Citations

Abstract Background Pneumocystis jirovecii pneumonia (PCP) is increasingly seen in patients who are non-HIV immunocompromised hosts, yet modern risk factors and outcomes are poorly recognized and defined. Methods A retrospective review was conducted of adult patients who met criteria for proven or probable PCP from 2017 to 2024 across a large academic multicenter health system. The primary outcome was mortality among cohorts, defined by etiology of immunosuppression through univariate and age-adjusted logistic regression. Secondary analyses included trends in annual diagnoses and testing patterns. Results A total of 701 patients met criteria for inclusion, representing one of the largest clinically characterized cohorts of PCP to date. The median age was 65 years (IQR, 54–73) and 62% were male. The most common risk groups were hematologic malignancy (32.2%), solid tumor cancers receiving chemotherapy (22.4%), and autoimmune disease with immunosuppression (17.7%). Annual PCP diagnoses increased at a rate of 15.8% (95% CI, 8.9%–23.2%) in parallel with increased testing. Only 5.4% of patients were receiving prophylaxis at the time of diagnosis. Overall mortality was 20% (95% CI, 17%–23%) and highest in cirrhosis (adjusted odds ratio, 6.24; 95% CI, 2.84–13.69; P < .001). Conclusions PCP in the current era affects a broad range of patients who are immunocompromised, with high associated mortality and low rates of prophylaxis. Patients with solid tumors and those with cirrhosis are at particularly high risk of mortality. These findings highlight the need to reassess and redefine PCP prophylaxis guidelines in specific populations and our understanding of who is at risk.

OBJECTIVE The aim of this study was to evaluate mortality and progression outcomes in patients undergoing stereotactic radiosurgery (SRS) for breast cancer brain metastases and to identify associated risk factors using a national quality registry. METHODS The NeuroPoint Alliance (NPA) SRS Registry was employed for this study, which conducted prospective enrollment of patients undergoing SRS at 16 participating centers from 2017 to 2024. Outcomes of interest included the post-SRS EQ-5D score change, overall survival, local progression, out-of-field progression, and overall intracranial progression. For all time-to-event analyses, Kaplan-Meier curves and multivariable Cox regressions with hazard ratios were used. RESULTS A total of 138 patients (127 female, mean age 59.8 years) were identified; 46.4% had a single lesion, 42.0% had 2–4 lesions, and 11.6% had ≥ 5 lesions, while 87.0% had a Karnofsky Performance Status (KPS) score between 80 and 100. The median overall survival was 17.9 months, and independent predictors of all-cause mortality included a KPS score ≤ 90 (HR 6.73) and diabetes mellitus (HR 3.35). The median time to local progression was 19.8 months. More than 5 lesions at baseline (HR 9.03) and a marginal dose ≤ 17.6 Gy (HR 8.00) were predictive of local recurrence. The median was not reached for out-of-field progression, and predictors included ≥ 2 lesions at the time of SRS (HR 3.20) and a marginal dose ≤ 17.6 Gy (HR 4.61). At the final follow-up assessment, 17.1% of patients experienced no change according to the EQ-5D, while 34.3% had improvement, 11.4% had mixed results, and 37.1% had worsened health. In the multivariable linear regression model, pre-SRS resection (r = 1.92) and baseline EQ-5D score (r = 1.29) were statistically significant predictors of quality of life at the final follow-up assessment. CONCLUSIONS Using real-world data from the NPA SRS Registry, this study demonstrated comparable outcomes in patients who underwent SRS for breast cancer brain metastases compared with those of previous literature. The number of lesions at the time of SRS and the marginal dose were independent risk factors for local recurrence, out-of-field progression, and overall intracranial progression. Pre-SRS resection and baseline EQ-5D score were independent predictors of quality of life following SRS.

PURPOSE Automated curation of breast cancer treatment data with minimal human involvement could accelerate the collection of statewide and nationwide evidence for patient management and assessing the effectiveness of treatment pathways. The primary challenges are the complexity and inconsistency of structured clinical data streams and accurate extraction of this information from free-text clinical narratives. MATERIALS AND METHODS We proposed a hybrid two-phase information extraction framework that combined a Unified Medical Language System parser (phase-1) with a fine-tuned large language model (LLM; phase-2) to extract longitudinal treatment timelines from time-stamped clinical notes. Our framework was developed through end-to-end joint learning as a question-answering model, where the model was trained to simultaneously answer five questions, each corresponding to a specific treatment. RESULTS We fine-tuned and internally validated the model on 26,692 patients with breast cancer (diagnosed between 2013 and 2020) receiving treatment at Mayo Clinic and externally validated the model on 162 randomly selected patients from Stanford Healthcare. Zero-shot LLM (out-of-the-box) had high specificity but low sensitivity, indicating that although these frameworks are useful for generic language understanding, they are lacking in terms of targeted clinical tasks. The proposed model achieved 0.942 average AUROC on the internal and 0.924 on the external data, demonstrating only marginal drop in performance when evaluated on external. The proposed model also achieved better trade-off between sensitivity (average: 79.2%) and specificity (average: 76.2%) compared with rule-based (average sensitivity: 70.5%, average specificity: 68.1%) and structured codes (average sensitivity: 64.1%, average specificity: 83.5%). CONCLUSION The proposed framework can extract temporal information about cancer treatments from various time-stamped clinic notes, regardless of the setting of treatment administration (inpatient or outpatient) or time frame. To support the cancer research community for such data curation and longitudinal analysis, we have packaged the code as a docker image, which needs minimal system reconfiguration and shared with an open-source academic license.

Abstract Introduction Endogenous Cushing's syndrome (CS) is a rare endocrine disorder that chronically exposes patients to supraphysiological cortisol levels. Primary therapy for CS consists of surgery. Medical therapies are also considered for many patients with CS, including those who are not surgical candidates or have persistent or recurrent hypercortisolism after surgery. Osilodrostat, an adrenal steroidogenesis inhibitor, demonstrated sustained efficacy and safety in phase 3 clinical trials and is currently approved to treat endogenous CS in Europe and the United States. Because of limited clinical experience, questions remain about how to individualize osilodrostat treatment for different clinical scenarios and special populations. Additional guidance from experts based on clinical study and real-world experiences with osilodrostat is needed. Methods A modified Delphi consensus panel study was conducted consisting of 13 specialists from high-volume endocrinology centers with experience prescribing osilodrostat. Advisors participated in 3 consensus rounds (2 anonymous surveys, 1 virtual workshop) over approximately 10 months to provide guidance and recommendations on optimal osilodrostat use. Results Over 2 surveys and a 2-hour virtual workshop, 26 statements related to osilodrostat achieved consensus among Delphi panelists and 5 were excluded. Topics included patient preparation before osilodrostat initiation, baseline testing, dosing at onset and during treatment, managing dose adjustments, monitoring during dose titration, and treatment alterations for planned and unexpected clinical events. Conclusion Treatment guidance and recommendations for osilodrostat use were obtained using the Delphi method. These statements are intended to provide physicians with education and guidance on using osilodrostat to optimally treat patients with CS.

Key Points Circulating proteins independently associated with kidney stone diagnosis are related to kidney stone matrix. Lower circulating uromodulin and higher scavenger receptor cysteine-rich domain-containing group B protein levels were associated with higher kidney stone risk, whereas kidney stone presence elevates plasma matrix metalloproteinase 7 level. The protective effect of uromodulin against kidney stones was independent of kidney function. Background Kidney stones are increasingly recognized as a systemic disorder with a high global prevalence. However, large proteomics studies are lacking. Methods An individual-level proteomics study with rigorous adjustments was performed on 35,331 UK Biobank participants to uncover the independent associations between 2922 circulating proteins and prevalent kidney stone disease. Mendelian randomization analysis was used to assess causal relationships. Findings were validated using genomic data from the Mayo Clinic Biobank ( N =43,744), concentration-response analysis, transcriptomics analyses, and additional genome-wide association studies. Results Nine plasma proteins were independently associated with a kidney stone diagnosis, including reduced uromodulin (UMOD; β , −0.10; 95% confidence interval [CI], −0.15 to −0.05) and elevated scavenger receptor cysteine-rich domain-containing group B protein (SSC4D; β , 0.28; 95% CI, 0.17 to 0.38) and were enriched in extracellular matrix pathways. Mendelian randomization analysis revealed that the presence of kidney stone contributed to elevated levels of matrix metalloproteinase 7. Conversely, lower plasma UMOD (odds ratio [OR], 0.93; 95% CI, 0.90 to 0.97) and higher plasma SSC4D (OR, 1.10; 95% CI, 1.02 to 1.18) were associated with kidney stone risk. These associations were consistently replicated in the Mayo Clinic Biobank dataset (UMOD; OR, 0.92; 95% CI, 0.86 to 0.98; SSC4D; OR, 1.13; 95% CI, 1.01 to 1.27) and further validated by a concentration-response analysis. Single-nucleus RNA sequencing and quantitative trait loci analyses confirmed consistent associations between thick ascending limb UMOD expression and stone former status and with blood and urine UMOD concentrations. Genome-wide association study analysis, adjusted for eGFR, suggested that the protective role of UMOD against kidney stones was independent of kidney function. Conclusions This study highlights significant associations between concentrations of specific blood proteins and a history of kidney stones. Several implicated proteins are related to kidney stone matrix, with UMOD independently associated with lower risk and SSC4D with higher risk of kidney stones.

Abstract Several complications are associated with total shoulder arthroplasty (TSA), including glenoid loosening and joint instability. These complications are linked to imbalances in glenohumeral muscle forces, which cause eccentric loading that occurs on the outer edge of the glenoid component, rather than in the center of the glenoid, and can be damaging to the implant and destabilizing the joint. The purpose of this study was to develop musculoskeletal models of TSA patients using their skeletal geometry acquired from CT and their kinematics acquired with high-speed stereo radiography (HSSR) to predict glenohumeral joint loading and muscle forces for abduction and flexion and describe how these loads differ from their native contralateral side. CT data was collected for both shoulders of 6 TSA patients (three anatomic and three reverse). Models were developed using CT reconstructions of each patient’s scapula and humerus, and placed implant geometry with CT-derived alignment. Mesh morphing was used to create personalized muscle attachment sites on the scapula. Simulation of abduction and flexion to quantify muscle and joint forces was driven with limb-specific HSSR kinematics. At 90 deg abduction, reverse TSA increased superior shear force by 11.2% bodyweight (BW) and decreased medial compressive force by 27.5%BW compared to each patient’s contralateral shoulder. Lateral deltoid elevation moment arms and stability ratios increased 9.61 mm and 0.58, respectively. At 90 deg abduction, anatomic TSA patients increased humeral internal rotation by 52.7 deg and decreased rotator cuff force by 9.4%BW. Patient-specific musculoskeletal models quantified differences in glenohumeral joint mechanics. This study revealed muscle and kinematic mechanisms that could lead to edge loading and glenoid loosening in TSA and can inform personalized surgical planning for implant alignment with the goal of improving patient outcomes.

ABSTRACT Bipolar disorder’s (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder—and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic–GABAergic gradient along the psychotic factor. BD’s genetic architecture appears hierarchical—a general liability resolving into dimensions of course and comorbidity beyond diagnostic subtypes.

Background: During acute hypoxia, Thehuman brainemploys complex regulatory mechanisms to compensate for high O 2 demand and low O 2 blood saturation. High hemoglobin-oxygen (Hb-O 2 ) affinity improves arterial oxygen saturation (S a O 2 ) in low oxygen environments providing a potential physiologic benefit in humans. However, the impact of high Hb-O 2 affinity on cerebral blood flow (CBF) and cerebral tissue oxygenation (S t O 2 ) has yet to be examined. This work aimed to determine the influence of an acute increase in Hb-O 2 affinity from Etavopivat, a selective red blood cell pyruvate kinase activator, on CBF regulation and S t O 2 during handgrip exercise in normoxia and hypoxia. Methods: 16 healthy adults (31±8 yr, 5 females) completed two visits; before and after Etavopivat (400 mg daily, 7 days) administration,. Each visit included graded handgrip (~3 min stages each) exercise (rest, 10% maximal voluntary contraction (MVC), 20% MVC) while participants inspired normoxic (NORM, 21% O 2 ), moderate (MH, 15% O 2 ), and severe (SH, 10% O 2 ) hypoxic gas mixtures. Hb-O 2 binding affinity (P 50 ), was measured using dual-wavelength spectrophotometry (pH~7.4 and 37ºC). Blood sampling through catheterization of the non-exercising arm measured S a O 2 . CBF was approximated by the peak middle cerebral artery velocity, measured with a 2MHz transcranial doppler ultrasound through the transtemporal window. S t O 2 was measured using frequency-domain near infrared spectroscopy of the frontal cortex. CBF and S t O 2 between visits were compared using separate two-way RM ANOVA models to determine the effects of Etavopivat [before (baseline) or after 7d Etavopivat exposure (post)] and exercise intensity [rest, 10% MVC, 20% MVC] for each inspirate. Results: P 50 was reduced after Etavopivat exposure (Baseline: 28.6±1.6 mmHg, Etavo: 24.8±1.3, P <0.001) without impacting hematocrit ( P =0.97). S a O 2 was higher following Etavopivat exposure during each inspirate ( P <0.001 for each). There was no significant effect of handgrip exercise on CBF or S t O 2 within any inspirate. Cerebral S t O 2 was higher during each inspirate (all P <0.002)– NORM (Baseline: 65.3±12.3%, Post: 68.8±9.8%), MH (Baseline: 61.0±11.7 %, Post: 66.1±10.5%) and SH (Baseline: 47.7±13.5%, Post: 56.6±11.5%). In addition, CBF was increased during each inspirate (all P <0.001)– NORM (Baseline: 62.2±12.2 cm/s, Post: 69.2±12.5 cm/s), MH (Baseline: 60.8±13.1 cm/s, Post: 67.9±12.3 cm/s) and SH (Baseline: 69.8±16.3 cm/s, Post: 79.2±18.0 cm/s). Conclusion: The acute pharmacological induction of high Hb-O 2 affinity leads to increased CBF and cerebral S t O 2 during acute hypoxic exposure in conditions of mild muscular exertion. Whether the improvement of cerebral S t O 2 is associated increased S a O 2 or CBF (or both) is unclear. These findings are the first to investigate the complex determinants of cerebral S t O 2 as a function of an acute increase in Hb-O 2 affinity. These improvements in S t O 2 during hypoxic exposure may lead to a host of theoretical benefits such as improved hypoxia tolerance, and mitigated decrements in cognitive function during hypoxic exposure. This study was funded by Forma Therapeutics Inc, which was acquired by Novo Nordisk on October 14, 2022, Novo Nordisk A/S. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Dynamic cerebral autoregulation (CA) refers to the brain's ability to maintain stable cerebral blood flow despite fluctuations in blood pressure (BP). Impaired CA has been associated with cardiovascular disease severity and cognitive decline. On the other hand, enhanced cardiorespiratory fitness appears to be protective against both cerebrovascular dysregulation and cognitive decline, with an unclear link between the two. However, among individuals with cardiovascular disease, the impact of exercise-based cardiac rehabilitation (CR) on CA remains unclear. Therefore, the aim of this study was to test the hypothesis that a 12-week CR program would improve dynamic CA in adults with CVD. To address this question, data were collected from 14 patients enrolled in the Mayo Clinic CR program following a cardiac-related hospital admission (age: 43-70 yrs; n=3 females), which included moderate-high intensity aerobic exercise 3 times/week for 12-weeks. Continuous measures of middle cerebral artery velocity (MCAv; transcranial doppler) and finger BP (photoplethysmography) were obtained during 3-minutes of rest and a 3-minute sit-to-stand protocol (0.025Hz frequency) pre- and post the CR program. Transfer function analyses were used to provide an index of dynamic CA. BP-MCAv coherence in the low frequency (LF) and very low frequency (vLF) domains at rest were not different pre- and post- CR (LF: 0.48±0.19 vs 0.43±0.16; P=0.54; vLF: 0.51±0.12 vs 0.47±0.16; P=0.14). Similarly, gain and phase values at rest were not different pre- and post- CR (gain LF: 0.66±0.37 vs 0.58±0.33; P=0.16; vLF: 0.87±0.53 vs 0.74±0.43; P=0.21; phase LF: 0.41±0.30 vs 0.43±0.26; P=0.64; vLF: 0.72±0.53 vs 0.66±0.16; P=0.18). In contrast, during the sit-to-stand protocol, coherence was lower following CR (pre vs post LF: 0.81±0.13 vs 0.79±0.16; p<0.01; vLF: 0.80±0.09 vs 0.79±0.14; p<0.01). In addition, gain was reduced post CR (pre vs post LF: 0.59±0.35 vs 0.55±0.31; P=0.02; vLF: 0.76±0.33 vs 0.61±0.37; p<0.01), suggesting CR-induced improvements in CA efficiency. However, phase remained unchanged pre- and post- CR during the sit-to-stand protocol (LF: 1.01±0.71 vs 0.84±0.58; P=0.17; vLF: 1.16±0.69 vs 1.08±0.60; P=0.19). Taken together, these findings demonstrate that a 12-week exercise-based CR program improves dynamic CA efficiency after a cardiac event. These novel results highlight the potential role of exercise training in improving cerebrovascular regulation. Funding: NIH AG073726 and Mayo Clinic This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.