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Animal models reveal that striatal projection neurons (SPNs) fluctuate between discrete electrophysiological states with distinct levels of cortical interaction. These dynamics and their behavioral relevance remain uncharacterized in humans. Leveraging neurobiologically informed modeling of over 3 billion voxel-frame-wise striatal coactivation profiles with cortex in functional magnetic resonance imaging (fMRI), we identified population-level striatal states in humans resembling canonical SPN states that reorganized systematically with task demands, arousal and behavior. A background of low- and moderate-coactivation "down-like" and "up-like" striatal rest states with high transition reciprocity modulated task reaction times and reward reactivity. Meanwhile, sparse, disproportionately high-magnitude "bursts" of striatal coactivation with cortex, which emerged preferentially from the up-like rest state and whose cortical input composition varied with task context, tracked task engagement and arousal level. Findings bring a critical feature of corticostriatal neurobiology into systems-level view in humans and reveal a subthreshold state architecture whose balance encodes behaviorally relevant information.

Caffeine is the most widely consumed psychoactive substance in the world, and abrupt cessation in habitual users produces a stereotyped withdrawal syndrome whose dominant feature is headache. Although caffeine withdrawal is a familiar diagnosis in ambulatory and perioperative practice, it is easily overlooked in hospitalized patients on a complex medical service, where the differential for new headache is dominated by autoimmune, infectious, and vascular etiologies. We report a 33-year-old woman with overlap connective tissue disease (systemic lupus erythematosus, mixed connective tissue disease, and systemic sclerosis) admitted for doxycycline-associated Stevens-Johnson syndrome and oral mucositis. On hospital day 3, she developed an excruciating bilateral throbbing headache with photophobia, phonophobia, and nausea. Magnetic resonance imaging of the brain and magnetic resonance angiography of the head were unremarkable apart from non-specific subcortical white matter foci. The headache was refractory to six acute migraine therapies and to a status migrainosus protocol, and a lumbar puncture was being prepared. After ingestion of approximately 8 oz of brewed black coffee from the nursing station, the headache resolved within 30 minutes and did not recur, and the planned lumbar puncture was deferred. The patient was discharged the same day. The presentation met the International Classification of Headache Disorders, 3rd edition, criteria for caffeine withdrawal headache. The case illustrates how an inexpensive caffeine challenge can serve as both a diagnostic and a therapeutic step before invasive workup in a hospitalized patient whose habitual oral caffeine intake has stopped abruptly. Routine intake history, including caffeine, should be elicited at admission for any patient anticipated to be nil per os or to have impaired oral intake.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. However, these therapies are associated with immune-related adverse events (irAEs), with thyroid dysfunction as one of the most common endocrine irAEs. The role of preexisting thyroid autoantibodies (Abs) in predicting endocrine irAEs and their impact on patient survival remains unclear. This study explored the relationship between preexisting thyroid antibodies and the development of endocrine irAEs, as well as their association with overall survival (OS) in patients treated with ICIs. We retrospectively reviewed patients with malignancy treated with one or more PD-(L)1 inhibitor between July 2018 and March 2022 at The First Affiliated Hospital of Nanjing Medical University, and 4,119 patients were initially included in this study. Ultimately, 585 patients whose anti-TPO and anti-Tg levels were measured before ICI treatment were analyzed. The patients were stratified based on their pre-existing thyroid antibody status. Multivariate Cox regression models were used to analyze the risk of thyroid irAEs and the differences in OS. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were employed to validate the robustness of the results. Patients with pre-existing thyroid Ab (N&#xa0;=&#xa0;80, 13.7%) had a significantly higher incidence of thyroid irAEs compared to the antibody-negative group (N&#xa0;=&#xa0;505) (HR&#xa0;=&#xa0;4.13, 95% CI: 2.69-6.35, p < 0.001). PSM and IPTW analyses further confirmed that patients with pre-existing thyroid Ab had a markedly increased risk of grade&#x2265;2 irAEs (HR&#xa0;=&#xa0;7.54, 95% CI: 2.74-20.75, p < 0.001). No significant difference in OS was observed between the two groups (log-rank p = 0.5). Notably, patients with pre-existing thyroid Abs and irAEs had better survival outcomes (log-rank p = 0.027). A landmark analysis at 12 months indicated that patients who developed thyroid irAEs between 0 and 12 months of age had relatively low mortality rates over this time period. However, from 12 months onwards, the survival curves of the two groups tended to overlap. Preexisting thyroid antibodies provide a significant risk factor for thyroid irAEs in patients treated with ICIs. The development of thyroid irAEs has been associated with improved survival, thus suggesting a potential link between immune activation and clinical benefits.

The Stieltjes moment problem is studied in a new framework within the general Gelfand-Shilov spaces defined via weight sequences. The novelty consists of allowing for a naturally larger target space for the moment mapping, which sends a function to its sequence of Stieltjes moments. The motivation comes from a recent version of the Borel-Ritt theorem, concerning the surjectivity of the Borel mapping in Carleman-Roumieu ultraholomorphic classes in sectors, whose defining weight sequence is subject to the condition, weaker than derivation closedness, of having shifted moments. The injectivity and surjectivity of the moment mapping in this new setting is studied and, in some cases, characterized. Finally, results are provided for general weight sequences of fast and regular enough growth when the condition of shifted moments fails to hold.

Avelumab maintenance therapy is an established therapeutic approach for patients with advanced urothelial carcinoma (UC) whose disease has not progressed after first-line platinum-based chemotherapy. However, evidence on its effectiveness and safety in elderly patients remains limited. This multicenter retro-prospective Italian study included 251 patients with advanced UC who received avelumab maintenance between 2021 and 2023. Outcomes were compared between patients aged &#x2265;75 and <75 years. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Among 96 elderly and 155 younger patients, median PFS was 7.2 months (95% CI, 4.9-17.5) and 6.7 months (95% CI, 4.9-9.3), respectively (p = 0.547), while median OS was 28.1 months (95% CI, 17.3-42.1) versus 18.5 months (95% CI, 12.0-38.6) (p = 0.238). Immune-related adverse events were infrequent and generally comparable across age groups. In multivariable analyses, lung metastases independently predicted worse OS in elderly patients, whereas bone metastases and concomitant corticosteroid therapy were adverse prognostic factors in younger patients. Avelumab maintenance demonstrated similar efficacy and safety in elderly and younger patients, supporting its use regardless of age. In the evolving therapeutic landscape of advanced UC, this treatment strategy remains a relevant and practical option, particularly for elderly or comorbid patients who may not be candidates for more intensive first-line combinations.

Idiopathicshort stature (ISS) has been used for more than five decades to label children whose height is below -2 SDS without an identified underlying cause. Although originally conceived as a pragmatic diagnosis of exclusion, ISS has gradually been reified as a disease entity and is now embedded in clinical guidelines, regulatory frameworks and indications for recombinant human growth hormone therapy. In parallel, advances in genomic technologies have uncovered a growing spectrum of monogenic and chromosomal variants among children previously classified as ISS, and highlighted the continuous, polygenic architecture of height in the remainder. These developments render the idiopathic construct increasingly misleading and unstable, as every new etiological discovery shrinks - and conceptually undermines - the ISS category. In this article, we review the historical evolution and current use of ISS, summarize the impact of modern genetic testing on the classification of short stature, and argue that most children currently labeled as having ISS are better described as having "Healthy Short Stature". We define Healthy Short Stature as short stature in otherwise healthy children without systemic, syndromic or endocrine disease, in whom short stature represents the lower extreme of normal growth variation. We discuss how adopting Healthy Short Stature can reduce stigma, remain compatible with ongoing genetic investigation, and provide a more robust framework for aligning clinical practice, research and health policy with contemporary knowledge of human growth biology.

Mitral valve aneurysm; defined as a bulge of the mitral valve leaflet toward the left atrium is a rare abnormality whose pathophysiology is poorly understood. The weakened aneurysmal wall may rupture and may cause severe mitral regurgitation and life-threatining conditions. In this case report we present a case of mitral anterior leaflet aneurysm rupture in a patient with immun deficiency and chronic renal failure.

Respiratory rate (RR) predicts short-term mortality in acute care settings, yet its prognostic significance in clinically stable outpatients remains poorly defined. To determine whether the median and variability of nocturnal respiratory rate (NRR) are independently associated with long-term cardiovascular and all-cause mortality in outpatients with cardiovascular disease. We analyzed overnight chest belt waveforms from elective polysomnography in 5,679 older adults with cardiovascular disease enrolled in the Sleep Heart Health Study (SHHS). NRR was quantified at 30-second resolution, and per-subject median NRR and within-night variability (standard deviation) were derived. Kaplan-Meier survival analysis and Cox proportional hazards models were used to evaluate associations with cardiovascular and all-cause mortality over 3-year and 15-year follow-up periods, adjusting for demographic characteristics, cardiopulmonary comorbidities, and sleep apnea severity. Higher median NRR and greater NRR variability were each associated with increased cardiovascular and all-cause mortality. Combining these metrics identified a high-risk group characterized by high median and high variability of NRR, with nearly five-fold higher 3-year all-cause mortality compared with a low-risk group (unadjusted HR: 2.61; 95% CI: 1.65, 4.14; p <0.001; adjusted HR: 2.15; 95% CI: 1.30, 3.55; p =0.003). Both the baseline level and variability of NRR independently predict morttality in clinically stable outpatients with cardiovascular disease. Densely profiled NRR represents a promising, underutilized biomarker for long-term risk stratification. Nocturnal respiratory rate (NRR) is an underutilized biomarker whose prognostic significance in stable cardiovascular outpatients is unknown. In 5,679 participants from the Sleep Heart Health Study, median NRR and within-night variability derived from overnight polysomnography independently predicted cardiovascular and all-cause mortality. Stratification based on these metrics identified a high-risk group with nearly five-fold higher 3-year mortality compared with a low-risk group (adjusted HR: 2.15; 95% CI: 1.30-3.55; p =0.003).

Human supragingival plaque (SUPP) is a polymicrobial biofilm whose contents undergo dysbiotic transitions during multiple oral diseases. The study of healthy SUPP may lead to future pro or prebiotic therapies, to help prevent or revert dysbiosis during disease. However, many oral plaque models focus on the cultivation of oral pathogens and do not well cultivate commensal SUPP populations. Here, we use a 16S microbiome guided iterative approach to develop a low-cost high sample number SUPP model. Our model demonstrates several findings including a surprisingly minimal impact on salivary preparation methods on model microbiota and the ability to test microbial interactions with added oral strains to assess their fitness. This model provides a reductionist system for the study of healthy oral commensals in a complex polymicrobial framework in the absence of host immune responses.

The classical Ginzburg-Landau model has long provided the foundation for modeling superconductivity, yet it does not fully capture the rich diversity of unconventional superconducting phenomena observed experimentally. Examples include magnetic superconductors, re-entrant superconductivity, and the cuprates-materials whose behaviors are not adequately explained by traditional Ginzburg-Landau and/or Bardeen-Cooper-Schrieffer (BCS) theories. In this work, we develop a thermodynamically consistent reformulation of the Ginzburg-Landau theory expressed in gauge-invariant variables. This framework, when extended to anisotropic settings, naturally predicts preferential domain orientations and, crucially, reveals a previously overlooked symmetry-allowed term that breaks time-reversal symmetry. Such a term is essential for capturing the behavior of magnetic superconductors, particularly antiferromagnetic systems where superconductivity and magnetism coexist. We further demonstrate that stabilization of antiferromagnetic superconducting states necessitates a loss of convexity in the free energy. Together, these results unify disparate phenomena within a single-component order parameter and offer a systematic route for understanding, modeling, and controlling unconventional superconducting states.

Fusarium graminearum is a plant pathogenic fungus that causes wheat scab. This pathogen is distributed worldwide and produces deoxynivalenol, which significantly affects humans and animals. Mob1 belongs to the MOB (Mps One Binder) family, whose members are present in a wide variety of eukaryotes, and is a core component of the MEN (mitotic exit network) pathway, regulating the mitotic exit process in yeast. However, the roles of Mob1 in pathogenic fungi remain poorly understood. In this study, we investigated the roles of FgMob1 in the development and pathogenicity of F. graminearum. Functional analyses showed that FgMob1 is important for vegetative growth, conidiation, ascospore formation, DON production, and pathogenicity. Subcellular localization results revealed that FgMob1 localizes to the spindle pole bodies. Furthermore, the average number of nuclei was significantly increased in the hyphae and conidia of the FgMOB1 deletion mutant, suggesting that FgMob1 is involved in MEN. Additionally, FgMob1 plays a significant role in the response to abiotic stress, deletion of the FgMOB1 gene affected sensitivity to cell wall, plasma membrane and oxidative stresses. In summary, this study demonstrates that FgMob1 is involved in MEN and is required for vegetative growth, asexual and sexual development, abiotic stress response, and pathogenicity in F. graminearum.

The cytoskeleton, comprising intracellular filamentous structures composed of polymerized proteins, is crucial for the survival of both eukaryotes and prokaryotes. Although bacterial cytoskeletal proteins have diverged, they generally do not drive cellular motility. Spiroplasma, a genus of wall-less helical bacteria, swims by propagating a helicity-switching point (kink) along its cell axis. Unlike typical walled bacteria, whose motility depends on widespread motility machineries such as flagella and pili, Spiroplasma swimming is powered by the coordinated dynamics of five isoforms of bacterial actin MreB (SMreB1-5), which are grouped into three phylogenetic classes: SMreB1 and 4, SMreB2 and 5, and SMreB3. Despite the efforts to understand Spiroplasma swimming, its molecular mechanism remains unclear. In this review, we summarize how in vitro analyses of SMreBs have provided mechanistic insights into Spiroplasma swimming. While all SMreBs conserve the canonical actin fold, each SMreB class exhibits unique characteristics in its polymerized structures, ATPase activities, polymerization dynamics, and membrane binding. Studies of an essential SMreB subset for Spiroplasma swimming, i.e. SMreB1 and SMreB5, have revealed that SMreB1 binds to polymerized SMreB5 and disassembles it depending on the nucleotide state. These results challenge the previous model in which Spiroplasma swimming is driven by the coordinated extension and contraction of two distinct SMreB filaments. Finally, we discuss potential molecular mechanisms underlying Spiroplasma swimming and highlight key questions that must be answered to validate these models.

Microglia mount coordinated, stage-dependent compensatory programs in response to early amyloid &#x3b2; (A&#x3b2;) accumulation that preserve proteostasis and neuronal integrity during preclinical Alzheimer's disease. We propose the "microglial compensation-depletion" framework that describes a distributed compensatory network whose failure constitutes a mechanistic tipping point. Once compensatory capacity falls below a critical threshold, positive-feedback loops amplify irreversible pathology, eventually leading to cognitive decline. Integrating single-cell transcriptomics, chromatin accessibility, and genetic evidence from human cohorts and animal models, we synthesize evidence for stage-dependent microglial transitions and for glial interactions that shape resilience or vulnerability. The microglial compensation-depletion framework in the revised amyloid hypothesis is a multiscale, dynamical perspective and highlights potential strategies for modeling and clinical intervention. Intercellular ligand-receptor networks may provide quantitative substrates for defining glial-state patterns and even identifying key communication axes that delineate transitions. For example, microglial triggering receptor expressed on myeloid cells 2 (TREM2)-apolipoprotein E (APOE) signaling exemplifies an intercellular axis that modulates microglial phenotype and A&#x3b2; handling. Clinically, in vivo imaging and biofluid biomarkers may offer potential means to track glial functional reserve and to detect approaching tipping points.

In a diagnostic test using multiplex assay, each individual biomarker is often expected to have monotonic association with the disease outcome and therefore the underlying disease classification rule is partially ordered with respect to the biomarkers. Nonparametric estimation of the classification rule can be accomplished by projecting an unconstrained Bayes estimator onto the partial ordering subspace. However, computing the projection is challenging as it involves performing maximization over a constrained parameter space whose size grows exponentially with the sample size. We introduce a novel sequential update method for projection-based nonparametric estimation of the disease classification rule and propose new recursive algorithms to implement the method. The proposed algorithms yields the exact Bayes solution that maximizes the posterior gain with respect to a classification-type gain function. When compared to an existing algorithm that gives approximate Bayes solution, our algorithms accomplish the same tasks with much reduced elapsed time in simulation study. We apply the sequential update method to evaluate a human papillomavirus test for cervical cancer precursor lesions and derive diagnostic rule that improves accuracy on existing estimation methods including parametric logistic regression and monotone generalized additive models.

Melanoma harbors highly heterogeneous tumor immune microenvironments shaped by driver mutations in BRAF, NRAS, and NF1. How mutational context modulates inflammatory signaling and immune evasion mechanisms of prognosis-related genes remains poorly understood. ssGSEA scored 15 inflammatory pathways across four cohorts (TCGA, GSE19234, GSE22153, and GSE65904). Cross-cohort univariate Cox regression and a 10-algorithm machine learning framework identified and optimized a prognostic model. Immune microenvironment differences across BRAF, NRAS, NF1, and Triple-WT subtypes were characterized using ESTIMATE, CIBERSORT, and GSVA. CCNE1 was validated by shRNA knockdown in melanoma cell lines, and a mutation subtype-specific virtual knockdown model was constructed from scRNA-seq data. The prognostic model achieved a 5-year AUC of 0.95 in TCGA and outperformed published signatures in three of four cohorts. High-risk patients showed markedly reduced immune infiltration (ImmuneScore r = -0.51) and an immunosuppressive phenotype. Mutation subtype analysis revealed distinct immune landscapes: NF1-mutant tumors showed the highest antigen presentation and IFN-&#x3b3; pathway enrichment; BRAF-mutant tumors displayed the highest stromal score and M0 macrophage proportions; and NRAS-mutant tumors exhibited the lowest NK cell activity and most pronounced immunosuppression. CCNE1 was the gene most strongly correlated with the risk score and was validated as an independent poor prognostic marker across all cohorts. shRNA-mediated knockdown inhibited migration and enhanced adhesion in melanoma cell lines. Virtual knockdown modeling showed that CCNE1 suppression upregulated antigen presentation genes (HLA-A/B/C, B2M, and TAP1/2) and downregulated immune checkpoint molecules in a mutation subtype-dependent manner, with the strongest proimmunogenic effects in NF1-mutant cells and LAG3 downregulation predominantly in BRAF-mutant cells. This study establishes a high-performance inflammatory pathway-based prognostic model for melanoma and demonstrates that driver mutation subtypes differentially shape the immune microenvironment landscape. CCNE1 functions as a key oncogenic immune regulator whose modulation of antigen presentation and immune checkpoint expression is contingent on mutational context, most prominently in NF1-mutant tumors, underscoring the value of mutation-informed personalized immunotherapy strategies in melanoma.

Many diseases arise from dysfunction of defined cell populations, yet most therapeutics distribute broadly, limiting efficacy and causing toxicity. We developed ExACT, a platform for cell-type-selective intracellular delivery that exploits membrane transporters. In vivo screening of combinatorial fluorescent small-molecule libraries in mouse brain identified chemistries whose uptake is dictated by endogenous transporter expression, yielding compounds with preferential entry into neurons, astrocytes, pericytes and endothelial cells. One series showed strong selectivity for brain and retinal endothelium, where Slco1a4 mediated uptake. This selectivity principle extended to the human orthologue SLCO1A2, highly expressed in brain endothelium and oligodendrocytes, where it mediated selective uptake in a humanized mouse model and human iPSC-derived oligodendrocytes. Ectopic expression of SLCO1A2 in neurons via gene therapy created a synthetic entry port, conferring ExACT conjugate uptake on otherwise inaccessible cells. Bifunctional compounds linking transporter-targeting motifs to antisense oligonucleotides or small-molecule drugs retained pharmacological activity while conferring transporter-dependent cell-type selectivity, illustrating how transporter diversity can be harnessed for precision pharmacotherapy.

Accurate RNA polymerase II (RNAPII) - dependent gene expression requires dynamic phosphorylation of the carboxy-terminal domain (CTD) of its largest subunit, Rpb1, whose heptapeptide repeats form a regulatory platform known as the CTD code. Transcription-associated cyclin-dependent kinases (tCDKs) and CTD phosphatases coordinate the phosphorylation - dephosphorylation cycle of RNAPII throughout transcription, coupling RNA synthesis to co-transcriptional processing and chromatin regulation. By controlling stage-specific modification of the CTD, these enzymes integrate RNAPII activity into broader regulatory networks. Disruption of the delicate kinase - phosphatase balance impairs transcriptional fidelity, RNA maturation, and genome stability, either directly through altered CTD phosphorylation or indirectly through associated pathways. Such alterations are increasingly associated with developmental disorders, neurodegeneration, and cancer. Here, we synthesize current knowledge of RNAPII phosphorylation dynamics, highlighting key mechanistic principles, links to human disease, and emerging therapeutic strategies targeting this central phosphorylation-dependent regulatory system.

Group A Streptococcus (GAS) is a human-restricted pathogen whose global incidence has surged in the post-COVID era. The ability of GAS to shift from a colonizing to invasive phenotype depends on coordinated virulence gene regulation in response to host-derived signals. However, the mechanisms by which individual stress-sensing systems interact to reshape the virulence gene regulatory landscape remain incompletely understood. Here we define the regulatory programs of two conserved transcriptional regulator paralogs, SpxA1 and SpxA2, using an integrated multi-omic approach combining RNA-seq, data-independent acquisition proteomics, NanoString-based transcriptional profiling across multiple host-relevant stress conditions, and chromatin immunoprecipitation with exonuclease treatment (ChIP-exo). RNA-seq revealed functionally distinct regulons with SpxA1 governing oxidative stress defense and SpxA2 coordinating virulence-associated gene expression linked to the CovRS two-component regulatory system. Proteomic analysis established SpxA2 as a ClpXP protease substrate in GAS and identified reciprocal paralog accumulation upon loss of either SpxA1 or SpxA2, consistent with compensatory transcriptional upregulation. NanoString profiling under bacitracin and human neutrophil peptide-1 challenge identified four gene modules with distinct stoichiometry-dependent and condition-dependent regulatory logic, revealing that the SpxA1/SpxA2 ratio rather than the activity of either paralog alone determines which transcriptional programs are engaged. ChIP-exo demonstrated that SpxA2 directly modulates CovR-DNA binding occupancy in a CovR binding motif-dependent manner, simultaneously antagonizing CovR dimer binding at an extended (25-bp) CovR motif and facilitating CovR monomer binding at the canonical ATTARA motif. These findings establish the LiaFSR-SpxA2-CovRS axis as a cross-regulatory circuit through which GAS cell envelope stress sensing is directly transduced into coordinated virulence gene regulatory changes. Group A Streptococcus (GAS) causes millions of infections annually, including a recent global surge in invasive disease. To survive in the human host, GAS must rapidly reprogram virulence gene expression in response to host-derived stresses. This study characterizes two conserved transcriptional regulators, SpxA1 and SpxA2, that govern this response through interaction with RNA polymerase to indirectly influence the DNA-binding activity of downstream transcription factors. We show that SpxA2, activated by a cell envelope stress-sensing system responding to human antimicrobial peptides, reshapes the binding of the master virulence regulator CovR in a promoter-specific manner, coupling cell envelope stress sensing to virulence gene regulation. The stoichiometric balance between SpxA1 and SpxA2 functions as a regulatory rheostat calibrating overall virulence gene regulatory tone, providing a framework for understanding how RNA polymerase-interacting regulators coordinate stress responses and virulence gene control across Gram-positive bacterial pathogens.

Trigeminal neuralgia can be a debilitating pain condition that affects women more frequently than men and for which there are only limited therapeutic avenues. Trigeminal neuralgia can either be idiopathic (where there is no clearly identifiable cause), classical (which typically involves neurovascular compression of the trigeminal root entry zone) or secondary which results from nerve damage due to other causes. First-line treatments for trigeminal neuralgia include the sodium channel blockers carbamazepine and oxcarbazepine, whose mechanism of action is to stabilize the inactivated state of sodium channels, thereby reducing the electrical activities of trigeminal neurons. Second-line treatments include gabapentinoids, which act on Cav&#x3b1;2&#x3b4; subunits of high voltage activated calcium channels to inhibit synaptic transmission in the trigeminal pain pathway. Both of these treatment avenues exhibit a number of adverse effects and many patients are refractory. Hence, new avenues for combatting trigeminal neuralgia are needed. In this review article, we discuss clinical evidence for efficacy and benefits of novel pharmacological treatment approaches for trigeminal neuralgia, including the inhibition of CGRP receptors, activation and desensitization of TRPV1 channels, the development of new generations of sodium channel blockers, and the use of botulinum toxin. We conclude that while there are potential benefits of these approaches, larger well-controlled cohort studies are needed to provide a definitive answer.