Publications by Year: 2025

BACKGROUND: Biologic therapies improve outcomes in severe asthma, but eligibility criteria vary globally, influencing the proportion of patients who qualify. We systematically reviewed studies to estimate the global prevalence of biologic eligibility in patients aged ≥12 years with American Thoracic Society / European Respiratory Society (ATS/ERS)-defined severe asthma and the proportion eligible for each biologic.

METHODS: Following PRISMA guidelines (PROSPERO CRD42023393897), we searched MEDLINE, EMBASE, Web of Science, and ClinicalTrials.gov for studies published between 2000 and 2025 that reported the proportion of biologic-naïve, severe asthma patients eligible for omalizumab, mepolizumab, benralizumab, reslizumab, dupilumab, or tezepelumab. Two reviewers independently screened studies, extracted data on eligibility proportions and criteria, and assessed quality using the AXIS tool.

RESULTS: Ten observational studies, including 3500 patients with ATS/ERS-defined severe asthma, met the inclusion criteria. Across all studies, 1770 patients (51%) were eligible for at least 1 biologic, though estimates ranged widely from 24% to 91%, largely reflecting differences in national eligibility criteria. Omalizumab eligibility was reported in 8 studies (16%, range 6%-66%), mepolizumab in 9 studies (27%, 19%-78%), benralizumab in 6 studies (25%, 19%-53%), reslizumab in 6 studies (17%, 6%-41%), and dupilumab in 2 studies (41%, 37%-75%). No study assessed tezepelumab. Overall, the lowest eligibility (24%) was reported in the European IDEAL cohort due to stringent exacerbation and biomarker criteria, whereas the highest (91%) was observed in a Canadian single-centre cohort using less restrictive national regulatory criteria.

CONCLUSION: Globally, approximately 51% of adults with severe asthma are eligible for biologic therapy, excluding tezepelumab. Among available biologics, eligibility is generally higher for anti-IL5/IL5Rα therapies than for anti-IgE, and appears highest for anti-IL4Rα, although data for the latter remain limited.

INTRODUCTION: Vascularized composite allotransplantation (VCA) has achieved significant clinical success, but lifelong immunosuppression remains essential to prevent rejection. Despite potent regimens, including tacrolimus, mycophenolate mofetil, and steroids, rejection episodes frequently occur within the first postoperative year. The side effects of immunosuppressive drugs must be carefully balanced against the risks of insufficient therapy. This review specifically aims to evaluate current immunosuppressive regimens and infection prophylaxis in VCA to identify evidence based approaches that attempt to mitigate rejection, prevent infections, and improve long-term graft survival.

METHODS: A systematic review was conducted across PubMed/MEDLINE, EMBASE, and Web of Science databases, adhering to PRISMA 2020 guidelines. Inclusion criteria focused on studies reporting immunosuppressive regimens, dosages, and infection prophylaxis in VCA surgery. Non-VCA, animal, feasibility studies, and non-English publications were excluded.

RESULTS: Of 1,150 screened articles, 42 met inclusion criteria. Upper extremity and facial VCAs represented 50% and 29% of cases, respectively, with traumatic amputation as the primary indication (37%). Antithymocyte globulin was the most common induction drug, while tacrolimus, mycophenolate mofetil, and steroids were predominant for maintenance therapy in 33% and 11% of cases, respectively. Infection prophylaxis was used in 31% of cases. Drug dosages varied widely, and no standardized immunosuppressive protocols were identified.

CONCLUSION: Current immunosuppressive strategies in VCA lack standardization, leading to variability in outcomes and increased risks. Infection prophylaxis remains underutilized despite recipient vulnerability. There is a critical need for standardized and tailored guidelines to optimize immunosuppressive therapy and infection control, ensuring graft survival and improved patient outcomes.

The acute inflammatory response is a highly coordinated protective process governed by a superfamily of mediators termed specialized proresolving mediators. This includes the recently uncovered 17R-Resolvin D2 (17R-RvD2). We report 17R-RvD2 is rapidly metabolized and locally inactivated by human macrophages. An analog was prepared in a stereospecific synthesis. This benzo-17R-RvD2 resists rapid enzymatic inactivation and shared 17R-RvD2's pro-resolving actions enhancing human macrophage efferocytosis (pico-nanomolar). In peritonitis, benzo-17R-RvD2 (1 ng/mouse; 2.7 pmol) limited neutrophil infiltration >70%, reduced tumor necrosis factor alpha (TNF-α), and increased interleukin-1 (IL-1) receptor antagonist. The analog (1 nM) also enhanced >50% Escherichia coli killing by human leukocytes, equi-molar potent to 17R-RvD2. Benzo-17R-RvD2 (5 nM) reduced the area of human neutrophil swarms on zymosan-targeted chips >30%, without reducing potency of neutrophil swarms against live Candida clusters. Benzo-17R-RvD2 activated human-RvD2 receptor, EC50 ∼1.5 nM, comparable to 17R-RvD2. This longer-acting benzo-17R-RvD2 stimulated critical events in resolution of inflammation, providing a manufacturable prototype for potent SPM mimetics.

Alzheimer's disease (AD) begins decades before clinical symptoms emerge. The "amyloid hypothesis" suggests that amyloid-β (Aβ) deposition initiates a cascade of tau hyperphosphorylation, neuroinflammation, and neuronal loss leading to cognitive decline. The recent success of anti-Aβ therapies such as Leqembi in prodromal or mild cognitive impaired patients underscores the importance of early intervention and Aβ clearance. However, safety and cost limitations highlight the need for alternative therapeutic strategies. Small-molecule modulators of Sigma-1 and Sigma-2 receptors (σ1R and σ2R) have emerged as promising candidates for AD treatment. σ1R agonists exhibit neuroprotective and anti-amnestic effects under pathological conditions without affecting normal cognition. Beyond AD, σ1R is implicated in several neurodegenerative diseases including ALS (amyotrophic lateral sclerosis), Parkinson's, and Huntington's diseases, stroke, and epilepsy. σ1R plays a key role at mitochondria-associated ER membranes (MAMs)-specialized lipid raft-like domains that form functional membrane contact sites between the endoplasmic reticulum (ER) and mitochondria. β-secretase (BACE1), γ-secretase, and their substrates APP and palmitoylated APP (palAPP) localize in the MAMs, promoting amyloidogenic Aβ production. MAMs serve as dynamic hubs for inter-organelle communication, calcium signaling, and lipid metabolism. The "MAM hypothesis" proposes that MAM dysregulation drives early AD pathology and persists throughout disease progression, contributing to neurofibrillary tangle formation, calcium imbalance, and neuroinflammation. This review aims to summarize the current understanding of σ1R-mediated regulation of MAMs and its neuroprotective mechanisms, highlighting potential therapeutic opportunities for targeting σ1R in AD and other neurodegenerative disorders.

INTRODUCTION: Sellar arachnoid cysts are rare intracranial lesions with variable clinical presentations, making their optimal management uncertain. This systematic review consolidates current knowledge on their epidemiology, radiological features, surgical management, and outcomes.

MATERIALS AND METHODS: A literature search, following PRISMA-P 2015 guidelines, was conducted in MEDLINE/PubMed, Google Scholar, and Ovid Embase. Studies published in English from the year 2000 onwards were included. Data extraction focused on patient demographics, clinical presentation, surgical approaches, outcomes, and complications.

RESULTS: Thirty-three studies (16 case reports, 17 case series) met the inclusion criteria, encompassing 154 patients (59.34% female, mean age 51.48 years). The most common symptoms were visual disturbances (57.14%), headaches (35.06%), and endocrine disorders (30.52%). Surgical intervention details were available for 144 patients. Endoscopic transsphenoidal surgery was the most frequent approach (73.38%), followed by microscopic transsphenoidal surgery (11.69%). Various sellar reconstruction techniques were employed, including fascia lata, abdominal fat grafts, and nasoseptal flaps. The mean follow-up was 42.90 months. Postoperative complications occurred in 15.58% of cases, with cerebrospinal fluid leaks (7.14%) being the most common. Cyst recurrence was observed in 6.49% of patients. Most individuals with visual disturbances and headaches improved postoperatively, while endocrine function recovery was less consistent.

DISCUSSION AND CONCLUSIONS: SACs can cause significant morbidity due to mass effect and endocrine dysfunction. Endoscopic transsphenoidal surgery is the preferred treatment, but effective reconstruction is crucial to minimizing cerebrospinal fluid leaks. The recurrence rate highlights the importance of long-term follow-up. Future research should aim to standardize management protocols for improved outcomes.

BACKGROUND: Colorectal cancer (CRC) is a common and highly lethal malignancy worldwide. Even after curative resection, patients with stage I-III disease remain at substantial risk of recurrence and mortality. The Prognostic Immune and Nutritional Index (PINI) and lymphocyte-to-monocyte ratio (LMR) have been validated as prognostic markers in cancer, yet their individual predictive performance remains limited. We developed a novel Immune-Nutritional Prognostic Ratio (INPR) integrating PINI and LMR to provide a more comprehensive assessment of immune, nutritional, and inflammatory status. This study further evaluated its value in predicting 1-, 3-, and 5-year survival in stage I-III CRC.

METHODS: We retrospectively analyzed data from 556 colorectal cancer patients at two hospitals, with one serving as the validation cohort. Receiver operating characteristic (ROC) curves were used to determine optimal cutoff values for PINI and LMR, and the area under the curve (AUC) was applied to assess predictive performance. KKaplan-Meier analysis showed that lower PINI and LMR were associated with shorter overall survival (OS). The INPR, integrating both markers, demonstrated superior accuracy. Variables linked to OS were selected using the Boruta algorithm and multivariable Cox regression, and a nomogram model was developed and validated internally and externally.

RESULTS: The Youden index identified optimal cutoff values of 3.50 for PINI and 2.65 for LMR, with low levels independently predicting shorter OS. The INPR, integrating both, stratified patients into low-, intermediate-, and high-risk groups, with 5-year OS rates of 93.30%, 59.35%, and 28.57% in the training cohort (p<0.001). INPR outperformed either marker alone, showing higher AUC. A nomogram incorporating variables selected by the Boruta algorithm and multivariable Cox regression demonstrated stable and superior prognostic performance in both internal and external validation.

CONCLUSION: Our findings demonstrate that INPR is a simple, accessible, and effective prognostic tool for postoperative risk stratification in stage I-III CRC patients, providing valuable guidance for optimizing individualized treatment strategies.

The German philosopher Walter Benjamin, who died attempting to cross a border to escape persecution, described both the impossibility and the possibilities of translation[ 1]. The impossibility is implicit in the very title of Benjamin's essay, Die Aufgabe des Übersetzers. The German word Aufgabe can mean "task" or "endeavor" but also a "giving up" or "surrender." There is no English word that conveys the ambiguities and nuances of Aufgabe. And as I write this, I am aware that translating my English sentences into Chinese will create new impossibilities. But the impossibility of "true" or "literal" translation also opens new possibilities, for interpretation, adaptation, and (re)creation of new meaning. The same holds for translating palliative care: both the term and the discipline or practice.

BACKGROUND: What is the minimum number of questions necessary to diagnose any given primary headache disorder? The answer to this question may provide clinicians with a more efficient approach to history taking and lead to a more concise form of ICHD3. In this project, we attempt to address this problem mathematically.

METHODS: We defined a headache phenotype as a collection of characteristics, variables that can take on a Boolean (true/false) value and correspond to elements of the diagnostic criteria for each headache in ICHD3. There may be multiple phenotypes that fit a given diagnosis in the ICHD3. We extracted all characteristics used to describe primary headaches up to two levels deep in the hierarchy in the ICHD3. Episodic syndromes associated with migraine-recurrent gastrointestinal disturbance, benign paroxysmal vertigo, benign paroxysmal torticollis-were excluded because these require a primary diagnosis of migraine. For each headache diagnosis, we determined its "necessary true" (NT) characteristics. We also generated a list of "necessary false" (NF) characteristics by identifying characteristics that logically contradict the NT for each given diagnosis. We then sought to algorithmically identify the smallest set of NT and NF needed to differentiate between all primary headache diagnoses. As a result, any primary ICHD3 headache phenotype can be diagnosed once both the NT and NF criteria are satisfied. We verified this by translating all the possible conditions described by the ICHD3 criteria to our phenotype encoding schema.

RESULTS: We were able to minimize the NT and NF criteria to a set of 22 and 6 characteristics, respectively, with 5 overlaps between the groups. This results in a final set of 23 unique characteristics. Though an even smaller NT set may be possible, we are limited by computational power. These characteristics can be queried by using the following questions to generate a headache phenotype: (1) duration, (2) frequency, (3) sudden/rapid onset, (4) laterality, (5) clearly remembered onset, (6) sharp contour, (7) severity, (8) relationship to sleep/awakening, (9) reversibility of aura, (10) stabbing quality, and whether the headache can be triggered by (11) sex, (12) compression, (13) traction, (14) cold, or (15) exercise.

CONCLUSION: Fifteen questions are necessary to differentiate the primary headache disorders in ICHD3. A smaller set may be possible, but we cannot prove its existence. Using this reduced set of questions, clinicians may be able to more efficiently arrive at ICHD3 diagnoses, but further research is required.

The Hatch-Waxman Act of 1984 was designed to accelerate generic drug entry by establishing a framework for resolving patent disputes between brand-name and generic manufacturers. While the Act has facilitated competition and expanded the availability of affordable medicines, brand-name firms have increasingly exploited its procedural structure to delay or deter generic competition through "serial litigation." This strategy involves filing successive, questionable lawsuits, often based on non-innovative continuation patents. Even if the brand ultimately loses, the delays and litigation costs can discourage generic firms from entering the market or compel them to settle on terms that undermine patients' timely access to affordable generics. In the case of Astellas's overactive bladder drug mirabegron (Myrbetriq), after an initial Hatch-Waxman case settled in 2020 with generic entry expected in 2024, Astellas pursued 4 additional lawsuits, each built on new but substantively indistinguishable patents. These tactics have delayed broad competition, leaving only 2 firms to launch in 2024 under the threat of massive damages. Similar patterns are observed with other drugs, including bimatoprost (Latisse), aflibercept (Eylea), and tasimelteon (Hetlioz).

In a secondary analysis from a randomized controlled trial of a peer advocacy training intervention for people living with HIV (PLWH), we examined effects on advocacy targeting specific HIV protective behaviors among enrolled social network members (alters), and whether alter behaviors were predicted by advocacy receipt and tone of delivery. 210 PLWH and 599 alters enrolled and were followed over 18 months. Repeated measures logistic regressions showed that PLWH in the intervention group targeted more alters with advocacy for HIV testing, condom use, pre-exposure prophylaxis, and HIV care, compared to those in the control group. Alters targeted with HIV testing advocacy were more likely to report increased HIV testing at the subsequent assessment. Among alters with HIV-negative main partners, receipt of condom use advocacy predicted increased consistent condom use at the subsequent assessment. Advocacy training for PLWH can increase targeted HIV prevention advocacy, which then promotes HIV testing and condom use.