Publications

Phenotypic heterogeneity is a defining feature of bacterial stress responses, long framed as irreducible noise arising from stochastic molecular events. This review builds on that view, advancing the idea that much of the apparent randomness instead reflects unmeasured determinants-hidden variables-that render cellular behavior predictable once revealed. We survey canonical cases such as antibiotic persistence, oxidative stress resistance, and DNA repair, highlighting how variability once thought to be stochastic can be traced with deterministic factors such as growth, cell-cycle state, microenvironment changes, or molecular inheritance. Cutting-edge tools-from lineage-resolved microfluidics, single-cell RNA-seq, and high-dimensional reporters to machine learning applied to cellular trajectories-are now beginning to expose these hidden layers of causality. By reframing noise as structure awaiting discovery, this perspective sets the stage for a predictive microbiology: one that links the microscopic state of individual cells to emergent population behaviors, with far-reaching implications for understanding pathogenesis and guiding antimicrobial strategies.

C-X3-C motif chemokine ligand 1 (CX3CL1), a structurally unique chemokine in the central nervous system (CNS), shapes physiological and pathological processes via specific binding to its receptor, C-X3-C motif chemokine receptor 1 (CX3CR1). Empirical evidence indicates that this signaling axis exerts dual neuroinflammatory effects: It restrains microglial hyperactivation, yet can promote inflammation under conditions such as chronic stress. Notably, it preserves synaptic plasticity and facilitates remyelination. Age-associated reductions in CX3CL1 exhibit a strong correlation with cognitive decline; administration of exogenous CX3CL1 partially mitigates these deficits. This study provides a comprehensive account of the multifaceted functions and regulatory mechanisms of CX3CL1 in CNS diseases, thereby establishing a basis for potential new therapeutic targets.

PURPOSE: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a unique myeloid malignancy with CD123 interleukin-3 receptor-α overexpression and poor prognosis.

METHODS: This phase I/II, open-label, multicenter study evaluated pivekimab sunirine (PVEK), a novel CD123 antibody-drug conjugate, 0.045 mg/kg once every 3 weeks, in adults with frontline (no previous systemic therapy and de novo BPDCN or coexisting hematologic malignancy) or relapsed/refractory BPDCN (ClinicalTrials.gov identifier: NCT03386513) The primary end point in the primary analysis population (PAP; frontline de novo) was composite complete response (CCR; CR+ clinical CR) rate.

RESULTS: Of 84 patients, 33 had frontline BPDCN (22 de novo [20 in PAP]; 11 with previous or concomitant malignancy) and 51 had relapsed/refractory disease. The median (range) age was 72 (63-76) years. In the PAP (n = 20), the CCR rate was 75% (95% CI, 51 to 91; n = 15; median duration: 10.6 [95% CI, 3.8 to not reached] months) and the median overall survival (OS) was 16.6 (95% CI, 7.2 to not reached) months. Eight of these 15 (53%) patients proceeded to stem-cell transplant (SCT). The corresponding rate for relapsed/refractory disease was 14% (95% CI, 6 to 26; n = 7; median duration: 9.2 [95% CI, 2.4 to not reached] months), and the median OS was 5.8 (95% CI, 3.9 to 8.4) months. Adverse events (AEs) included peripheral edema (54%), fatigue (26%), and infusion-related reactions (26%). Grade ≥3 events included neutropenia (16%), thrombocytopenia (14%), and peripheral edema (12%). Serious AEs included pneumonia (6%) and febrile neutropenia (5%). Two on-treatment cases of reversible veno-occlusive disease (VOD) occurred. Of the total 19 patients who proceeded to SCT, VOD was reported in five patients (four with relapsed/refractory BPDCN).

CONCLUSION: PVEK, with convenient dosing, led to high, durable responses, especially in frontline BPDCN, and a manageable safety profile.

The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice-weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry. Prim Care Companion CNS Disord 2026;28(1):25f04061. Author affiliations are listed at the end of this article.

To elucidate the molecular basis underlying differential response and resistance to ibrutinib in Waldenström's macroglobulinemia (WM), we conducted a prospective phase II trial (ClinicalTrials.gov; NCT02604511) of ibrutinib monotherapy in treatment-naïve patients. Seventy-four sequential bone marrow (BM) aspirates from 17 patients, collected from baseline through 48 treatment cycles, were profiled using single-cell multi-omics. BM cells segregated primarily into B/plasma cell and T-cell compartments. Longitudinal clonal tracking of malignant B/plasma cells identified three distinct evolutionary patterns: "evolution" (early clone contraction with late clone expansion and increasing genomic complexity), "devolution" (early clone expansion with late clone contraction and genomic simplification), and "no-evolution" (stable clonal architecture). The "evolution" pattern was strongly associated with disease progression, whereas "devolution" correlated with durable clinical response. Transcriptomic profiling of resistant clones enabled development and validation of the Waldenström's Ibrutinib Prediction (WIP) score, which predicted treatment response at baseline. Within the WIP signature, LYN emerged as a key regulator; LYN knockdown or inhibition significantly increased WM cell sensitivity to ibrutinib, suggesting a rational combinatorial strategy. In parallel, GZMB⁺ CD8⁺ effector-memory (TEM) cells expanded post-treatment in progressing patients and co-existed with tumor "evolution". These cells exhibited persistently impaired cytotoxic programs (e.g., GNLY), a de-differentiated memory-like state, elevated PDCD1 expression, and reduced TCR diversity. Together, this study provides the first single-cell framework of tumor clonal evolution and T-cell dysfunction under ibrutinib in WM; introduces the WIP score as a predictive biomarker for treatment response; and identifies actionable tumor-intrinsic and immune mechanisms driving resistance.

Immunotherapies revolutionized cancer treatment, yet their efficacy remains constrained by the tumor's immunosuppressive microenvironment. Here, we evaluated whether combining CD39 blockade with other modalities of immunotherapy such as IL-2/anti-IL-2 complexes (IL-2cx) administration could further enhance T cell-mediated antitumor responses and improve tumor control. We demonstrated that CD39 deficiency in MC38 tumor-bearing CD39KO (Entpd1 null) mice decreases tumor growth. This better tumor growth control was associated with increased infiltration of PD-1High CD8+ T cells, expressing elevated levels of exhaustion markers and transcription factors such as TOX. This PD-1High CD8+ T cell subset also exhibited a higher frequency of IFN-γ-producing and cytotoxic (Granzyme B+, Perforin+) cells. In contrast, the less immunogenic B16F10-OVA model did not show significant differences in tumor growth; however, CD39KO mice displayed an increased frequency of antigen-specific, pre-exhausted (PD-1Int) CD8+ T cells, a population recognized as a key target of immunotherapy. Pharmacological CD39 blockade with POM-1, when combined with IL-2cx treatment to redirect IL-2 activity, enhanced the accumulation of pre-exhausted CD8+ T cells with cytotoxic potential, thereby improving tumor control. This combinatorial strategy also reshaped the tumor immune landscape by increasing activated NK cells, elevating Granzyme B expression in CD4+ T cells, and decreasing immunosuppressive M-MDSCs expressing CD39, CD38, and CD73. Collectively, our findings demonstrate that integrating purinergic pathway inhibition with IL-2-based immunotherapies can coordinately reprogram lymphoid and myeloid compartments, attenuate immunosuppressive mechanisms within the tumor microenvironment, and amplify antitumor immunity, providing a strong rationale for advancing this strategy toward clinical translation.

PURPOSE: Pontine diffuse midline gliomas (PDMGs) are among the most lethal pediatric brain tumors with a median survival of approximately one year. Reliable prognostic markers are needed to guide treatment strategies and inform families. Our study aims to investigate the prognostic utility of delta-radiomic features in PDMGs.

MATERIALS AND METHODS: We retrospectively analyzed 35 pediatric patients with PDMG diagnosed between 2012 and 2020, all treated with radiotherapy plus concomitant and adjuvant temozolomide. Pre- and post-treatment MRI (T1-weighted, T2-weighted, and ADC maps) were subjected to manual segmentation and texture feature extraction using MaZda software. Delta radiomics features were calculated as ratios between post- and pre-treatment values. Diagnostic performance for predicting survival below or above 12 months was assessed using ROC analysis, while overall survival was further evaluated with Kaplan–Meier and Cox regression models.

RESULTS: Median overall survival was 13 months (range: 6–69). Among baseline features, only sum average from non-contrast T1 was significant, with lower values (indicating higher heterogeneity) associated with shorter OS. In the post-radiotherapy setting, sum entropy from T1 images emerged as an independent prognostic predictor, with higher values correlating with longer OS. Delta radiomics parameters, particularly sum entropy derived from T1 and T2 sequences, yielded higher AUC values than single post-treatment features, suggesting superior prognostic accuracy.

CONCLUSION: Our preliminary results indicate that delta-radiomics outperforms static texture analysis in predicting overall survival in pediatric PDMGs, and to the best of our knowledge, this is the first study to investigate the prognostic utility of delta-radiomics in this population. Evidence is provided that delta radiomics can serve as a non-invasive marker for early prognostic stratification in pediatric PDMGs. Validation in larger, multi-center cohorts is required to confirm its clinical utility.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11060-026-05457-y.

IMPORTANCE: People experiencing unsheltered homelessness face high rates of psychiatric illness and substantial barriers to care. Field-based psychiatric services built on direct outreach (known as street psychiatry) may improve care and facilitate housing while possibly reducing total health care spending, but inadequate funding limits implementation.

OBSERVATIONS: Literature shows that street psychiatric services are currently financially supported by a variety of sources, though with outsized reliance on public and private grants and contracts. Health plan reimbursement for this care remains limited. Existing payment innovations that support street medicine and other care models illustrate the spectrum of possible reimbursement mechanisms available to payers. Payers could ensure that services are reimbursed by facilitating use of the new outreach site/street place of service code, compensating necessary activities of outreach and reimbursing activities of peer specialists and other interdisciplinary team members. To pay for services outside the scope of billable encounters, payers could develop programs to directly fund or incentivize care coordination, housing support, and other services. Sufficient fee-for-service rates and risk adjustment may encourage and support care for this population. Maintaining or expanding Medicaid eligibility and limiting administrative barriers to coverage for people experiencing homelessness are essential.

CONCLUSIONS AND RELEVANCE: The need for outreach-informed psychiatric care continues to grow. Payment model reforms may enable practitioners to deliver evidence-based street psychiatry at scale. Successful programs and states demonstrate that the described reforms are likely feasible and effective. Patients experiencing unsheltered homelessness, some of whom have substantial psychiatric care needs, are likely to benefit greatly from improved reimbursement for these services.

As US homelessness grows, so too does the forced removal of individuals and their belongings from where they are staying, also known as encampment sweeps, which have been associated with increased overdose and reduced healthcare access. We examined associations between past-year experiences of encampment sweeps and suboptimal health behaviors, outcomes, and healthcare access from 155 people who use drugs (PWUD) in Massachusetts. Thirty-eight percent of participants experienced a sweep in the past year, with 73% citing difficulty accessing health or social services following sweeps. Those who had been relocated were more likely to report worse mental health symptoms and feeling unwelcome in medical settings (both p < 0.05). Findings provide additional evidence that encampment sweeps disrupt access to essential services, likely further marginalizing PWUD and people who are homeless. Strategies that support, rather than punish, these populations are needed.

BACKGROUND: Enteral nutrition (EN) delivery is often interrupted in the intensive care unit (ICU), and while continuous 24-hour feeding is standard practice, emerging evidence from circadian biology and pilot trials suggests that daytime-restricted EN may enhance nutritional adequacy and patient outcomes by aligning feeding with biological rhythms.

METHODS: This quality improvement study describes a novel, standardized daytime-restricted EN protocol in a community hospital ICU and retrospectively evaluate its real-world implementation. The protocol involved a stepwise transition in EN delivery, beginning with continuous trophic feeding (acute/initial phase), followed by daytime-restricted 12-hour cyclic feeding (anabolic recovery phase), and advancing to intermittent daytime-restricted feeding (chronic recovery phase). A convenience sample of 22 adult ICU patients (12 received continuous 24-hour EN; 10 with the daytime-restricted EN protocol) was analyzed. Clinical data were extracted from electronic medical records, including EN infusion rates, duration, and interruptions.

RESULTS: Patients in the daytime-restricted group received EN at higher infusion rates (median 87.5 vs. 40.0 mL/hr), over fewer hours per day (11.0 vs. 14.5 hours), experienced fewer interruptions (1.0 vs. 9.5 hours/day), and received a greater percentage of their prescribed nutritional volume (90.0% vs. 57.5%) compared to the continuous group (all P value < 0.05). Vomiting was more frequently reported in the daytime-restricted group, while constipation was more common in the continuous group, though these differences were not statistically significant.

CONCLUSION: This preliminary evaluation supports the feasibility of implementing a daytime-restricted EN protocol in an adult ICU and suggests potential advantages in delivery consistency and nutritional adequacy. To support broader implementation, larger prospective studies across broader ICU populations are necessary.