization of sporadic EOAD in the United States to date. EOAD presents with widespread cognitive impairment within and across clinical phenotypes, with differences in APOE ε4 allele carrier status appearing to be relevant., Highlights: Findings represent the most comprehensive baseline characterization of sporadic early-onset Alzheimer's disease (EOAD) to date. Cognitive impairment was widespread for EOAD participants and more severe than other groups. EOAD participants were homozygous apolipoprotein E (APOE) ε4 carriers at higher rates than the EOnonAD group. Amnestic presentation predominated in EOAD and EOnonAD participants, but other clinical phenotypes were present., (© 2023 the Alzheimer's Association.)

Objective: We aimed to determine whether surgeon variation in management of intraductal papillary mucinous neoplasms (IPMN) is driven by differences in risk perception and quantify surgeons' risk threshold for changing their recommendations., Background: Surgeons vary widely in management of IPMN., Methods: We conducted a survey of members of the Americas HepatoPancreatoBiliary Association, presented participants with 2 detailed clinical vignettes and asked them to choose between surgical resection and surveillance. We also asked them to judge the likelihood that the IPMN harbors cancer and that the patient would have a serious complication if surgery was performed. Finally, we asked surgeons to rate the level of cancer risk at which they would change their treatment recommendation. We examined the association between surgeons' treatment recommendations and their risk perception and risk threshold., Results: One hundred and fifty surgeons participated in the study. Surgeons varied in their recommendations for surgery [19% for vignette 1 (V1) and 12% for V2] and in their perception of the cancer risk (interquartile range: 2%-10% for V1 and V2) and risk of surgical complications (V1 interquartile range: 10%-20%, V2 20%-30%). After adjusting for surgeon characteristics, surgeons who were above the median in cancer risk perception were 22 percentage points (27% vs. 5%) more likely to recommend resection than those who were below the median (95% CI: 11.34%; P <0.001). The median risk threshold at which surgeons would change their recommendation was 15% (V1 and V2). Surgeons who recommended surgery had a lower risk threshold for changing their recommendation than those who recommended surveillance (V1: 10.0 vs. 15.0, P =0.06; V2: 7.0 vs. 15.0, P =0.05)., Conclusions: The treatment that patients receive for IPMNs depends greatly on how their surgeons perceive the risk of cancer in the lesion. Efforts to improve cancer risk prediction for IPMNs may lead to decreased variations in care., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Palliative care (PC) is a model of care centered around improving the quality of life for individuals with life-limiting illnesses. Few studies have examined its impact in patients on extracorporeal membrane oxygenation (ECMO). We aimed to describe demographics, clinical characteristics, and complications associated with PC consultation in adult patients requiring ECMO support. We analyzed data from an ECMO registry, including patients aged 18 years and older who have received either venoarterial (VA)- or venovenous (VV)-ECMO support between July 2016 and September 2021. We used analysis of variance and Fisher exact tests to identify factors associated with PC consultation. Of 256, 177 patients (69.1%) received VA-ECMO support and 79 (30.9%) received VV-ECMO support. Overall, 115 patients (44.9%) received PC consultation while on ECMO. Patients receiving PC consultation were more likely to be non-white (47% vs. 53%, p = 0.016), have an attending physician from a medical versus surgical specialty (65.3% vs. 39.6%), have VV-ECMO (77.2% vs. 30.5%, p < 0.001), and have longer ECMO duration (6.2 vs. 23.0, p < 0.001). Patients were seen by the PC team on an average of 7.6 times (range, 1-35), with those who died having significantly more visits (11.2 vs. 5.6, p < 0.001) despite the shorter hospital stay. The average time from cannulation to the first PC visit was 5.3 ± 5 days. Congestive heart failure in VA-ECMO, coronavirus disease 2019 infection in VV-ECMO, and non-white race and longer ECMO duration for all patients were associated with PC consultation. We found that despite the benefits of PC, it is underused in this population., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2023.)

Introduction: We aimed to describe baseline amyloid-beta (Aβ) and tau-positron emission tomograrphy (PET) from Longitudinal Early-onset Alzheimer's Disease Study (LEADS), a prospective multi-site observational study of sporadic early-onset Alzheimer's disease (EOAD)., Methods: We analyzed baseline [18F]Florbetaben (Aβ) and [18F]Flortaucipir (tau)-PET from cognitively impaired participants with a clinical diagnosis of mild cognitive impairment (MCI) or AD dementia aged < 65 years. Florbetaben scans were used to distinguish cognitively impaired participants with EOAD (Aβ+) from EOnonAD (Aβ-) based on the combination of visual read by expert reader and image quantification., Results: 243/321 (75.7%) of participants were assigned to the EOAD group based on amyloid-PET; 231 (95.1%) of them were tau-PET positive (A+T+). Tau-PET signal was elevated across cortical regions with a parietal-predominant pattern, and higher burden was observed in younger and female EOAD participants., Discussion: LEADS data emphasizes the importance of biomarkers to enhance diagnostic accuracy in EOAD. The advanced tau-PET binding at baseline might have implications for therapeutic strategies in patients with EOAD., Highlights: 72% of patients with clinical EOAD were positive on both amyloid- and tau-PET. Amyloid-positive patients with EOAD had high tau-PET signal across cortical regions. In EOAD, tau-PET mediated the relationship between amyloid-PET and MMSE. Among EOAD patients, younger onset and female sex were associated with higher tau-PET., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Synovial cysts are a common finding in degenerative spine disease, most frequently involving the facet joints of the lumbar spine. Synovial cysts are less common in the cervical spine and rarely involve the atlantoaxial junction., Observations: In this case report, the authors detail a unique presentation of a left atlantoaxial synovial cyst with large intracranial extension into the cerebellopontine angle causing progressive cranial nerve palsies resulting in tinnitus, vertigo, diminished hearing, gait imbalance, left trigeminal hypesthesia, left facial weakness, and dysarthria. The patient underwent a retromastoid craniectomy for resection of the synovial cyst, resulting in improvement and resolution of symptoms. Follow-up occurred at 6 weeks, 3 months, and 5 months postoperatively without recurrence on imaging., Lessons: The authors describe acute and long-term management of a unique presentation of an atlantoaxial synovial cyst including retromastoid craniectomy, intervals for follow-up for recurrence, and possible treatment options in cases of recurrence. A systematic literature review was also performed to explore all reported cases of craniocervical junction synovial cysts and subsequent surgical management.

A crucial step in lead selection during drug development is accurate estimation and optimization of hepatic clearance using in vitro methods. However, current methods are limited by factors such as lack of physiological relevance, short culture/incubation times that are not consistent with drug exposure patterns in patients, use of drug absorbing materials, and evaporation during long-term incubation. To address these technological needs, we developed a novel milli-fluidic human liver tissue chip (LTC) that was designed with continuous media recirculation and optimized for hepatic cultures using human primary hepatocytes. Here, we characterized the LTC using a series of physiologically relevant metrics and test compounds to demonstrate that we could accurately predict the PK of both low- and high-clearance compounds. The non-biological characterization indicated that the cyclic olefin copolymer (COC)-based LTC exhibited negligible evaporation and minimal non-specific binding of drugs of varying ionic states and lipophilicity. Biologically, the LTC exhibited functional and polarized hepatic culture with sustained metabolic CYP activity for at least 15 days. This long-term culture was then used for drug clearance studies for low- and high-clearance compounds for at least 12 days, and clearance was estimated for a range of compounds with high in vitro-in vivo correlation (IVIVC). We also demonstrated that LTC can be induced by rifampicin, and the culture age had insignificant effect on depletion kinetic and predicted clearance value. Thus, we used advances in bioengineering to develop a novel purpose-built platform with high reproducibility and minimal variability to address unmet needs for PK applications., (© 2023. The Author(s).)

Objective: New paediatric sepsis criteria are being developed by an international task force. However, it remains unknown what type of clinical decision support (CDS) tools will be most useful for dissemination of those criteria in resource-poor settings. We sought to design effective CDS tools by identifying the paediatric sepsis-related decisional needs of multidisciplinary clinicians and health system administrators in resource-poor settings., Design: Semistructured qualitative focus groups and interviews with 35 clinicians (8 nurses, 27 physicians) and 5 administrators at health systems that regularly provide care for children with sepsis, April-May 2022., Setting: Health systems in Africa, Asia and Latin America, where sepsis has a large impact on child health and healthcare resources may be limited., Participants: Participants had a mean age of 45 years, a mean of 15 years of experience, and were 45% female., Results: Emergent themes were related to the decisional needs of clinicians caring for children with sepsis and to the needs of health system administrators as they make decisions about which CDS tools to implement. Themes included variation across regions and institutions in infectious aetiologies of sepsis and available clinical resources, the need for CDS tools to be flexible and customisable in order for implementation to be successful, and proposed features and format of an ideal paediatric sepsis CDS tool., Conclusion: Findings from this study will directly contribute to the design and implementation of CDS tools to increase the uptake and impact of the new paediatric sepsis criteria in resource-poor settings., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In almost all sexually reproducing organisms, meiotic recombination and cell division require the synapsis of homologous chromosomes by a large proteinaceous structure, the synaptonemal complex (SC). While the SC's overall structure is highly conserved across eukaryotes, its constituent proteins diverge between phyla. Transverse filament protein, SYCP1, spans the width of the SC and undergoes amino-terminal head-to-head self-assembly in vitro through a motif that is unusually highly conserved across kingdoms of life. Here, we report creation of mouse mutants, Sycp1 L102E and Sycp1 L106E , that target SYCP1's head-to-head interface. L106E resulted in a complete loss of synapsis, while L102E had no apparent effect on synapsis, in agreement with their differential effects on the SYCP1 head-to-head interface in molecular dynamics simulations. In Sycp1 L106E mice, homologs aligned and recruited low levels of mutant SYCP1 and other SC proteins, but the absence of synapsis led to failure of crossover formation and meiotic arrest. We conclude that SYCP1's conserved head-to-head interface is essential for meiotic chromosome synapsis in vivo.

The senataxin (SETX, Sen1 in yeasts) RNA-DNA hybrid resolving helicase regulates multiple nuclear transactions, including DNA replication, transcription, and DNA repair, but the molecular basis for Sen1 activities is ill defined. Here, Sen1 cryoelectron microscopy (cryo-EM) reconstructions reveal an elongated inchworm-like architecture. Sen1 is composed of an amino terminal helical repeat Sen1 N-terminal (Sen1N) regulatory domain that is flexibly linked to its C-terminal SF1B helicase motor core (Sen1 Hel ) via an intrinsically disordered tether. In an autoinhibited state, the Sen1 Sen1N domain regulates substrate engagement by promoting occlusion of the RNA substrate-binding cleft. The X-ray structure of an activated Sen1 Hel engaging single-stranded RNA and ADP-SO 4 shows that the enzyme encircles RNA and implicates a single-nucleotide power stroke in the Sen1 RNA translocation mechanism. Together, our data unveil dynamic protein-protein and protein-RNA interfaces underpinning helicase regulation and inactivation of human SETX activity by RNA-binding-deficient mutants in ataxia with oculomotor apraxia 2 neurodegenerative disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

The homodimeric PolG2 accessory subunit of the mitochondrial DNA polymerase gamma (Pol γ) enhances DNA binding and processive DNA synthesis by the PolG catalytic subunit. PolG2 also directly binds DNA, although the underlying molecular basis and functional significance are unknown. Here, data from Atomic Force Microscopy (AFM) and X-ray structures of PolG2-DNA complexes define dimeric and hexameric PolG2 DNA binding modes. Targeted disruption of PolG2 DNA-binding interfaces impairs processive DNA synthesis without diminishing Pol γ subunit affinities. In addition, a structure-specific DNA-binding role for PolG2 oligomers is supported by X-ray structures and AFM showing that oligomeric PolG2 localizes to DNA crossings and targets forked DNA structures resembling the mitochondrial D-loop. Overall, data indicate that PolG2 DNA binding has both PolG-dependent and -independent functions in mitochondrial DNA replication and maintenance, which provide new insight into molecular defects associated with PolG2 disruption in mitochondrial disease., (Published by Oxford University Press on behalf of Nucleic Acids Research 2023.)

Objective: To examine the association of COVID-19 convalescent plasma transfusion with mortality and the differences between subgroups in hospitalized patients with COVID-19., Patients and Methods: On October 26, 2022, a systematic search was performed for clinical studies of COVID-19 convalescent plasma in the literature from January 1, 2020, to October 26, 2022. Randomized clinical trials and matched cohort studies investigating COVID-19 convalescent plasma transfusion compared with standard of care treatment or placebo among hospitalized patients with confirmed COVID-19 were included. The electronic search yielded 3841 unique records, of which 744 were considered for full-text screening. The selection process was performed independently by a panel of 5 reviewers. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were extracted by 5 independent reviewers in duplicate and pooled using an inverse-variance random effects model. The prespecified end point was all-cause mortality during hospitalization., Results: Thirty-nine randomized clinical trials enrolling 21,529 participants and 70 matched cohort studies enrolling 50,160 participants were included in the systematic review. Separate meta-analyses reported that transfusion of COVID-19 convalescent plasma was associated with a decrease in mortality compared with the control cohort for both randomized clinical trials (odds ratio [OR], 0.87; 95% CI, 0.76-1.00) and matched cohort studies (OR, 0.76; 95% CI, 0.66-0.88). The meta-analysis of subgroups revealed 2 important findings. First, treatment with convalescent plasma containing high antibody levels was associated with a decrease in mortality compared with convalescent plasma containing low antibody levels (OR, 0.85; 95% CI, 0.73 to 0.99). Second, earlier treatment with COVID-19 convalescent plasma was associated with a decrease in mortality compared with the later treatment cohort (OR, 0.63; 95% CI, 0.48 to 0.82)., Conclusion: During COVID-19 convalescent plasma use was associated with a 13% reduced risk of mortality, implying a mortality benefit for hospitalized patients with COVID-19, particularly those treated with convalescent plasma containing high antibody levels treated earlier in the disease course., Competing Interests: Drs Senefeld, Carter, Joyner, Fairweather, Bruno, and Wright reported being investigators in the US Expanded Access Program of COVID-19 convalescent plasma. Drs Paneth, Casadevall, and Joyner reported serving as leadership for the COVID-19 Convalescent Plasma Project outside the submitted work., (© 2023 The Authors.)

Osteoarthritis (OA) can be debilitating and is related to impaired resolution of synovial inflammation. Current treatments offer temporary relief of clinical signs, but have potentially deleterious side effects. Bone marrow mononuclear cells (BMNC) are a rich source of macrophage progenitors that have the ability to reduce OA symptoms in people and inflammation in experimentally-induced synovitis in horses. The objective of this study was to evaluate the ability of intra-articular BMNC therapy to improve clinical signs of naturally occurring equine OA. Horses presenting with clinical and radiographic evidence of moderate OA in a single joint were randomly assigned to 1 of 3 treatment groups: saline (negative control), triamcinolone (positive control), or BMNC (treatment group). Lameness was evaluated subjectively and objectively, joint circumference measured, and synovial fluid collected for cytology and growth factor/cytokine quantification at 0, 7, and 21 days post-injection. Data were analyzed using General Estimating Equations with significance set at p  < 0.05. There were no adverse effects noted in any treatment group. There was a significant increase in synovial fluid total nucleated cell count in the BMNC-treated group on day 7 (median 440; range 20-1920 cells/uL) compared to day 0. Mononuclear cells were the predominant cell type across treatments at all time points. Joint circumference decreased significantly in the BMNC-treated group from days 7 to 21 and was significantly lower at day 21 in the BMNC-treated group compared to the saline-treated group. Median objective lameness improved significantly in the BMNC group between days 7 and 21. GM-CSF, IL-1ra, IGF-1, and TNF-α were below detectable limits and IL-6, IL-1β, FGF-2 were detectable in a limited number of synovial fluid samples. Inconsistent and limited differences were detected over time and between treatment groups for synovial fluid PGE 2 , SDF-1, MCP-1 and IL-10. Decreased lameness and joint circumference, coupled with a lack of adverse effects following BMNC treatment, support a larger clinical trial using BMNC therapy to treat OA in horses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Everett, Menarim, Barrett, Bogers, Byron, Pleasant, Werre and Dahlgren.)

Study Question: Is Mycoplasma genitalium-infection associated with reduced fecundability?, Summary Answer: Preconception M. genitalium-infection was associated with 27% lower fecundability though confidence intervals were wide, and the association between M. genitalium and fecundability may be dependent on concurrent bacterial vaginosis (BV)., What Is Known Already: M. genitalium has been associated with cervicitis, pelvic inflammatory disease, infertility, and preterm birth, but the extent to which M. genitalium is causally related to adverse reproductive sequelae in women is debated., Study Design, Size, Duration: Kenyan women enrolled in a prospective preconception cohort provided vaginal fluid specimens and underwent monthly pregnancy testing. Stored samples from 407 women who had been trying to conceive for ≤6 months were tested for M. genitalium using a nucleic acid amplification test., Participants/materials, Setting, Methods: Data on first day of last menstrual period, sexual behavior, pregnancy status, and vaginal specimens were collected at monthly preconception visits. The association between M. genitalium detected at the visit prior to each pregnancy test and fecundability was estimated using discrete time proportional probabilities models. Secondary analyses explored the influence of concurrent BV on the association between M. genitalium and fecundability., Main Results and the Role of Chance: The 407 participants experienced 1220 menstrual cycles and 213 pregnancies. The prevalence of M. genitalium at enrollment was 7.7%. After adjustment for age, frequency of condomless sex in the last 4 weeks, and study site, M. genitalium was associated with a 27% lower fecundability, but confidence intervals were wide (adjusted fecundability ratio (aFR) 0.73, 95% CI 0.44, 1.23). In secondary analyses, when compared to cycles without M. genitalium or BV at the visit prior, women with both M. genitalium and BV at the visit prior had a 51% lower fecundability (aFR = 0.49, 95% CI 0.22, 1.09) whereas there was no association of M. genitalium alone (aFR = 0.98 (95% CI 0.54, 1.76)), and a smaller reduction in fecundability for women with BV only (aFR = 0.80 (95% CI 0.60, 1.07))., Limitations, Reasons for Caution: Results should be interpreted cautiously given the relatively low prevalence of M. genitalium and wide confidence intervals., Wider Implications of the Findings: In this cohort of Kenyan women trying to conceive, the association between M. genitalium and fecundability was influenced by concurrent BV status, suggesting there may be a synergistic effect of M. genitalium and BV on fecundability., Study Funding/competing Interest(s): This work was supported by a National Institutes of Health grant (NICHD R01 HD087346-RSM). R.S.M. received additional support for mentoring (NICHD K24 HD88229). E.M.L. was supported by pre- and post-doctoral fellowships (NIAID T32 AI07140, NICHD F32 HD100202). Data collection and management were completed using REDCap electronic data capture tools hosted at the University of Washington's Institute of Translational Health Science supported by grants from NCATS/NIH (UL1 TR002319). The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. R.S.M. receives research funding, paid to the University of Washington, from Hologic Corporation and consulting fees from Lupin Pharmaceuticals. L.E.M. receives research funding and material for research studies, paid to the University of Washington, from Hologic Corporation and Nabriva Therapeutics, travel support from Hologic, and consulting fees from Health Advances. E.M.L.'s contributions to this study primarily occurred while affiliated with the University of Washington; at the time of submission, E.M.L. was an employee of and holds stock or stock grants for AbbVie, Inc. The other authors have no conflicts of interest., Trial Registration Number: N/A., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Malignant melanoma in-situ, lentigo maligna (MMIS-LM) can be successfully treated with several different surgical techniques; however, the literature is inconsistent in defining them., Objective: To comprehensively define and describe the national guideline recommended surgical techniques used to treat MMIS-LM to help clarify and standardize this terminology to ensure compliance with the guidelines., Methods: A targeted literature review was performed from 1990 to 2022 focusing on articles that discussed the national guideline recommended surgical techniques of wide local excision, Mohs micrographic surgery (MMS), modified Mohs surgery, and staged excision/Slow-Mohs for MMIS-LM, as well as the related methods of tissue processing. National Comprehensive Cancer Network and American Academy of Dermatology guidelines were reviewed to identify how the techniques need to be employed to be compliant with guideline recommendations., Results: We describe the various surgical and tissue processing techniques and discuss advantages and disadvantages of each., Limitations: This paper was styled as a narrative review defining and clarifying terminology and technique and does not investigate these topics more broadly., Conclusion: Understanding the methodology and terminology for these surgical procedures and tissue processing methods is critical so that both general dermatologists and surgeons can employ these techniques effectively for optimal patient care., Competing Interests: Conflicts of interest None disclosed., (Published by Elsevier Inc.)

Phenotypic plasticity allows organisms to optimize traits for their environment. As organisms age, they experience diverse environments that benefit from varying degrees of phenotypic plasticity. Developmental transitions can control these age-dependent changes in plasticity, and as such, the timing of these transitions can determine when plasticity changes in an organism. Here, we investigate how the transition from juvenile-to adult-vegetative development known as vegetative phase change (VPC) contributes to age-dependent changes in phenotypic plasticity and how the timing of this transition responds to environment using both natural accessions and mutant lines in the model plant Arabidopsis thaliana. We found that the adult phase of vegetative development has greater plasticity in leaf morphology than the juvenile phase and confirmed that this difference in plasticity is caused by VPC using mutant lines. Furthermore, we found that the timing of VPC, and therefore the time when increased plasticity is acquired, varies significantly across genotypes and environments. The consistent age-dependent changes in plasticity caused by VPC suggest that VPC may be adaptive. This genetic and environmental variation in the timing of VPC indicates the potential for population-level adaptive evolution of VPC., (© 2023 The Authors New Phytologist © 2023 New Phytologist Foundation.)

Background: Cryoanalgesia uses the application of cold temperatures to temporarily disrupt peripheral sensory nerve function for pain control. This review outlines the principles of cryoablation, clinical applications, and clinical data for its use in pediatric thoracic surgery. Methods: A comprehensive PubMed search was performed using the principal terms and combinations of cryoablation, cryoanalgesia, Nuss, Nuss repair, pectus, pectus excavatum, thoracic surgery, thoracotomy, and chest wall. Pediatric articles were reviewed and included if relevant. Adult articles were reviewed for supporting information as needed. Reference lists of included articles were reviewed for possible additional sources. Discussion: The scientific and clinical principles of cryoablation are outlined, followed by a focused review of current clinical application and outcome data. Conclusion: Postoperative pain is a major challenge following thoracic surgery. Cryoanalgesia is emerging as an adjunct in pediatric thoracic surgery, particularly for the Nuss procedure or minimally invasive repair of pectus excavatum. It effectively controls pain, decreasing postoperative opioid use and hospital length of stay with few short-term complications. Although more long-term studies are needed, early evidence suggests there is reliable return of sensation to the chest wall and long-term neuropathic pain is rare.

The metabolism of lufotrelvir, a novel phosphate prodrug of PF-00835231 for the treatment of COVID-19, was evaluated in healthy human volunteers and clinical trial participants with COVID-19 following intravenous infusion. The prodrug was completely converted to PF-00835231 that was subsequently cleared by hydrolysis, hydroxylation, ketoreduction, epimerization, renal clearance, and secretion into the feces. The main circulating metabolite was a hydrolysis product (M7) that was present at concentrations greater than PF-00835231, and this was consistent between healthy volunteers and participants with COVID-19. On administration of [ 14 C]lufotrelvir, only 63% of the dose was obtained in excreta over 10 days and total drug-related material demonstrated a prolonged terminal phase half-life in plasma. A considerable portion of the labeled material was unextractable from fecal homogenate and plasma. The position of the carbon-14 atom in the labeled material was at a leucine carbonyl, and pronase digestion of the pellet derived from extraction of the fecal homogenate showed that [ 14 C]leucine was released. SIGNIFICANCE STATEMENT: Lufotrelvir is an experimental phosphate prodrug intravenous therapy investigated for the potential treatment of COVID-19 in a hospital setting. The overall metabolism of lufotrelvir was determined in human healthy volunteers and clinical trial participants with COVID-19. Conversion of the phosphate prodrug to the active drug PF-00835231 was complete and the subsequent metabolic clearance of the active drug was largely via amide bond hydrolysis. Substantial drug-related material was not recovered due to loss of the carbon-14 label to endogenous metabolism., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

Introduction: Available literature comparing spinal anesthesia (SA) to general anesthesia (GA) in the pediatric population describes multiple benefits in appropriately selected patients including cost reduction, lower incidence of complications, and shorter operative times. In patients undergoing urologic procedures, data are sparse., Objective: Our goal was to expand on the paucity of existing urologic literature as SA appears to be uniquely suited for a substantial number of its common pediatric procedures., Methods: Within a single institution, patients who had a urologic procedure performed under SA between May 2019 and July 2021 and were less than 18 months old were compared with a matched cohort of patients who had GA. The SA and GA groups were compared by two-sample t-tests, chi-square test for independence, and Fisher's exact test., Results: There were a total of 184 SA and 202 GA patients. There was no significant difference in the demographics except that SA patients were younger and weighed less than GA patients. The patients in the SA group needed less opioids both during the surgery (0% vs 26.1% p N/A) and in the immediate postoperative period when compared with GA patients (0% vs 18.2% p N/A). The patients who had SA had fewer complications necessitating PICU admission, or cancellation of surgery (0% vs 6.8% p = 0.03). Total anesthesia and emergence time were lower for SA patients (41 vs 50.2 p = 0.001 & 3.4 vs 6.1 p = 0.001). Both surgery and total OR time were not different between the groups (37.6 vs 35.5 p = 0.35 and 56.3 vs 54.4 p = 0.49). Overall, raw material cost was also found to be lower per procedure in the SA group vs the GA group ($8.90 vs $38.8: 77% reduction). Adjusted total mean costs for the surgery were not different between groups. The reduction in opioid use postoperatively also suggests reduced cost in the management of postoperative pain in the SA group., Discussion: Total anesthesia time, opioid use, and serious complications were all significantly lower in the SA group. We did not find significant difference in total surgery cost between two groups. However, patients who had SA had better pain control and needed less rescue analgesics in the immediate postoperative period. No patients in either group were sent home with opioids., Conclusion: Spinal anesthesia was found to be an equally effective and appropriate alternative to GA with many proposed benefits for common pediatric urologic procedures. With further research, SA may prove to be a safer alternative in patients at risk for complications related to GA general anesthesia while also offering a cost benefit., Competing Interests: Conflicts of interest None to report., (Copyright © 2023 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Teopod1 (Tp1), Teopod2 (Tp2), and Early phase change (Epc) have profound effects on the timing of vegetative phase change in maize. Gain-of-function mutations in Tp1 and Tp2 delay all known phase-specific vegetative traits, whereas loss-of-function mutations in Epc accelerate vegetative phase change and cause shoot abortion in some genetic backgrounds. Here, we show that Tp1 and Tp2 likely represent cis-acting mutations that cause the overexpression of Zma-miR156j and Zma-miR156h, respectively. Epc is the maize ortholog of HASTY, an Arabidopsis gene that stabilizes miRNAs and promotes their intercellular movement. Consistent with its pleiotropic phenotype and epistatic interaction with Tp1 and Tp2, epc reduces the levels of miR156 and several other miRNAs., Competing Interests: Conflicts of interest statement The authors declare no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America.)

Importance: The Clinical Dementia Rating (CDR) is a well-validated instrument widely used to detect and stage dementia due to Alzheimer disease. The digital Electronic Clinical Dementia Rating (eCDR) can be remotely self-administered and automatically scored, with potential to facilitate efficient dementia screening and staging., Objective: To evaluate the association of the eCDR with the CDR and other in-clinic assessments for screening older adults for cognitive impairment., Design, Setting, and Participants: This multisite, cross-sectional study used baseline data from a longitudinal, observational study from 2020 to 2023, including up to 3 years of follow-up. Participants were enrolled from 3 Alzheimer Disease Research Centers and the Brain Health Registry. Participants (aged ≥55 years, with a study partner, and no acute or unstable major medical conditions) were recruited during in-clinic visits or by automated emails., Exposures: Participants completed the Uniform Data Set Version 3 (UDS; including the CDR) in supervised clinical research settings, and then completed the eCDR remotely, online and unsupervised, using their own device., Main Outcomes and Measures: The primary outcomes were eCDR scores (item; categorical box and global; continuous box and global), CDR scores (item; categorical box and global), and UDS assessment scores. Associations were evaluated using linear and logistic regressions., Results: A total of 3565 participants were contacted, and 288 were enrolled. Among 173 participants with item-level data (mean [SD] age, 70.84 [7.65] years; 76 women [43.9%]), eCDR to CDR concordance was 90% or higher for 33 items (63%) and 70% to 89% for 13 items (25%). Box (domain) level concordance ranged from 80% (memory) to 99% (personal care). The global score concordance rate was 81%. κ statistics were fair to moderate. Among 206 participants with box and global scores (mean [SD] age, 71.34 [7.68] years; 95 women [46.1%]), eCDR continuous global score was associated with CDR global (categorical) score with an area under the receiver operating characteristic curve of 0.79 (95% CI, 0.70-0.87). Correlations between eCDR and in-clinic UDS assessments were similar to those between CDR sum of box scores and the same in-clinic assessments., Conclusions and Relevance: These findings suggest that the eCDR is valid and has potential use for screening and assessment of older adults for cognitive and functional decline related to Alzheimer disease. Instrument optimization and validation in diverse cohorts in remote settings are crucial for evaluating scalability and eCDR utility in clinical research, trials, and health care settings.

Background: Availability of laboratory confirmation of sexually transmitted infections is increasing in low- and middle-income countries, but costs continue to limit their access. Chlamydia trachomatis (CT) is a sexually transmitted infection of significant clinical importance, particularly among women. This study aimed to develop a risk score to identify women with a higher likelihood of CT infection, who could then be prioritized for laboratory testing, in a population of Kenyan women planning pregnancies., Methods: Women with fertility intentions were included in this cross-sectional analysis. Logistic regression was used to estimate odds ratios for the association between demographic, medical, reproductive, and behavioral characteristics and the prevalence of CT infection. A risk score was developed and validated internally based on the regression coefficients in the final multivariable model., Results: The prevalence of CT was 7.4% (51 of 691). A risk score for predicting CT infection, with scores 0 to 6, was derived from participants' age, alcohol use, and presence of bacterial vaginosis. The prediction model yielded an area under the receiver operating curve of 0.78 (95% confidene interval [Cl], 0.72-0.84). A cutoff of ≤2 versus >2 identified 31.8% of women as higher risk with moderate sensitivity (70.6%; 95% Cl, 56.2-71.3) and specificity (71.3%; 95% Cl, 67.7-74.5). The bootstrap-corrected area under the receiver operating curve was 0.77 (95% Cl, 0.72-0.83)., Conclusions: In similar populations of women planning pregnancies, this type of risk score could be useful for prioritizing women for laboratory testing and would capture most women with CT infections while performing more costly testing in less than half of the population., Competing Interests: Conflict of Interest and Sources of Funding: The authors declare that they have o affiliations with or involvement in any organization or entity with any financial interest in the subject matter or materials discussed in this article. E.M.L.'s contributions to this study occurred while affiliated with the University of Washington; at the time of submission, E.M.L. was an employee of AbbVie, Inc, and holds stock or stock grants., (Copyright © 2023 American Sexually Transmitted Diseases Association. All rights reserved.)

There is strong evidence linking stimulant use, namely methamphetamine use, to sexual risk behavior among sexual minority men (SMM); we do not, however, have a good understanding of this relationship among other at-risk populations. In this study, we systematically reviewed associations between stimulant use (i.e., methamphetamine, crack cocaine, cocaine) and sexual risk behaviors among populations facing elevated risk of HIV transmission and acquisition (i.e., SMM, people who inject drugs (PWID), and people living with HIV/AIDS (PLWH)). Random-effects meta-analyses and sensitivity analyses that included crude and adjusted estimates separately were conducted to evaluate the impact of potential confounding variables. The results showed strong relationships between stimulant use and condomless sex, transactional sex, and multiple sexual partners. Results were broadly consistent when analyses were stratified by type of stimulant (methamphetamine, crack cocaine, and other stimulants) and risk group. Sensitivity analyses with confounding variables did not greatly impact results. The results indicate that stimulant use is associated with numerous sexual risk behaviors regardless of risk group, suggesting prevention efforts focused on reducing methamphetamine-related HIV risk should target a range of at-risk populations., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Corky root rot is an important disease in tomato production systems and is caused by Pseudopyrenochaeta terrestris and P. lycopersici (formerly Pyrenochaeta lycopersici Types 1 and 2, respectively). The corky root rot pathogens are slow growing and difficult to isolate and quantify in soil and plant tissue. A multiplex hydrolysis probe-based qPCR assay was designed to allow for simultaneous detection and quantification of P. lycopersici and P. terrestris with a competitive internal control to indicate if qPCR inhibitors are present. Single species and multiplex assays for Pseudopyrenochaeta spp. detected DNA levels above 0.013 pg of DNA per reaction. These highly specific assays had no nontarget amplification of other fungal and oomycete pathogens or rhizosphere-associated fungi of tomatoes that were tested. This assay can be used to quantify Pseudopyrenochaeta populations in roots and soils in tomato production systems to better determine the impacts of disease management strategies on Pseudopyrenochaeta spp. and provides a tool to study the biology of Pseudopyrenochaeta spp., Competing Interests: The author(s) declare no conflict of interest.

Introduction: Over the last 200 years, the "medic" has demonstrated its value at the point of injury care. Unfortunately, when medics leave military service with their medical skills, they have limited direct employment options available to them without added educational requirements. Fortunately, the Veterans Health Administration's (VHA) innovation of the Intermediate Care Technician (ICT) Program has a solution for that problem. This article will look at the Veterans Affairs' creation of the ICT Program, investigate its origins, evaluate where it is today through the lens of the WHO Task-Shifting Model for healthcare system implementation, and address the ICT Programs' potential for tomorrow., Materials and Methods: A descriptive, non-experimental research method design was used to collect and analyze the ICT Program's quantitative and qualitative data., Results: Through a decade of quality clinical care, Authority of Veteran Affairs Professionals to Practice Health Care Rule, and comparative evaluation of the WHO Task-Shifting Criteria, the ICT Program will bring incredible clinical value to VHA., Conclusion: The VHA ICT Program demonstrates to the U.S. Healthcare System a validated and reliable program to address healthcare worker shortages, reduce healthcare costs, increase access to care, and manage increasing demand for healthcare., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Immune responses differ between females and males, although such sex-based variance is incompletely understood. Observing that bacteremia of the opportunistic pathogen Burkholderia gladioli caused many more deaths of female than male mice bearing genetic deficiencies in adaptive immunity, we determined that this was associated with sex bias in the innate immune memory response called trained immunity. Female attenuation of trained immunity varies with estrous cycle stage and correlates with serum progesterone, a hormone that decreases glycolytic capacity and recall cytokine secretion induced by antigen non-specific stimuli. Progesterone receptor antagonism rescues female trained immune responses and survival from controlled B. gladioli infection to magnitudes similar to those of males. These data demonstrate progesterone-dependent sex bias in trained immunity where attenuation of female responses is associated with survival outcomes from opportunistic infection., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cutaneous lymphoproliferative disorders include cutaneous manifestations of systemic B-cell or T-cell lymphoma and primary cutaneous lymphomas. Primary cutaneous B-cell lymphomas are subcategorised into four groups: primary cutaneous marginal zone lymphoma (PCMZL), primary cutaneous follicle centre lymphoma, primary cutaneous diffuse large B-cell lymphoma, leg-type and EBV-positive mucocutaneous tumour. Each of these cutaneous lymphoproliferative disorders has unique clinical and pathological features necessitating biopsy and staging to establish proper treatment. We present a case of PCMZL manifesting as secondary chilblains of the toes that was diagnosed with punch skin biopsy. The patient's chilblains resolved with rituximab. This case underscores the importance of considering PCMZL and other cutaneous lymphoproliferative disorders in patients with dermatological manifestations and wounds refractory to first-line treatment., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The minimally invasive repair of pectus excavatum (PE) is a painful procedure that can result in long-term hospitalization and opioid use. To mitigate the length of stay and opioid consumption, many different analgesia strategies have been implemented. The aim of this study is to review the use and patient outcomes of intercostal nerve cryoablation (INC) during PE repair reported in the literature., Methods: An unfunded literature search using PubMed identifying articles discussing INC during PE repair from 1946 to 1 July 2023 was performed. Articles were included if they discussed patient outcomes with INC use during PE repair. Articles were excluded if they were reviews/meta-analyses, editorials, or not available in English. Each article was reviewed for bias by analyzing the study methods, data analysis, patient selection, and patient follow-up. Articles comparing outcomes of INC were considered significant if p -value was <0.05., Results: A total of 34 articles were included in this review that described INC use during pectus repair. Most supported a decreased hospital length of stay and opioid use with INC. Overall, INC was associated with fewer short-term and long-term complications. However, the researchers reported varied results of total hospital costs with the use of INC., Conclusion: The review was limited by a paucity of prospective studies and low number of patients who received INC. Despite this, the present data support INC as a safe and effective analgesic strategy during the repair of PE., Competing Interests: LM is an educational consultant for AtriCure. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Eldredge and McMahon.)

Background: Women's increased risk of HIV acquisition during pregnancy and postpartum may be mediated by changes in vaginal microbiota and/or cytokines., Methods: A cohort of 80 Kenyan women who were HIV-1 seronegative contributed 409 vaginal samples at 6 pregnancy time points: periconception, positive pregnancy test result, first trimester, second trimester, third trimester, and postpartum. Concentrations of vaginal bacteria linked with HIV risk and Lactobacillus spp were measured using quantitative polymerase chain reaction. Cytokines were measured by immunoassay., Results: Based on Tobit regression, later pregnancy time points were associated with lower concentrations of Sneathia spp (P = .01), Eggerthella sp type 1 (P = .002), and Parvimonas sp type 2 (P = .02) and higher concentrations of Lactobacillus iners (P < .001), Lactobacillus crispatus (P < .001), Lactobacillus vaginalis (P < .001), interleukin 6 (P < .001), TNF (P = .004), C-X-C motif chemokine ligand 10 (CXCL10; P < .001), C-C motif ligand 3 (P = .009), C-C motif ligand 4 (P < .001), C-C motif ligand 5 (P = .002), interleukin 1β (P = .02), and interleukin 8 (P = .002). Most cervicovaginal cytokines and vaginal bacteria clustered separately in principal component analysis, except for CXCL10, which did not group with either cytokines or bacteria. The shift toward a Lactobacillus-dominated microbiota during pregnancy mediated the relationship between pregnancy time point and CXCL10., Conclusions: Increases in proinflammatory cytokines, but not vaginal bacterial taxa linked with higher HIV risk, could provide an explanation for increased HIV susceptibility during pregnancy and postpartum., Competing Interests: Potential conflicts of interest. R. S. M. receives research funding, paid to the University of Washington, from Hologic Corporation. B. A. R. receives honoraria from Gilead for serving on data safety monitoring boards. D. N. F. and T. L. F. receive a royalty from BD. S. S. has received speaking honoraria from Lupin Pharmaceuticals. E. M. L.'s contributions to this study primarily occurred while affiliated with the University of Washington; at the time of submission, E. M. L. was an employee of AbbVie and holds stock or stock grants. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Investigation of neural circuits underlying visceral pain is hampered by the difficulty in achieving selective manipulations of individual circuit components. In this study, we adapted a dual AAV approach, used for projection-specific transgene expression in the CNS, to explore the potential for targeted delivery of transgenes to primary afferent neurons innervating visceral organs. Focusing on the extrinsic sensory innervation of the mouse colon, we first characterized the extent of dual transduction following intrathecal delivery of one AAV9 vector and intracolonic delivery of a second AAV9 vector. We found that if the two AAV9 vectors were delivered one week apart, dorsal root ganglion (DRG) neuron transduction by the second vector was greatly diminished. Following delivery of the two viruses on the same day, we observed colocalization of the transgenes in DRG neurons, indicating dual transduction. Next, we delivered intrathecally an AAV9 vector encoding the inhibitory chemogenetic actuator hM4D(Gi) in a Cre-recombinase dependent manner, and on the same day injected an AAV9 vector carrying Cre-recombinase in the colon. DRG expression of hM4D(Gi) was demonstrated at the mRNA and protein level. However, we were unable to demonstrate selective inhibition of visceral nociception following hM4D(Gi) activation. Taken together, these results establish a foundation for development of strategies for targeted transduction of primary afferent neurons for neuromodulation of peripheral neural circuits., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Gore, Esmail, Pflepsen, Marron Fernandez de Velasco, Kitto, Riedl, Karlen, McIvor, Honda, Fairbanks and Vulchanova.)

Extracorporeal membrane oxygenation (ECMO) is an invaluable resource in the treatment of critically ill children with cardiopulmonary failure.  To date, over 36,000 children have been placed on ECMO and the utilization of this life saving treatment continues to expand with advances in ECMO technology.  This article offers a review of pediatric ECMO including modes and sites of ECMO cannulation, indications and contraindications, and cannulation techniques.  Furthermore, it summarizes the basic principles of pediatric ECMO including circuit maintenance, nutritional support, and clinical decision making regarding weaning pediatric ECMO and decannulation.  Finally, it gives an overview of common pediatric ECMO complications including overall mortality and long-term outcomes of ECMO survivors. The goal of this article is to provide a comprehensive review for healthcare professionals providing care for pediatric ECMO patients., (Copyright © 2023. Published by Elsevier Inc.)

To understand the impact of COVID-19-related disruptions on PrEP services, we reviewed PrEP prescriptions at NYC Health + Hospitals/Bellevue from July 2019 through July 2021. PrEP prescriptions were examined as PrEP person-equivalents (PrEP PE) in order to account for the variable time of refill duration (i.e., 1-3 months). To assess "PrEP coverage", we calculated PrEP medication possession ratios (MPR) while patients were under study observation. Pre-clinic closure, mean PrEP PE = 244.2 (IQR 189.2, 287.5; median = 252.5) were observed. Across levels of clinic closures, mean PrEP PE = 247.3, (IQR 215.5, 265.4; median = 219.9) during 100% clinic closure, 255.4 (IQR 224, 284.3; median = 249.0) during 80% closure, and 274.6 (IQR 273.0, 281.0; median = 277.2) during 50% closure were observed. Among patients continuously prescribed PrEP pre-COVID-19, the mean MPR mean declined from 83% (IQR 72-100%; median = 100%) to 63% (IQR 35-97%; median = 66%) after the onset of COVID-19. For patients newly initiated on PrEP after the onset of COVID-19, the mean MPR was 73% (IQR 41-100%; median = 100%). Our ability to sustain PrEP provisions, as measured by both PrEP PE and MPR, can likely be attributed to our pre-COVID-19 system for PrEP delivery, which emphasizes navigation, same-day initiation, and primary care integration. In the era of COVID-19 as well as future unforeseen healthcare disruptions, PrEP programs must be robust and flexible in order to sustain PrEP delivery., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Minimally invasive repair of pectus excavatum (MIRPE) and cartilaginous rib excision (CRE) for slipping rib syndrome (SRS) are painful procedures. Intercostal nerve cryoablation (Cryo) controls pain and decreases opioid use in MIRPE. Herein, we describe our experience with cryoablation in CRE., Methods: A retrospective chart review was performed of all patients undergoing CRE between 2018 and 2022. Data on demographics, clinical characteristics, operative details, and hospital course were collected., Results: A total of 98 patients underwent CRE: 68 CRE without cryo, 22 CRE + Cryo, and 8 combined MIRPE + CRE + Cryo. Ninety percent of patients underwent bioabsorbable rib plating. Patients were predominantly female (79%, 73%, 50% respectively) with median ages 17.6, 16.9, and 14.2 years respectively. CRE + Cryo patients used significantly less opioids in hospital (0.6 OME/kg [0.1,1.2]) compared to CRE without cryo (1.0 OME/kg [0.6,2.1]), p < 0.05. The median length of stay (LOS) in CRE + Cryo was 1 day [1,2] compared to 2 days in CRE without cryo [1,2], p = 0.09. MIRPE + CRE + Cryo patients used 0.6 OME/kg [0.2,8.0] with a 2 day [1,5.5] LOS. Ninety-one percent of Cryo patients had cryoablation of T9 and/or T10 intercostal nerves, with no documented abdominal wall laxity at median follow-up of 16 days. Cryo was applied extra-thoracically in CRE + cryo without thoracoscopy or lung isolation, while MIRPE + CRE + Cryo used a combination extra-/intra-thoracic cryoablation in with thoracoscopy., Conclusion: Intercostal nerve cryoablation reduces opioid use and LOS in patients undergoing cartilaginous rib excision for slipping rib syndrome. Cryotherapy to as low as T10 did not result in abdominal wall laxity and can be applied extra-thoracically without the need for thoracoscopy. Ongoing prospective studies are required to assess the long-term outcomes., Level of Evidence: III., (Copyright © 2023 Elsevier Inc. All rights reserved.)

For women living with HIV (WLH) in serodiscordant partnerships, decisions about childbearing can challenge condom use and antiretroviral adherence. In a prospective cohort of 148 WLH in serodiscordant partnerships, 58 (39%) wanted more children in the future but were not currently trying to conceive (fertility desire), and 32 (22%) were currently trying to become pregnant (fertility intent). Detection of prostate specific antigen (PSA) in vaginal secretions, a marker for recent condomless sex, was lowest in women with fertility desire and highest in women with fertility intent. Detectable viral load followed a similar pattern. Risk of HIV transmission, when condomless sex and PSA detection occurred concurrently, was three to fourfold higher at visits with fertility intent compared to visits with fertility desire. Qualitative interviews underscored the importance women place on childbearing and suggested that they had limited information about the role of antiretroviral therapy in reducing sexual HIV transmission., (© 2023. The Author(s).)

Objectives: Cardiac surgery using cardiopulmonary bypass contributes to a robust systemic inflammatory process. Local intrapericardial postsurgical inflammation is believed to trigger important clinical implications, such as postoperative atrial fibrillation and postsurgical intrathoracic adhesions. Immune mediators in the pericardial space may underlie such complications., Methods: In this prospective pilot clinical study, 12 patients undergoing isolated coronary artery bypass graft surgery were enrolled. Native pericardial fluid and venous blood samples (baseline) were collected immediately after pericardiotomy. Postoperative pericardial fluid and venous blood samples were collected 48-hours after cardiopulmonary bypass and compared with baseline. Flow cytometry determined proportions of specific immune cells, whereas multiplex analysis probed for inflammatory mediators., Results: Neutrophils are the predominant cells in both the pericardial space and peripheral blood postoperatively. There are significantly more CD163 lo macrophages in blood compared with pericardial effluent after surgery. Although there are significantly more CD163 hi macrophages in native pericardial fluid compared with baseline blood, after surgery there are significantly fewer of these cells present in the pericardial space compared with blood. Postoperatively, concentration of interleukin receptor antagonist 6, and interleukin 8 were significantly higher in the pericardial space compared with blood. After surgery, compared with blood, the pericardial space has a significantly higher concentration of matrix metalloproteinase 3, matrix metalloproteinase 8, and matrix metalloproteinase 9. The same trend was observed with transformational growth factor β., Conclusions: Cardiac surgery elicits an inflammatory response in the pericardial space, which differs from systemic inflammatory responses. Future work should determine whether or not this distinct local inflammatory response contributes to postsurgical complications and could be modified to influence clinical outcomes., (© 2023 The Author(s).)

Objective: The objective is to describe the initial Canadian experience using novel aortic arch branched endograft technologies., Methods: We performed a retrospective consecutive case series of all patients undergoing aortic arch branched repair with newly available endograft technology since 2020 at our site. We describe the patient characteristics, treatment characteristics, and postoperative outcomes., Results: Eleven patients received arch branched endografts, indicated for penetrating aortic ulcer in seven patients (64%), arch degeneration after prior aortic dissection repair in three (27%), and acute aortobronchial fistula in one patient (9%). Their average age was 72 ± 7 years. Complete arch repair from zone 0 to 4 was performed in six cases (55%); the remaining repairs landed proximally in zones 1 or 2. Seven repairs used a single retrograde facing inner branch (thoracic branch endoprosthesis; W.L. Gore & Associates), three used double antegrade inner branch (Bolton Relay; Terumo Interventional Systems), and one emergent case used double in situ fenestrations. Seven repairs (64%) used an adjunctive extra-anatomic bypass to complete great vessel perfusion, two of which were created during a prior aortic repair. Inferior vena cava balloon inflow occlusion during deployment was used in all cases. No mortalities, transient or permanent spinal cord paralysis, myocardial infarction, dialysis dependence, venous thromboembolism, or bleeding requiring reintervention occurred. No patient undergoing elective arch branch repair experienced a stroke. The one patient undergoing emergent repair did suffer a stroke. The median length of stay was 5 days (interquartile range, 2-8 days). Two endoleaks developed: a type Ia endoleak successfully treated with a Palmaz stent (Cordis) during the index admission, and a type II endoleak with ongoing sac regression on postoperative follow-up. Postoperatively, one patient suffered a suspected aortic graft infection that was treated with lifelong antibiotics. During a mean radiographic follow-up of 7.2 months, no cases of branch vessel instability (ie, no migration, reintervention, arterial rupture, intraluminal thrombus, occlusion, stenosis, or kinking of the branch grafts) developed. Three patients experienced sac regression of >5 mm, and no patient experienced continued postoperative dilation., Conclusions: To the best of our knowledge, this is the largest reported Canadian volume of aortic arch repair using novel branched or fenestrated technology. The series demonstrates that a multidisciplinary program and properly selected patients can yield excellent results using endovascular repair for complex aortic arch pathology., (© 2023 The Authors.)