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[This corrects the article DOI: 10.3389/fped.2022.750126.].
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William Halsted wrote to aging surgeon, Stephen Smith, in 1919, that he remembered the lessons Smith had taught him, "when I walked with you through the wards of Bellevue Hospital." Smith was an early advocate of Joseph Lister's antiseptic method, and because of his public health work, he was also an early advocate of environmental hygiene and microbial control based on the unproved germ theory. While Lister's work at the time emphasized germ-killing around the operative site with carbolic acid (antisepsis), Smith adopted and encouraged surgical practices at Bellevue that would be hallmarks of the germ-preventing (asepsis) surgical approach that fully developed after German bacteriologic discoveries in the mid-1880s, and with which Halsted is historically identified. Some physicians and historians have emphasized temporal and conceptual differences between Lister's antisepsis and German asepsis, but Smith and Halsted's experiences argue that surgical asepsis was the evolutionary outcome of germ theory-based surgical changes that began well before scientific proof arrived.
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Importance: Choosing Wisely recommendations advocate against routine use of axillary staging in older women with early-stage, clinically node-negative (cN0), hormone receptor-positive (HR+), and HER2-negative breast cancer. However, rates of sentinel lymph node biopsy (SLNB) in this population remain persistently high. Objective: To evaluate whether an electronic health record (EHR)-based nudge intervention targeting surgeons in their first outpatient visit with patients meeting Choosing Wisely criteria decreases rates of SLNB. Design, Setting, and Participants: This nonrandomized controlled trial was a hybrid type 1 effectiveness-implementation study with subsequent postintervention semistructured interviews and lasted from October 2021 to October 2023. Data came from EHRs at 8 outpatient clinics within an integrated health care system; participants included 7 breast surgical oncologists. Data were collected for female patients meeting Choosing Wisely criteria for omission of SLNB (aged ≥70 years with cT1 and cT2, cN0, HR+/HER2- breast cancer). The study included a 12-month preintervention control period; baseline surveys assessing perceived acceptability, appropriateness, and feasibility of the designed intervention; and a 12-month intervention period. Intervention: A column nudge was embedded into the surgeon's schedule in the EHR identifying patients meeting Choosing Wisely criteria for potential SLNB omission. Main Outcomes and Measures: The primary outcome was rate of SLNB following nudge deployment into the EHR. Results: Similar baseline demographic and tumor characteristics were observed before (control period, n = 194) and after (intervention period, n = 193) nudge deployment. Patients in both the control and intervention period had a median (IQR) age of 75 (72-79) years. Compared with the control period, unadjusted rates of SLNB decreased by 23.1 percentage points (46.9% SLNB rate prenudge to 23.8% after; 95% CI, -32.9 to -13.8) in the intervention period. An interrupted time series model showed a reduction in the rate of SLNB following nudge deployment (adjusted odds ratio, 0.26; 95% CI, 0.07 to 0.90; P = .03). The participating surgeons scored the intervention highly on acceptability, appropriateness, and feasibility. Dominant themes from semistructured interviews indicated that the intervention helped remind the surgeons of potential Choosing Wisely applicability without the need for additional clicks or actions on the day of the patient visit, which facilitated use. Conclusions and Relevance: This study showed that a nudge intervention in the EHR significantly decreased low-value axillary surgery in older women with early-stage, cN0, HR+/HER2- breast cancer. This user-friendly and easily implementable EHR-based intervention could be a beneficial approach for decreasing low-value care in other practice settings or patient populations. Trial Registration: ClinicalTrials.gov Identifier: NCT06006910.
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Traditional skin sampling methods include punch or shave biopsies to produce a solid tissue sample for analysis. These biopsy procedures are painful, require anesthesia, and leave permanent scars. This unit describes a suction blister skin biopsy method that can be used in place of traditional biopsy methodologies as a minimally invasive, non-scarring skin sampling technique. The induction of suction blisters uses an instrument with a chamber that applies negative pressure and gentle heat to the skin. Blister formation occurs within 1 hr, producing up to five blisters, each 10 mm in diameter per biopsy site. Blister fluid can be extracted and centrifuged to retrieve cells from the epidermis and upper dermis for flow cytometry, single-cell RNA sequencing, cell culture, and more without the need for digestion protocols. In addition, the blister fluid can be used to measure soluble proteins and metabolites. This unit describes the preparation of supplies and subjects, the suction blister biopsy procedure and blister formation, fluid extraction, and post-blistering care. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Preparation of supplies and subject Basic Protocol 2: Suction blister biopsy procedure and formation Basic Protocol 3: Blister fluid extraction Basic Protocol 4: Post-blister care and clean up.
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Vesícula , Pele , Humanos , Vesícula/patologia , Sucção , Biópsia/métodos , Pele/patologia , Manejo de Espécimes/métodosRESUMO
Western armies have relied on surgical field manuals to help physicians deal with unfamiliar combat medical conditions from the Napoleonic wars to the present day, but there has been little discussion of whether these handbooks have been used or improved outcomes. Recent research shows that the Union Army's American Civil War (1861-1865) surgical case fatality rates improved as the war progressed, much like the US Army's experience in later wars, and were generally superior to comparable European results. These positive Civil War outcomes have been attributed to field experience, adoption of best practices, and enhanced communication, without consideration of New York surgeon Stephen Smith's widely-used Hand-Book of Surgical Operations. The Army of the Potomac added Smith's pocket-sized Hand-Book to its supply table in 1862. Northern medical journals applauded it, and Smith's contemporaries documented its wide use. Smith's handbook explained and demonstrated surgical techniques that were adopted as the war progressed, such as the use of general anesthesia and limb-sparing resection (debridement) of gunshot wounds. It offered pithy, well-documented advice from recognized experts along with numerous illustrations, which allowed untrained physicians to visualize anatomical relationships and see contemporary best practices in a way that no other wartime publication provided, making it an exemplar of a mass-media surgical improvement change agent.
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Background: Janus kinase (JAK) inhibition is a promising approach for treating vitiligo. We aimed to assess the efficacy and safety of upadacitinib, an oral selective JAK inhibitor, in adults with non-segmental vitiligo. Methods: This was a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-ranging study completed at 33 clinical centres in the United States, Canada, France, and Japan. Eligible patients were aged 18-65 years with non-segmental vitiligo and had a Facial Vitiligo Area Scoring Index (F-VASI) ≥0.5 and a Total Vitiligo Area Scoring Index (T-VASI) ≥5. Patients were randomly assigned (2:2:2:1:1) using an interactive response technology to receive upadacitinib 6 mg (UPA6), upadacitinib 11 mg (UPA11), upadacitinib 22 mg (UPA22), or placebo (PBO; preassigned to switch to either UPA11 or UPA22 in period 2) once daily for 24 weeks (period 1). For weeks 24-52 (period 2), patients randomly assigned to upadacitinib continued their treatment, and patients receiving PBO switched to their preassigned upadacitinib dose in a blinded fashion. The primary endpoint was the percent change from baseline in F-VASI at week 24. Efficacy was analysed in the intention-to-treat population, and safety was examined in all randomly assigned patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT04927975. Findings: Between June 16, 2021, and June 27, 2022, 185 patients (including 115 [62%] who were female and 70 [38%] who were male) were randomly assigned to UPA6 (n = 49), UPA11 (n = 47), UPA22 (n = 43), or PBO (n = 46). At week 24, the LS mean difference versus PBO in the percent change from baseline in F-VASI was -7.60 (95% CI -22.18 to 6.97; p = 0.3037) for UPA6, -21.27 (95% CI -36.02 to -6.52; p = 0.0051) for UPA11, and -19.60 (95% CI -35.04 to -4.16; p = 0.0132) for UPA22. The LS mean difference versus PBO in the percent change from baseline in T-VASI was -7.45 (95% CI -16.86 to 1.96; p = 0.1198) for UPA6, -10.84 (95% CI -20.37 to -1.32; p = 0.0259) for UPA11 and -14.27 (95% CI -24.24 to -4.30; p = 0.0053) for UPA22. Ongoing treatment with upadacitinib induced continuous skin repigmentation over time without reaching a plateau through week 52. The rates for study drug discontinuation and serious treatment-emergent adverse events (TEAEs) were higher in the UPA22 group than in the UPA11 and UPA6 groups. Eight serious TEAEs, including one death of unknown cause and one case of infiltrating lobular breast carcinoma, were reported through 52 weeks; only two serious TEAEs (coronary artery arteriosclerosis [UPA6 (n = 1)] and non-fatal ischemic stroke [UPA11 (n = 1)]) were deemed by the investigator to have a reasonable possibility of being related to study drug. The one case of breast cancer in the UPA11 group was deemed unrelated to study drug, and the one death of unknown cause in the UPA22 group was reviewed and adjudicated and was deemed to be unrelated to study drug. The most common TEAEs were COVID-19, headache, acne, and fatigue. No new safety signals were observed. Interpretation: Upadacitinib monotherapy led to substantial repigmentation of both facial and total body vitiligo lesions and may offer an effective treatment option for adults with extensive non-segmental vitiligo. Based on these findings, upadacitinib 15 mg is being investigated in adults and adolescents with non-segmental vitiligo in an ongoing phase 3 randomised controlled trial. Funding: AbbVie Inc.
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A life of the mind can be lived only by creatures who know that they have minds. We call these creatures "persons," and currently, all such persons THAT we know OF are "alive" in the biological sense. But are there, or could there be, either in the future or elsewhere in the universe, creatures with "a life of the mind" that are not "alive" in the sense that we humans usually understand this term today?
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The notion of consumerism and that students are customers of pharmacy colleges was explored by proponents and opponents of the idea. First, a working definition of a "customer" in pharmacy education is pondered with respect to the roles and responsibilities of students and schools/colleges of pharmacy. Second, the pros and cons of "student-centered" education are considered in the light of students and their families being consumers of the educational experience. Third, the duality of student-centered education is discussed including student engagement/disengagement in their learning, professional/unprofessional behaviors, and shared/individual responsibilities. Lastly, learning and teaching environment dynamics are discerned when higher education becomes more student-centric and how that may affect the overall outcome of the student and the goals of pharmacy educational programs.
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Educação em Farmácia , Estudantes de Farmácia , Humanos , Comportamento do Consumidor , Faculdades de Farmácia , Aprendizagem , CurrículoRESUMO
OBJECTIVES: Severe obesity in nursing home (NH) residents is associated with specialized care needs, limited mobility, and challenges in daily living. The COVID-19 pandemic strained NH resources and exacerbated staffing shortages. This study aimed to assess the ability of US NHs to accept and care for residents with severe obesity post-COVID, as well as associated NH factors. DESIGN: Cross-sectional nationwide survey of NH administrators (2021-2022). SETTING AND PARTICIPANTS: 290 NHs from a national sample (n = 224) and a targeted sample in Massachusetts and New Jersey (n = 66). METHODS: A survey designed to assess how NHs approach admitting and caring for people with severe obesity before and after COVID was fielded from 2021 to 2022. Responses were linked to facility information from the Certification and Survey Provider Enhanced Reports, Minimum Data Set, Nursing Home Compare, Area Health Resources File, and US Diabetes Surveillance System. Multivariable logistic regression was used to assess the effect of organizational and survey response variables. RESULTS: Of the 2503 surveys sent to US NHs, 1923 were sent to the national NH stratified sample, and 580 were sent to the MA/NJ sample. Overall, 12% (301 of 2503) of NHs surveyed responded. The response rates were similar between the 2 samples. Of 290 NHs with complete data, 34% reported being unlikely to accept residents with severe obesity after COVID-19, compared with 25% before the pandemic (P < .001). The main barriers to acceptance were staffing shortages and difficulties meeting equipment and space needs. NHs with higher proportions of Black residents were more likely to admit individuals with severe obesity. CONCLUSIONS AND IMPLICATIONS: The decline in acceptance of residents with severe obesity during and after COVID-19 highlights potential challenges that this population faces in accessing care. Our results also raise concerns that an intersection of disparities may exist in Black patients with severe obesity.
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COVID-19 , Casas de Saúde , Obesidade Mórbida , SARS-CoV-2 , Humanos , COVID-19/epidemiologia , Estudos Transversais , Estados Unidos , Obesidade Mórbida/epidemiologia , Masculino , Feminino , Idoso , PandemiasRESUMO
OBJECTIVE: To assess the effect of geographic factors on fertility-sparing treatment or assisted reproductive technology (ART) utilization among women with gynecologic or breast cancers. METHODS: We conducted a cohort study of reproductive-aged patients (18-45 years) with early-stage cervical, endometrial, or ovarian cancer or stage I-III breast cancer diagnosed between January 2000 and December 2015 using linked data from the California Cancer Registry, the California Office of Statewide Health Planning and Development, and the Society for Assisted Reproductive Technology. Generalized linear mixed models were used to evaluate associations between distance from fertility and gynecologic oncology clinics, as well as California Healthy Places Index score (a Census-level composite community health score), and ART or fertility-sparing treatment receipt. RESULTS: We identified 7,612 women with gynecologic cancer and 35,992 women with breast cancer. Among all patients, 257 (0.6%) underwent ART. Among patients with gynecologic cancer, 1,676 (22.0%) underwent fertility-sparing treatment. Stratified by quartiles, residents who lived at increasing distances from gynecologic oncology or fertility clinics had decreased odds of undergoing fertility-sparing treatment (gynecologic oncology clinics: Q2, odds ratio [OR] 0.76, 95% CI, 0.63-0.93, P =.007; Q4, OR 0.72, 95% CI, 0.56-0.94, P =.016) (fertility clinics: Q3, OR 0.79, 95% CI, 0.65-0.97, P =.025; Q4, OR 0.67, 95% CI, 0.52-0.88, P =.004), whereas this relationship was not observed among women who resided within other quartiles (gynecologic oncology clinics: Q3, OR 0.81 95% CI, 0.65-1.01, P =.07; fertility clinics: Q2, OR 0.87 95% CI, 0.73-1.05, P =.15). Individuals who lived in communities with the highest (51 st -100 th percentile) California Healthy Places Index scores had greater odds of undergoing fertility-sparing treatment (OR 1.29, 95% CI, 1.06-1.57, P =.01; OR 1.66, 95% CI, 1.35-2.04, P =.001, respectively). The relationship between California Healthy Places Index scores and ART was even more pronounced (Q2 OR 1.9, 95% CI, 0.99-3.64, P =.05; Q3 OR 2.86, 95% CI, 1.54-5.33, P <.001; Q4 OR 3.41, 95% CI, 1.83-6.35, P <.001). CONCLUSION: Geographic disparities affect fertility-sparing treatment and ART rates among women with gynecologic or breast cancer. By acknowledging geographic factors, health care systems can ensure equitable access to fertility-preservation services.
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Neoplasias da Mama , Preservação da Fertilidade , Neoplasias dos Genitais Femininos , Acessibilidade aos Serviços de Saúde , Disparidades em Assistência à Saúde , Humanos , Feminino , Neoplasias da Mama/terapia , Preservação da Fertilidade/estatística & dados numéricos , Adulto , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Disparidades em Assistência à Saúde/estatística & dados numéricos , California , Pessoa de Meia-Idade , Neoplasias dos Genitais Femininos/terapia , Adulto Jovem , Adolescente , Estudos de Coortes , Técnicas de Reprodução Assistida/estatística & dados numéricos , Sistema de RegistrosRESUMO
BACKGROUND: Equine grass sickness (EGS) is a frequently fatal multisystem neuropathy of equids. The aetiology is unknown; proposed causes include toxicoinfection with Clostridium botulinum and a mycotoxicosis. The effect of EGS on the organisation and structural integrity of the skeletal neuromuscular junction (NMJ), the target of botulinum neurotoxins (BoNTs), is unknown. OBJECTIVES: To compare the organisation and structural integrity of skeletal NMJs from EGS horses, control horses and one horse with a presumptive diagnosis of botulism. STUDY DESIGN: Blinded, retrospective case control. METHODS: NMJs in samples of diaphragm or intercostal muscle from six EGS horses, three control horses and one equine botulism case were compared using electron microscopy, morphometry and confocal light microscopy. RESULTS: A significantly higher percentage of EGS NMJs had abnormal morphology (EGS 72.2%, 95% CI 55.6-84.4; Controls 6.9%, 1.7-23.8; OR 35.1, 8.47-244.8; p < 0.001). EGS NMJs had a significantly lower mean volume fraction occupied by synaptic vesicles (SVs) (EGS 18.7%, 12.6-28.0; Controls 36.3%, 20.8-63.4; p = 0.024). EGS NMJs had evidence of accelerated SV exocytosis and SV depletion, accumulation of neurofilament-like material in terminal boutons and/or bouton degeneration. NMJs from the botulism horse had dense packing of SVs towards the presynaptic membrane active zone, consistent with BoNT intoxication, but had absence of the abnormalities identified in EGS NMJs. MAIN LIMITATIONS: Group sizes were limited by difficulties obtaining suitably processed samples. Ages of control and EGS horses differed. Botulism was diagnosed based on clinical and post mortem findings. CONCLUSIONS: EGS is associated with major changes in skeletal NMJ ultrastructure that are inconsistent with the effects of BoNTs. SV depletion may reflect increased exocytosis coupled with reduced repopulation of SVs via anterograde axonal transport and endocytosis, consistent with the action of an excitatory presynaptic toxin and/or neurotransmitter reuptake inhibitor. Skeletal NMJs represent a previously unrecognised target for the toxin that causes EGS.
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Identifying therapeutic oligonucleotides that are cross-reactive to experimental animal species can dramatically accelerate the process of preclinical development and clinical translation. Here, we identify fully chemically-modified small interfering RNAs (siRNAs) that are cross-reactive to Janus kinase 1 (JAK1) in humans and a large variety of other species. We validated the identified siRNAs in silencing JAK1 in cell lines and skin tissues of multiple species. JAK1 is one of the four members of the JAK family of tyrosine kinases that mediate the signaling transduction of many inflammatory cytokine pathways. Dysregulation of these pathways is often involved in the pathogenesis of various immune disorders, and modulation of JAK family enzymes is an effective strategy in the clinic. Thus, this work may open up unprecedented opportunities for evaluating the modulation of JAK1 in many animal models of human inflammatory skin diseases. Further chemical engineering of the optimized JAK1 siRNAs may expand the utility of these compounds for treating immune disorders in additional tissues.
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Chemokines play critical roles in the recruitment and activation of immune cells in both homeostatic and pathologic conditions. Here, we examined chemokine ligand-receptor pairs to better understand the immunopathogenesis of cutaneous lupus erythematosus (CLE), a complex autoimmune connective tissue disorder. We used suction blister biopsies to measure cellular infiltrates with spectral flow cytometry in the interface dermatitis reaction, as well as 184 protein analytes in interstitial skin fluid using Olink targeted proteomics. Flow and Olink data concordantly demonstrated significant increases in T cells and antigen presenting cells (APCs). We also performed spatial transcriptomics and spatial proteomics of punch biopsies using digital spatial profiling (DSP) technology on CLE skin and healthy margin controls to examine discreet locations within the tissue. Spatial and Olink data confirmed elevation of interferon (IFN) and IFN-inducible CXCR3 chemokine ligands. Comparing involved versus uninvolved keratinocytes in CLE samples revealed upregulation of essential inflammatory response genes in areas near interface dermatitis, including AIM2. Our Olink data confirmed upregulation of Caspase 8, IL-18 which is the final product of AIM2 activation, and induced chemokines including CCL8 and CXCL6 in CLE lesional samples. Chemotaxis assays using PBMCs from healthy and CLE donors revealed that T cells are equally poised to respond to CXCR3 ligands, whereas CD14+CD16+ APC populations are more sensitive to CXCL6 via CXCR1 and CD14+ are more sensitive to CCL8 via CCR2. Taken together, our data map a pathway from keratinocyte injury to lymphocyte recruitment in CLE via AIM2-Casp8-IL-18-CXCL6/CXCR1 and CCL8/CCR2, and IFNG/IFNL1-CXCL9/CXCL11-CXCR3.
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BACKGROUND: Non-word repetition (NWR) tests are an important way speech and language therapists (SaLTs) assess language development. NWR tests are often scored whilst participants make their responses (i.e., in real time) in clinical and research reports (documented here via a secondary analysis of a published systematic review). AIMS: The main aim was to determine the extent to which real-time coding of NWR stimuli at the whole-item level (as correct/incorrect) was predicted by models that had varying levels of detail provided from phonemic transcriptions using several linear mixed method (LMM) models. METHODS & PROCEDURES: Live scores and recordings of responses on the universal non-word repetition (UNWR) test were available for 146 children aged between 3 and 6 years where the sample included all children starting in five UK schools in one year or two consecutive years. Transcriptions were made of responses to two-syllable NWR stimuli for all children and these were checked for reliability within and between transcribers. Signal detection analysis showed that consonants were missed when judgments were made live. Statistical comparisons of the discrepancies between target stimuli and transcriptions of children's responses were then made and these were regressed against live score accuracy. Six LMM models (three normalized: 1a, 2a, 3a; and three non-normalized: 1b, 2b, 3b) were examined to identify which model(s) best captured the data variance. Errors on consonants for live scores were determined by comparison with the transcriptions in the following ways (the dependent variables for each pair of models): (1) consonants alone; (2) substitutions, deletions and insertions of consonants identified after automatic alignment of live and transcribed materials; and (3) as with (2) but where substitutions were coded further as place, manner and voicing errors. OUTCOMES & RESULTS: The normalized model that coded consonants in non-words as 'incorrect' at the level of substitutions, deletions and insertions (2b) provided the best fit to the real-time coding responses in terms of marginal R2, Akaike's information criterion (AIC) and Bayesian information criterion (BIC) statistics. CONCLUSIONS & IMPLICATIONS: Errors that occur on consonants when non-word stimuli are scored in real time are characterized solely by the substitution, deletion and insertion measure. It is important to know that such errors arise when real-time judgments are made because NWR tasks are used to assess and diagnose several cognitive-linguistic impairments. One broader implication of the results is that future work could automate the analysis procedures to provide the required information objectively and quickly without having to transcribe data. WHAT THIS PAPER ADDS: What is already known on this subject Children and patients with a wide range of cognitive and language difficulties are less accurate relative to controls when they attempt to repeat non-words. Responses to non-words are often scored as correct or incorrect at the time the test is conducted. Limited assessments of this scoring procedure have been conducted to date. What this study adds to the existing knowledge Live NWR scores made by 146 children were available and the accuracy of these judgements was assessed here against ones based on phonemic transcriptions. Signal detection analyses showed that live scoring missed consonant errors in children's responses. Further analyses, using linear mixed effect models, showed that live judgments led to consonant substitution, deletion and insertion errors. What are the practical and clinical implications of this work? Improved and practicable NWR scoring procedures are required to provide SaLTs with better indications about children's language development (typical and atypical) and for clinical assessments of older people. The procedures currently used miss substitutions, deletions and insertions. Hence, procedures are required that provide the information currently only available when materials are transcribed manually. The possibility of training automatic speech recognizers to provide this level of detail is raised.
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Julgamento , Fonética , Criança , Humanos , Idoso , Pré-Escolar , Reprodutibilidade dos Testes , Teorema de Bayes , Sais , Testes de LinguagemRESUMO
Characterizing the mechanisms influencing the distribution of genetic variation in aquatic species can be difficult due to the dynamic nature of hydrological landscapes. In North America's Central Highlands, a complex history of glacial dynamics, long-term isolation, and secondary contact have shaped genetic variation in aquatic species. Although the effects of glacial history have been demonstrated in many taxa, responses are often lineage- or species-specific and driven by organismal ecology. In this study, we reconstruct the evolutionary history of a freshwater mussel species complex using a suite of mitochondrial and nuclear loci to resolve taxonomic and demographic uncertainties. Our findings do not support Pleurobema rubrum as a valid species, which is proposed for listing as threatened under the U.S. Endangered Species Act. We synonymize P. rubrum under Pleurobema sintoxia-a common and widespread species found throughout the Mississippi River Basin. Further investigation of patterns of genetic variation in P. sintoxia identified a complex demographic history, including ancestral vicariance and secondary contact, within the Eastern Highlands. We hypothesize these patterns were shaped by ancestral vicariance driven by the formation of Lake Green and subsequent secondary contact after the last glacial maximum. Our inference aligns with demographic histories observed in other aquatic taxa in the region and mirrors patterns of genetic variation of a freshwater fish species (Erimystax dissimilis) confirmed to serve as a parasitic larval host for P. sintoxia. Our findings directly link species ecology to observed patterns of genetic variation and may have significant implications for future conservation and recovery actions of freshwater mussels.