Liposuction as a Treatment for Lipedema: A Scoping Review.

Background: Lipedema is the progressive symmetrical deposition of subcutaneous fat and fluid in the lower body, ordinarily sparing the trunk, upper limbs, face, and neck. It may follow an autosomal dominant inheritance pattern. The gold standard treatment for lipedema is complete decongestive therapy, consisting of manual lymphatic drainage and compression garments. This scoping review assessed the existing literature on the effectiveness of liposuction as an alternative treatment for lipedema. Methods: A scoping review of electronically available literature within PubMed, Scopus, and Cochrane focused on liposuction as a treatment for lipedema considering the following inclusion criteria: human studies, case series of 10 or more, controlled trials, randomized controlled trials, patient-reported outcome measurement studies, survey analyses, descriptive studies, retrospective analyses, recurrence included, follow-up of 6 months or more, age 18 years or older, and treatment modality being liposuction. Results: Thirteen studies were selected. Nine studies reported decreased compression therapy use among patients following liposuction. No studies reported a long-term increase in compression therapy following liposuction. Studies found self-reported improvements in pain, mobility, bruising, and overall quality of life for patients following liposuction, many of whom had previously been on compressive therapy. Studies reported low rates of serious adverse events following liposuction, including deep vein thrombosis, pulmonary embolism, and infection. Conclusions: These results suggest that liposuction can be a viable treatment alternative to compression therapy for lipedema in patients whose compression therapy has not been helpful. However, there is not enough evidence to say whether liposuction is as effective as compression for patients first presenting with lipedema.

Gut colonization with multidrug resistant organisms in the intensive care unit: a systematic review and meta-analysis.

BACKGROUND: Gut colonization with multidrug-resistant organisms (MDRO) frequently precedes infection among patients in the intensive care unit (ICU), although the dynamics of colonization are not completely understood. We performed a systematic review and meta-analysis of ICU studies which described the cumulative incidence and rates of MDRO gut acquisition. METHODS: We systematically searched PubMed, Embase, and Web of Science for studies published from 2010 to 2023 reporting on gut acquisition of MDRO in the ICU. MDRO were defined as multidrug resistant non-Pseudomonas Gram-negative bacteria (NP-GN), Pseudomonas spp., and vancomycin-resistant Enterococcus (VRE). We included observational studies which obtained perianal or rectal swabs at ICU admission (within 48 h) and at one or more subsequent timepoints. Our primary outcome was the incidence rate of gut acquisition of MDRO, defined as any MDRO newly detected after ICU admission (i.e., not present at baseline) for all patient-time at risk. The study was registered with PROSPERO, CRD42023481569. RESULTS: Of 482 studies initially identified, 14 studies with 37,305 patients met criteria for inclusion. The pooled incidence of gut acquisition of MDRO during ICU hospitalization was 5% (range: 1-43%) with a pooled incidence rate of 12.2 (95% CI 8.1-18.6) per 1000 patient-days. Median time to acquisition ranged from 4 to 26 days after ICU admission. Results were similar for NP-GN and Pseudomonas spp., with insufficient data to assess VRE. Among six studies which provided sufficient data to perform curve fitting, there was a quasi-linear increase in gut MDRO colonization of 1.41% per day which was stable through 30 days of ICU hospitalization (R2 = 0.50, p < 0.01). CONCLUSIONS: Acquisition of gut MDRO was common in the ICU and increases with days spent in ICU through 30 days of follow-up. These data may guide future interventions seeking to prevent gut acquisition of MDRO in the ICU.

Attitudes, Knowledge, and Risk Perceptions of Patients who Received Elective Genomic Testing as a Clinical Service.

BACKGROUND: Elective genomic testing (EGT) is increasingly available clinically. Limited real world evidence exists about attitudes and knowledge of EGT recipients. METHODS: After web-based education, patients who enrolled in an EGT program at a rural nonprofit healthcare system completed a survey that assessed attitudes, knowledge, and risk perceptions. RESULTS: From August 2020 to April 2022, 5,920 patients completed the survey and received testing. Patients most frequently cited interest in learning their personal disease risks as their primary motivation. Patients most often expected results to guide medication management (74.0%), prevent future disease (70.4%), and provide information about risks to offspring (65.4%). Patients were "very concerned" most frequently about the privacy of genetic information (19.8%) and how well testing predicted disease risks (18.0%). On average, patients answered 6.7 of 11 knowledge items correctly (61.3%). They more often rated their risks for colon and breast cancers as lower rather than higher than the average person, but more often rated their risk for a heart attack as higher rather than lower than the average person (all p<0.001). CONCLUSION: Patients pursued EGT because of the utility expectations, but often misunderstood the test's capabilities.

The DNA methyltransferase inhibitor 5-aza-4'-thio-2'-deoxycytidine induces C>G transversions and acute lymphoid leukemia development.

DNA methyltransferase inhibitors (DNMTi), most commonly cytidine analogs, are compounds that decrease 5'-cytosine methylation. DNMTi are used clinically based on the hypothesis that cytosine demethylation will lead to re-expression of tumor suppressor genes. 5-Aza-4'-thio-2'-deoxycytidine (Aza TdCyd or ATC) is a recently described thiol substituted DNMTi that has been shown to have anti-tumor activity in solid tumor models. Here, we investigated the therapeutic potential of ATC in a murine transplantation model of myelodysplastic syndrome. ATC treatment led to transformation of transplanted wild-type bone marrow nucleated cells into lymphoid leukemia, and healthy mice treated with ATC also developed lymphoid leukemia. Whole exome sequencing revealed thousands of acquired mutations, almost all of which were C>G transversions in a specific 5'-NCG-3' context. These mutations involved dozens of genes involved in human lymphoid leukemia, such as Notch1, Pten, Pax5, Trp53, and Nf1. Human cells treated in vitro with ATC showed thousands of acquired C>G transversions in a similar context. Deletion of Dck, the rate-limiting enzyme for the cytidine salvage pathway, eliminated C>G transversions. Taken together, these findings demonstrate a highly penetrant mutagenic and leukemogenic phenotype associated with ATC.

Assessing the impact of extracellular matrix fiber orientation on breast cancer cellular metabolism.

The extracellular matrix (ECM) is a dynamic and complex microenvironment that modulates cell behavior and cell fate. Changes in ECM composition and architecture have been correlated with development, differentiation, and disease progression in various pathologies, including breast cancer [1]. Studies have shown that aligned fibers drive a pro-metastatic microenvironment, promoting the transformation of mammary epithelial cells into invasive ductal carcinoma via the epithelial-to-mesenchymal transition (EMT) [2]. The impact of ECM orientation on breast cancer metabolism, however, is largely unknown. Here, we employ two non-invasive imaging techniques, fluorescence-lifetime imaging microscopy (FLIM) and intensity-based multiphoton microscopy, to assess the metabolic states of cancer cells cultured on ECM-mimicking nanofibers in a random and aligned orientation. By tracking the changes in the intrinsic fluorescence of nicotinamide adenine dinucleotide and flavin adenine dinucleotide, as well as expression levels of metastatic markers, we reveal how ECM fiber orientation alters cancer metabolism and EMT progression. Our study indicates that aligned cellular microenvironments play a key role in promoting metastatic phenotypes of breast cancer as evidenced by a more glycolytic metabolic signature on nanofiber scaffolds of aligned orientation compared to scaffolds of random orientation. This finding is particularly relevant for subsets of breast cancer marked by high levels of collagen remodeling (e.g. pregnancy associated breast cancer), and may serve as a platform for predicting clinical outcomes within these subsets [3-6].

Metaplastic neuromodulation via transcranial direct current stimulation has no effect on corticospinal excitability and neuromuscular fatigue.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation tool with potential for managing neuromuscular fatigue, possibly due to alterations in corticospinal excitability. However, inconsistencies in intra- and inter- individual variability responsiveness to tDCS limit its clinical use. Emerging evidence suggests harnessing homeostatic metaplasticity induced via tDCS may reduce variability and boost its outcomes, yet little is known regarding its influence on neuromuscular fatigue in healthy adults. We explored whether cathodal tDCS (ctDCS) prior to exercise combined with anodal tDCS (atDCS) could augment corticospinal excitability and attenuate neuromuscular fatigue. 15 young healthy adults (6 males, 22 ± 4 years) participated in four pseudo-randomised neuromodulation sessions: sham stimulation prior and during exercise, sham stimulation prior and atDCS during exercise, ctDCS prior and atDCS during exercise, ctDCS prior and sham stimulation during exercise. The exercise constituted an intermittent maximal voluntary contraction (MVC) of the right first dorsal interosseous (FDI) for 10 min. Neuromuscular fatigue was quantified as an attenuation in MVC force, while motor evoked potential (MEP) amplitude provided an assessment of corticospinal excitability. MEP amplitude increased during the fatiguing exercise, whilst across time, force decreased. There were no differences in MEP amplitudes or force between neuromodulation sessions. These outcomes highlight the ambiguity of harnessing metaplasticity to ameliorate neuromuscular fatigue in young healthy individuals.

Normal Ovarian Function in Subfertile Mouse with Amhr2-Cre-Driven Ablation of Insr and Igf1r.

Insulin receptor signaling promotes cell differentiation, proliferation, and growth which are essential for oocyte maturation, embryo implantation, endometrial decidualization, and placentation. The dysregulation of insulin signaling in women with metabolic syndromes including diabetes exhibits poor pregnancy outcomes that are poorly understood. We utilized the Cre/LoxP system to target the tissue-specific conditional ablation of insulin receptor (Insr) and insulin-like growth factor-1 receptor (Igf1r) using an anti-Mullerian hormone receptor 2 (Amhr2) Cre-driver which is active in ovarian granulosa and uterine stromal cells. Our long-term goal is to examine insulin-dependent molecular mechanisms that underlie diabetic pregnancy complications, and our conditional knockout models allow for such investigation without confounding effects of ligand identity, source and cross-reactivity, or global metabolic status within dams. Puberty occurred with normal timing in all conditional knockout models. Estrous cycles progressed normally in Insrd/d females but were briefly stalled in diestrus in Igf1rd/d and double receptor (DKO) mice. The expression of vital ovulatory genes (Lhcgr, Pgr, Ptgs2) was not significantly different in 12 h post-hCG superovulated ovaries in knockout mice. Antral follicles exhibited an elevated apoptosis of granulosa cells in Igf1rd/d and DKO mice. However, the distribution of ovarian follicle subtypes and subsequent ovulations was normal in all insulin receptor mutants compared to littermate controls. While ovulation was normal, all knockout lines were subfertile suggesting that the loss of insulin receptor signaling in the uterine stroma elicits implantation and decidualization defects responsible for subfertility in Amhr2-Cre-derived insulin receptor mutants.

Disparities in Stress Exposure and Later-Life Disability.

Background and Objectives: Drawing from cumulative inequality theory and the weathering hypothesis, this study examined the relationship between life-course stress exposure (measured cumulatively and by domains) and the onset of disability in later life among White, Black, U.S.-born Hispanic, and foreign-born Hispanic older adults. Research Design and Methods: Cross-sectional and longitudinal models were estimated using nationally representative data from the Health and Retirement Study (N = 11,483). We used logistic regression models to examine associations between stress exposure and Wave 1 disability (i.e., occurrence), and Weibull-accelerated failure-time models to examine the relationship between stress exposure and age of onset of disability 12-14 years later (i.e., incidence). We tested for moderation between stress and disability by race, ethnicity, and Hispanic nativity. Results: At Wave 1, higher odds of disability occurrence were associated with cumulative stress burden (CSB; odds ratio [OR] = 4.93, 95% confidence interval [CI]: 2.95-8.23). In a model specifying domains of stressors, disability occurrence was associated with childhood financial strain (OR = 1.22, CI: 1.01-1.46), lifetime traumatic events (OR = 1.92, CI: 1.41-2.62), neighborhood disadvantage (OR = 1.32, CI: 1.01-1.73), and major lifetime discrimination (OR = 1.64, CI: 1.12-2.41). Over time, earlier onset of disability was associated with CSB (ß = -0.39), childhood traumatic events (ß = -0.16), adult financial strain (ß = -0.17), everyday discrimination (ß = -0.15), and major lifetime discrimination (ß = -0.13). The effect of childhood traumatic events on the transition to disability was stronger for U.S.-born Hispanic adults than White adults (occurring 33% earlier). Discussion and Implications: To reduce racial, ethnic, and nativity disparities in disability, it is important to consider the historical and structural disadvantages associated with stress exposure across the life course. It is also important to acknowledge that nativity influences stratification processes associated with disparities in racial and ethnic health trajectories.

Familial communication and cascade testing following elective genomic testing.

Familial communication of results and cascade genetic testing (CGT) can extend the benefits of genetic screening beyond the patient to their at-risk relatives. While an increasing number of health systems are offering genetic screening as an elective clinical service, data are limited about how often results are shared and how often results lead to CGT. From 2018 to 2022, the Sanford Health system offered the Sanford Chip, an elective genomic test that included screening for medically actionable predispositions for disease recommended by the American College of Medical Genetics and Genomics for secondary findings disclosure, to its adult primary care patients. We analyzed patient-reported data about familial sharing of results and CGT among patients who received Sanford Chip results at least 1 year previously. Among the patients identified with medically actionable predispositions, 94.6% (53/56) reported disclosing their result to at least one family member, compared with 46.7% (423/906) of patients with uninformative findings (p < 0.001). Of the patients with actionable predispositions, 52.2% (12/23) with a monogenic disease risk and 12.1% (4/33) with a carrier status reported that their relatives underwent CGT. Results suggest that while the identification of monogenic risk during elective genomic testing motivates CGT in many at-risk relatives, there remain untested at-risk relatives who may benefit from future CGT. Findings identify an area that may benefit from increased genetic counseling and the development of tools and resources to encourage CGT for family members.

Nasolacrimal duct obstruction prevalence is 0.3% among alpacas evaluated with ophthalmic disease at a veterinary teaching hospital between 2000 and 2023.

OBJECTIVE: To examine the prevalence of nasolacrimal duct (NLD) obstruction in hospital populations and assess signalment, diagnostics, and clinical approaches for alpacas and llamas diagnosed with NLD atresia or obstruction. ANIMALS: 29 alpacas and 2 llamas. CLINICAL PRESENTATION: Medical records were reviewed to identify camelids with NLD evaluated between 2000 and 2023. Signalment, history, physical examination data, diagnosis, and treatments were recorded. Follow-up information was gathered via phone and email questionnaire. Data were evaluated to determine prevalence and describe signalment and treatments for NLD disease. RESULTS: 31 camelids met the inclusion criteria. A total of 8,027 alpacas and 1,998 llamas were seen within the study period at 1 teaching institution. The prevalence of NLD obstruction for this population of alpacas was 0.3% (26/8,027). Nineteen of 31 (61%) camelids presented at 1 year of age or younger. The most common physical exam finding was ocular discharge (68%). The most common diagnosis was NLD atresia (16/31 [51%]). Patency was established by surgical opening or lavage of the NLD. Long-term follow-up was available for 13 alpacas and 2 llamas, of which 11 (73%) had successful outcomes. CLINICAL RELEVANCE: Results indicate that NLD obstruction is a condition that most commonly affects alpacas < 1 year of age and is associated with a good prognosis for treatment success.

The long-term impact of cerebellar tumor resection on executive functioning, anxiety, and fear of pain: A mixed methodology pilot study.

This pilot study investigated the long-term impact of a surgery-only treatment (no exposure to other treatments, such as chemotherapy and radiation) for pediatric cerebellar low-grade gliomas on executive function, anxiety, and fear of pain (FOP) beliefs. Twelve patients who underwent surgical glioma resection during childhood (surgery age was 4-16 years, study visit age was 10-28 years), and 12 pain-free controls matched for age, sex, race, and handedness were tested. The spatial extent of resection was precisely mapped using magnetic resonance imaging (MRI). Executive function, anxiety, and FOP were assessed using validated self-report age-appropriate questionnaires for children and adults. Structured clinical interviews at a post-surgery follow-up visit were completed (average: 89 months, range: 20-99). No significant differences in FOP (FOPQ-C t[14 = 1.81, p = 0.09; FOPQ-III t[4] = 0.29, p = 0.79), executive function scores (BRIEF t[20] = 0.30, p = 0.28), or anxiety scores (MASC t[16] = 0.19, p = 0.85; MAQ t[4] = 1.80, p = 0.15) were found in pediatric or adult patients compared to pain-free controls. Clinical interviews mainly categorized pediatric patients as not anxious. One participant reported mild/subclinical anxiety, and one had moderate clinical anxiety. Neither psychologists nor patients endorsed impairments to executive functioning, anxiety, or FOP. Our pilot results suggest that pediatric cerebellar tumor survivors treated with surgery-only have favorable long-term functioning related to these themes. While these results are promising, they will need to be replicated in a larger patient sample.

Educational Inequalities in Dual-Function Life Expectancy.

OBJECTIVES: This study investigates educational inequalities in dual functionality, a new concept that captures a combination of physical and cognitive functioning, both of which are important for independent living and quality of life. METHODS: Using data from the Health and Retirement Study and the National Health Interview Survey Linked Mortality Files, we define a measure of dual functionality based on the absence of limitations in activities of daily living and dementia. We estimate age-graded dual-function rates among adults 65+ and age-65 dual-function life expectancy across levels of education stratified by gender. RESULTS: In their mid-60s, 67% of women with less than a high school degree manifest dual functionality as compared with over 90% of women with at least a 4-year college degree. A similar pattern holds among men. These education-based gaps in dual functionality remain across later life, even as dual-function rates decline at older ages. Lower dual-function rates among older adults with less education translate into inequalities of 6.7 and 7.3 years in age-65 dual-function life expectancy between men and women, respectively, with at least a 4-year college degree compared to their counterparts with less than a high school degree. DISCUSSION: Older adults, particularly women, with less than a high school degree are estimated to live a smaller percentage of their remaining years with dual functionality compared with older adults with at least a college degree. These inequalities have implications for the distribution of caregiving resources of individuals, family members, and the broader healthcare community.

Evasion of NKG2D-mediated cytotoxic immunity by sarbecoviruses.

SARS-CoV-2 and other sarbecoviruses continue to threaten humanity, highlighting the need to characterize common mechanisms of viral immune evasion for pandemic preparedness. Cytotoxic lymphocytes are vital for antiviral immunity and express NKG2D, an activating receptor conserved among mammals that recognizes infection-induced stress ligands (e.g., MIC-A/B). We found that SARS-CoV-2 evades NKG2D recognition by surface downregulation of MIC-A/B via shedding, observed in human lung tissue and COVID-19 patient serum. Systematic testing of SARS-CoV-2 proteins revealed that ORF6, an accessory protein uniquely conserved among sarbecoviruses, was responsible for MIC-A/B downregulation via shedding. Further investigation demonstrated that natural killer (NK) cells efficiently killed SARS-CoV-2-infected cells and limited viral spread. However, inhibition of MIC-A/B shedding with a monoclonal antibody, 7C6, further enhanced NK-cell activity toward SARS-CoV-2-infected cells. Our findings unveil a strategy employed by SARS-CoV-2 to evade cytotoxic immunity, identify the culprit immunevasin shared among sarbecoviruses, and suggest a potential novel antiviral immunotherapy.

Toward Development of a Novel Proprioceptive Trail-Making Test: Comparing Healthy Dancers and Non-Dancers.

There is a pressing need for ecologically valid versions of traditional neuropsychological tests indexing executive function (EF), such as the Trail-Making Task (TMT), that incorporate movement and bodily awareness in healthy participants with varying abilities. We designed a proprioceptive version of the TMT (pTMT) that involved coordinated gross motor movement and proprioceptive awareness to investigate whether this measure of visual attention, task switching, and working memory positively correlated with a computerized version of the TMT (the dTMT). We aimed to establish the initial validity of our proprioceptive TMT (pTMT) by comparing performances on the dTMT and pTMT among a cohort of 36 healthy participants (18 dancers, 18 non-dancers; M age = 22, SD = 5.27; 64% female) anticipating that dancers would express higher intrinsic bodily awareness than non-dancers. Results revealed a mild to moderate but statistically significant positive correlation between dTMT and pTMT completion times [part A: r (36) = .33, p = .04; part B: r (36) = .37, p = .03] and numbers of errors [part B: r (36) = .41, p = .01] across both participant groups. These data suggest partial measurement convergence between these two TMT versions. Relative to non-dancers, dancers exhibited a higher level of performance (likely due to their better proprioceptive ability) through their faster completion times on dTMT-B [t (34) = 3.81, p = .006, d = 1.27] and pTMT-B [t (34) = 2.97, p = .005, d = .99], and their fewer errors on dTMT-B [t (34) = 2.93, p = .006, d = 1.0]. By identifying cognitive differences between these different groups of healthy individuals, our data contribute to both a theoretical understanding and the initial development of gross motor movement-based cognitive assessments, providing a path toward the further refinement of an ecologically valid full-body TMT.

Would You Rather: Quantifying Traumatic Brain Injury Survivor Perceptions of Functional Status Through Their Surrogates.

OBJECTIVE: To quantify health utilities of the Glasgow Outcome Scale-Extended (GOSE) states after actual traumatic brain injury (TBI). BACKGROUND: Recovery after TBI is measured using the GOSE, a validated clinical trial endpoint. A recent public survey quantified the health utilities of some GOSE states after hypothetical TBI as worse than death. However, no health utilities exist for disability after actual TBI. METHODS: This national computer-adaptive survey followed Enhancing the Quality and Transparency of Health Research-Checklist for Reporting Results of Internet E-Surveys guidelines and recruited adult TBI survivors (injury >1 year prior) through their available surrogates. Using a standard gamble approach in randomized order, participants gave preferences for post-TBI categorical health states ranging from GOSE 2 to GOSE 8. We calculated median (interquartile range) health utilities for each GOSE state, from -1 (worse than death) to 1 (full health), with 0 as reference (death, GOSE 1). RESULTS: Of 515 eligible, 298 surrogates (58%) consented and completed the scenarios on TBI survivors' behalf. TBI survivors had a current median GOSE 5 (3-7). GOSE 2, GOSE 3, and GOSE 4 were rated worse than death by 89%, 64%, and 38%, respectively. The relationship was nonlinear, and intervals were unequal between states, with a bimodal distribution for GOSE 4. CONCLUSIONS: In this index study of actual post-TBI disability, poor neurological outcomes represented by GOSE 2 to GOSE 4 were perceived as worse than death by at least one in 3 survivors. Similar to previously reported public perceptions after a hypothetical TBI, these long-term perceptions may inform earlier post-TBI shared decision-making, as well as help shape value-based research and quality of care. LEVEL OF EVIDENCE: Level II-economic and value-based evaluations.

Clinical impact of preemptive pharmacogenomic testing on antiplatelet therapy in a real-world setting.

CYP2C19 genotyping to guide antiplatelet therapy after patients develop acute coronary syndromes (ACS) or require percutaneous coronary interventions (PCIs) reduces the likelihood of major adverse cardiovascular events (MACE). Evidence about the impact of preemptive testing, where genotyping occurs while patients are healthy, is lacking. In patients initiating antiplatelet therapy for ACS or PCI, we compared medical records data from 67 patients who received CYP2C19 genotyping preemptively (results >7 days before need), against medical records data from 67 propensity score-matched patients who received early genotyping (results within 7 days of need). We also examined data from 140 patients who received late genotyping (results >7 days after need). We compared the impact of genotyping approaches on medication selections, specialty visits, MACE and bleeding events over 1 year. Patients with CYP2C19 loss-of-function alleles were less likely to be initiated on clopidogrel if they received preemptive rather than early or late genotyping (18.2%, 66.7%, and 73.2% respectively, p = 0.001). No differences were observed by genotyping approach in the number of specialty visits or likelihood of MACE or bleeding events (all p > 0.21). Preemptive genotyping had a strong impact on initial antiplatelet selection and a comparable impact on patient outcomes and healthcare utilization, compared to genotyping ordered after a need for antiplatelet therapy had been identified.

The Internet is a scary place: How does evidence source and examinee race or ethnicity influence determinations of threat?

Violent rhetoric online is becoming increasingly relevant to the practice of forensic mental health assessment as examinee's virtual lives may transform into real-world acts of violence. With the rise of a diverse subculture of violent online communities, the aim of the present study was to inform how concerns with online sources of collateral data and racial/ethnic biases may influence determinations of violence potential. Using an experimental design, jury-eligible participants (N = 278) and forensic mental health experts (N = 78) were presented with mock Twitter (now referred to as X) posts that varied by data source (i.e., how information was accessed) and the examinee's race/ethnicity. Results showed no differences in participants' ratings of data credibility, how much weight they would place on the posts in a threat assessment, or how likely the examinee was to act violently against his intended target. Implications regarding the interpretation of social media evidence, relevant limitations, and future research are discussed.

JAK/STAT defects and immune dysregulation, and guiding therapeutic choices.

Inborn errors of immunity (IEIs) encompass a diverse spectrum of genetic disorders that disrupt the intricate mechanisms of the immune system, leading to a variety of clinical manifestations. Traditionally associated with an increased susceptibility to recurrent infections, IEIs have unveiled a broader clinical landscape, encompassing immune dysregulation disorders characterized by autoimmunity, severe allergy, lymphoproliferation, and even malignancy. This review delves into the intricate interplay between IEIs and the JAK-STAT signaling pathway, a critical regulator of immune homeostasis. Mutations within this pathway can lead to a wide array of clinical presentations, even within the same gene. This heterogeneity poses a significant challenge, necessitating individually tailored therapeutic approaches to effectively manage the diverse manifestations of these disorders. Additionally, JAK-STAT pathway defects can lead to simultaneous susceptibility to both infection and immune dysregulation. JAK inhibitors, with their ability to suppress JAK-STAT signaling, have emerged as powerful tools in controlling immune dysregulation. However, questions remain regarding the optimal selection and dosing regimens for each specific condition. Hematopoietic stem cell transplantation (HSCT) holds promise as a curative therapy for many JAK-STAT pathway disorders, but this procedure carries significant risks. The use of JAK inhibitors as a bridge to HSCT has been proposed as a potential strategy to mitigate these risks.

Regenerating murine CD8+ lung tissue resident memory T cells after targeted radiation exposure.

Radiation exposure occurs during medical procedures, nuclear accidents, or spaceflight, making effective medical countermeasures a public health priority. Naïve T cells are highly sensitive to radiation-induced depletion, although their numbers recover with time. Circulating memory CD8+ T cells are also depleted by radiation; however, their numbers do not recover. Critically, the impact of radiation exposure on tissue-resident memory T cells (TRM) remains unknown. Here, we found that sublethal thorax-targeted radiation resulted in the rapid and prolonged numerical decline of influenza A virus (IAV)-specific lung TRM in mice, but no decline in antigen-matched circulating memory T cells. Prolonged loss of lung TRM was associated with decreased heterosubtypic immunity. Importantly, boosting with IAV-epitope expressing pathogens that replicate in the lungs or peripheral tissues or with a peripherally administered mRNA vaccine regenerated lung TRM that was derived largely from circulating memory CD8+ T cells. Designing effective vaccination strategies to regenerate TRM will be important in combating the immunological effects of radiation exposure.