Association of tibial acceleration during walking to pain and impact loading in adults with knee osteoarthritis.

BACKGROUND: Higher impact loading during walking is implicated in the pathogenesis of knee osteoarthritis. Accelerometry enables the measurement of peak tibial acceleration outside the laboratory. We characterized the relations of peak tibial acceleration to knee pain and impact loading during walking in adults with knee osteoarthritis. METHODS: Adults with knee osteoarthritis reported knee pain then walked at a self-selected speed on an instrumented treadmill for 3 min with an ankle-worn inertial measurement unit. Ground reaction forces and tibial acceleration data were sampled for 1 min. Vertical impact peaks, and average and peak instantaneous load rates were determined and averaged across 10 steps. Peak tibial acceleration was extracted for all steps and averaged. Pearson's correlations and multiple linear regression analyses assessed the relation of peak tibial acceleration to pain and impact loading metrics, independently and after controlling for gait speed and pain. FINDINGS: Higher peak tibial acceleration was associated with worse knee pain (r = 0.39; p = 0.01), and higher vertical average (r = 0.40; p = 0.01) and instantaneous (r = 0.46; p = 0.004) load rates. After adjusting for gait speed and pain, peak tibial acceleration was a significant predictor of vertical average (R2 = 0.33; p = 0.003) and instantaneous (R2 = 0.28; p = 0.02) load rates, but not strongly associated with vertical impact peak. INTERPRETATIONS: Peak tibial acceleration during walking is associated with knee pain and vertical load rates in those with knee osteoarthritis. Clinicians can easily access measures of peak tibial acceleration with wearable sensors equipped with accelerometers. Future work should determine the feasibility of improving patient outcomes by using peak tibial acceleration to inform clinical management.

MLL3 regulates the CDKN2A tumor suppressor locus in liver cancer.

Mutations in genes encoding components of chromatin modifying and remodeling complexes are among the most frequently observed somatic events in human cancers. For example, missense and nonsense mutations targeting the mixed lineage leukemia family member 3 (MLL3, encoded by KMT2C) histone methyltransferase occur in a range of solid tumors, and heterozygous deletions encompassing KMT2C occur in a subset of aggressive leukemias. Although MLL3 loss can promote tumorigenesis in mice, the molecular targets and biological processes by which MLL3 suppresses tumorigenesis remain poorly characterized. Here, we combined genetic, epigenomic, and animal modeling approaches to demonstrate that one of the mechanisms by which MLL3 links chromatin remodeling to tumor suppression is by co-activating the Cdkn2a tumor suppressor locus. Disruption of Kmt2c cooperates with Myc overexpression in the development of murine hepatocellular carcinoma (HCC), in which MLL3 binding to the Cdkn2a locus is blunted, resulting in reduced H3K4 methylation and low expression levels of the locus-encoded tumor suppressors p16/Ink4a and p19/Arf. Conversely, elevated KMT2C expression increases its binding to the CDKN2A locus and co-activates gene transcription. Endogenous Kmt2c restoration reverses these chromatin and transcriptional effects and triggers Ink4a/Arf-dependent apoptosis. Underscoring the human relevance of this epistasis, we found that genomic alterations in KMT2C and CDKN2A were associated with similar transcriptional profiles in human HCC samples. These results collectively point to a new mechanism for disrupting CDKN2A activity during cancer development and, in doing so, link MLL3 to an established tumor suppressor network.

Inter-joint coordination variability is associated with pain severity and joint loading in persons with knee osteoarthritis.

As the lower extremity is a linked-joint system, the contribution of movements at the hip and ankle, in addition to the knee, to gait patterns should be considered for persons with knee osteoarthritis (OA). However, the relationships of joint coordination variability to OA symptoms, particularly knee pain, and joint loading is unknown. The purpose of this study was to determine the relationship of joint coordination variability to knee pain severity and joint loading in persons with knee OA. Thirty-four participants with knee OA underwent gait analysis. Vector coding was used to assess coordination variability during the early, mid, and late stance phase. Hip-knee coupling angle variability (CAV) during midstance was associated with Knee Injury and Osteoarthritis Outcome Score (KOOS) pain (r = -0.50, p = 0.002) and Visual Analog Scale pain (r = 0.36, p = 0.04). Knee-ankle CAV during midstance was associated with KOOS pain (r = -0.34, p = 0.05). Hip-knee CAV during early and midstance were associated with knee flexion moment (KFM) impulses (r = -0.46, p = 0.01). Knee-ankle CAV during early and midstance were associated with peak KFM (r = -0.51, p < 0.01; r = -0.70, p < 0.01). Moreover, knee-ankle CAV during early, mid, and late stance phase were associated with KFM impulses (r = -0.53, p < 0.01; r = -0.70, p < 0.01; r = -0.54, p < 0.01). These findings suggest that joint coordination variability may be a factor that influences pain and knee joint loading in persons with knee OA. Statement of Clinical Significance: Movement coordination of the hip, knee, and ankle should be considered in the clinical management and future research related to knee OA.

Gait speed and kinesiophobia explain physical activity level in adults with osteoarthritis: A cross-sectional study.

Identifying potential contributing factors for physical inactivity in people with knee osteoarthritis is vital for designing practical activity promoting interventions. Walking is a common activity, but it is unknown how gait characteristics may influence physical activity and if psychological factors, specifically fear of movement (kinesiophobia), contribute to this relationship. The aim of our study was to investigate the contributions of select gait parameters and kinesiophobia to activity levels. Cross-sectional data from 40 participants (F 24|M 16; age 57.6 ± 8.9 years; BMI 34.7 ± 7.0 kg/m2 ) with uni- or bilateral knee osteoarthritis were included. Physical activity and kinesiophobia were assessed by self-report using the University of California, Los Angeles activity rating scale, and Tampa scale for kinesiophobia, respectively. Gait parameters were collected with three-dimensional gait analysis while participants walked on an instrumented split-belt treadmill at a self-selected speed. Higher peak sagittal plane joint moments at the ankle (ρ = 0.418, p = 0.007), and hip (ρ = 0.348, p = 0.028), faster self-selected gait speed (ρ = 0.553, p < 0.001), and less kinesiophobia or fear of movement (ρ = -0.695, p < 0.001) were independently related to higher physical activity level in adults with knee osteoarthritis. In hierarchical regression models, after accounting for covariates, only self-selected gait speed, and kinesiophobia significantly contributed to explaining the variation in physical activity level. Statement of clinical significance: Interventions aimed at improving physical activity participation in those with lower limb osteoarthritis should consider assessing the contribution of pain-related fear of movement.

Quest for singlet fission of organic sulfur-containing systems in the higher lying singlet excited state: application prospects of anti-Kasha's rule.

In this study, we explore the possibilities of the deactivating pathways of organic thione containing systems through first-principles calculations. We particularly pay attention to the second lying singlet excited state, S2, due to its large energy difference from the lowest lying S1 state in the sulfur-containing systems. Several theoretical models including the previously synthesized thiones and the strategically designed molecules are investigated to search for the basic conjugation unit that exhibits the prospect of S2 fission. Various molecular motifs and different substituents are combined to maneuver the relative alignment of the relevant low excited energy states. The results lead us to conclude that the thione derivatives, under rational and delicate molecular designs, may be engineered to possess a sufficiently high S2-S1 energy gap as high as 2 eV and that these systems may exhibit S2 fission to triplet excitons in the red to near infrared region.

A Review on Microfluidics-Based Impedance Biosensors.

Electrical impedance biosensors are powerful and continuously being developed for various biological sensing applications. In this line, the sensitivity of impedance biosensors embedded with microfluidic technologies, such as sheath flow focusing, dielectrophoretic focusing, and interdigitated electrode arrays, can still be greatly improved. In particular, reagent consumption reduction and analysis time-shortening features can highly increase the analytical capabilities of such biosensors. Moreover, the reliability and efficiency of analyses are benefited by microfluidics-enabled automation. Through the use of mature microfluidic technology, complicated biological processes can be shrunk and integrated into a single microfluidic system (e.g., lab-on-a-chip or micro-total analysis systems). By incorporating electrical impedance biosensors, hand-held and bench-top microfluidic systems can be easily developed and operated by personnel without professional training. Furthermore, the impedance spectrum provides broad information regarding cell size, membrane capacitance, cytoplasmic conductivity, and cytoplasmic permittivity without the need for fluorescent labeling, magnetic modifications, or other cellular treatments. In this review article, a comprehensive summary of microfluidics-based impedance biosensors is presented. The structure of this article is based on the different substrate material categorizations. Moreover, the development trend of microfluidics-based impedance biosensors is discussed, along with difficulties and challenges that may be encountered in the future.

Sagittal plane ankle kinetics are associated with dynamic hip range of motion and gait efficiency in women with hip osteoarthritis.

Loss of sagittal plane hip range of motion (ROM) is a commonly reported walking gait impairment in people with hip osteoarthritis (OA). The purpose of this study was to evaluate whether sagittal plane hip ROM reduction and the resulting altered sagittal plane ankle kinetics during gait influence the energy cost of walking in people with hip OA. We evaluated 24 women with unilateral hip OA (60 ± 9.1 years; 29.4 ± 6.1 kg/m2 ). Sagittal plane hip ROM and peak ankle dorsiflexion moment were assessed by instrumented gait analysis. We also used a portable metabolic system to measure the energy cost of walking. Pearson correlations and regression analyses were performed to test our hypotheses. We found that greater involved limb sagittal plane hip ROM was associated with a larger ankle peak dorsiflexion moment at push-off during gait (R = 0.50, p = 0.01). Greater involved limb peak ankle dorsiflexion moment at push-off was associated with a lower oxygen consumption during gait (R = -0.51, p = 0.01). Involved limb peak ankle dorsiflexion moment at push-off predicted 26% of the variance in O2 cost. Statement of Clinical Significance: Sagittal plane hip ROM was associated with peak ankle dorsiflexion moment at push-off during gait in women with hip OA. Moreover, peak ankle dorsiflexion moment at push-off was associated with the energy cost of walking. Therefore, modifying sagittal plane hip ROM and peak ankle dorsiflexion moment could be a possible rehabilitation strategy to improve gait efficiency in women with hip OA.

Description of Photodegradation Mechanisms and Structural Characteristics in Carbon@Titania Yolk-Shell Nanostructures by XAS.

Carbon@titania yolk-shell nanostructures are successfully synthesized at different calcination conditions. These unique structure nanomaterials can be used as a photocatalyst to degrade the emerging water pollutant, acetaminophen (paracetamol). The photodegradation analysis studies have shown that the samples with residual carbon nanospheres have improved the photocatalytic efficiency. The local electronic and atomic structure of the nanostructures are analyzed by X-ray absorption spectroscopy (XAS) measurements. The spectra confirm that the hollow shell has an anatase phase structure, slight lattice distortion, and variation in Ti 3d orbital orientation. In situ XAS measurements reveal that the existence of amorphous carbon nanospheres inside the nano spherical shell inhibit the recombination of electron-hole pairs; more mobile holes are formed in the p-d hybridized bands near the Fermi surface and enables the acceleration of the carries that significantly enhance the photodegradation of paracetamol under UV-visible irradiation. The observed charge transfer process from TiO2  hybridized orbital to the carbon nanospheres reduces the recombination rate of electrons and holes, thus increasing the photocatalytic efficiency.

Endogenous spacing enables co-processing of microRNAs and efficient combinatorial RNAi.

We present Multi-miR, a microRNA-embedded shRNA system modeled after endogenous microRNA clusters that enables simultaneous expression of up to three or four short hairpin RNAs (shRNAs) from a single promoter without loss of activity, enabling robust combinatorial RNA interference (RNAi). We further developed complementary all-in-one vectors that are over one log-scale more sensitive to doxycycline-mediated activation in vitro than previous methods and resistant to shRNA inactivation in vivo. We demonstrate the utility of this system for intracranial expression of shRNAs in a glioblastoma model. Additionally, we leverage this platform to target the redundant RAF signaling node in a mouse model of KRAS-mutant cancer and show that robust combinatorial synthetic lethality efficiently abolishes tumor growth.

A preclinical platform for assessing antitumor effects and systemic toxicities of cancer drug targets.

Anticancer drug development campaigns often fail due to an incomplete understanding of the therapeutic index differentiating the efficacy of the agent against the cancer and its on-target toxicities to the host. To address this issue, we established a versatile preclinical platform in which genetically defined cancers are produced using somatic tissue engineering in transgenic mice harboring a doxycycline-inducible short hairpin RNA against the target of interest. In this system, target inhibition is achieved by the addition of doxycycline, enabling simultaneous assessment of efficacy and toxicity in the same animal. As proof of concept, we focused on CDK9­a cancer target whose clinical development has been hampered by compounds with poorly understood target specificity and unacceptable toxicities. We systematically compared phenotypes produced by genetic Cdk9 inhibition to those achieved using a recently developed highly specific small molecule CDK9 inhibitor and found that both perturbations led to robust antitumor responses. Remarkably, nontoxic levels of CDK9 inhibition could achieve significant treatment efficacy, and dose-dependent toxicities produced by prolonged CDK9 suppression were largely reversible upon Cdk9 restoration or drug withdrawal. Overall, these results establish a versatile in vivo target validation platform that can be employed for rapid triaging of therapeutic targets and lend support to efforts aimed at advancing CDK9 inhibitors for cancer therapy.

Bilateral lacrimal glands and paranasal sinus diffuse large B-cell lymphoma following lung mucosa-associated lymphoid tissue lymphoma in one patient.

We report an atypical case of diffuse large B-cell lymphoma (DLBCL) of bilateral lacrimal glands and paranasal sinus following mucosa-associated lymphoid tissue (MALT) lymphoma of the lung. Bilateral DLBCL is rare in the literature, and only few cases of DLBCL in bilateral lacrimal gland are reported. A 71-year-old male presented with bilateral, slowly enlarging, and swelling of both eyelids. Computed tomography scan images showed bilateral symmetric, hyperdense, circumferential masses over lacrimal glands occupying most of the orbital compartment. Neither optic nerve involvement nor adjacent orbital walls erosion was noted. Bilateral excisional biopsy and pathological examination confirmed the diagnosis of DLBCL. Since DLBCL of bilateral lacrimal gland can occur in case of systemic MALT lymphoma, excision and pathological examination is mandatory, and further metastatic workup is essential.

Successful Resection of Retrobulbar Carcinosarcoma without Recurrence: A Case Report.

Carcinosarcomas are biphasic tumors comprising carcinoma and sarcoma components that occur in many tissues but are rarely found in the orbit. A 70-year-old male presented to the ophthalmic clinic with progressive proptosis, having decreased vision in the left eye for 8 months. On examination, severe exophthalmos and lagophthalmos with limited extraocular movement were noted. Orbital computed tomography scans revealed a large, well-defined, heterogeneously enhanced mass in the left retrobulbar orbital cavity. The tumor was completely resected, and the pathological examination revealed a carcinosarcoma. The prognosis was excellent without local recurrence at 48 months postoperatively. Thus, when considering treatment for effective management of such tumors, tumor resection followed by radiotherapy or chemotherapy is highly recommended.

Receptor-Interacting Protein 140 Enhanced Temozolomide-Induced Cellular Apoptosis Through Regulation of E2F1 in Human Glioma Cell Lines.

Glioblastoma (GBM), a grade IV glioma, is responsible for the highest years of potential life lost among cancers. The poor prognosis is attributable to its high recurrence rate, caused in part by the development of resistance to chemotherapy. Receptor-interacting protein 140 (RIP140) is a very versatile coregulator of nuclear receptors and transcription factors. Although many of the pathways regulated by RIP140 contribute significantly to cancer progression, the function of RIP140 in GBM remains to be determined. In this study, we found that higher RIP140 expression was associated with prolonged survival in patients with newly diagnosed GBM. Intracellular RIP140 levels were increased after E2F1 activation following temozolomide (TMZ) treatment, which in turn modulated the expression of E2F1-targeted apoptosis-related genes. Overexpression of RIP140 reduced glioma cell proliferation and migration, induced cellular apoptosis, and sensitized GBM cells to TMZ. Conversely, knockdown of RIP140 increased TMZ resistance. Taken together, our results suggest that RIP140 prolongs the survival of patients with GBM both by inhibiting tumor cell proliferation and migration and by increasing cellular sensitivity to chemotherapy. This study helps improve our understanding of glioma recurrence and may facilitate the development of more effective treatments.

Strength and physical activity in osteoarthritis: The mediating role of kinesiophobia.

The aim of this study was to investigate the association between muscle strength and physical activity level in people with knee osteoarthritis (OA), and determine whether this association is mediated by pain-related fear of movement (kinesiophobia) and self-reported pain. Cross-sectional data from 37 subjects (age 58.8 ± 8.6 years, 25F/12M, BMI 33.5 ± 6.4 kg/m2 ) with OA of the knee were used. Isometric knee extensor and flexor muscle strength were measured using an isokinetic dynamometer. Physical activity, kinesiophobia, and pain were assessed by self-report using the University of California, Los Angeles activity rating scale, Tampa Scale for Kinesiophobia, and The Knee Injury and Osteoarthritis Outcome Score pain subscale, respectively. The associations between strength measures, physical activity, kinesiophobia, and pain scores, were modeled by performing a parallel multiple mediation analysis and the significance of mediational effects (kinesiophobia and pain) were tested using a bootstrap approach. Lower knee flexion and extension strength were associated with lower physical activity scores and these relationships were mediated by higher kinesiophobia scores (more fear) but not pain scores. Knee extension strength was directly associated with physical activity scores after controlling for kinesiophobia and pain scores. These results suggest that muscle strength can influence physical activity directly and indirectly through fear of movement. Assessing these measures together in this population may help clinicians identify patients that are more likely to avoid physical activities due to not only muscle weakness but also fear of movement.

Impact of step length asymmetry on walking energetics in women with hip Osteoarthritis: A pilot study.

A step length difference between the involved and uninvolved limbs in participants with hip osteoarthritis (OA) has been reported. The implications of step length asymmetry on other aspects of walking mechanics are as yet unknown. The objective of the current study was to evaluate the consequences of step length asymmetry on motion of the center of mass (COM) and energy cost of walking. We hypothesized that (i) increased step length asymmetry is associated with decreased mechanical energy exchange; (ii) decreased mechanical energy exchange is associated with increased O2 cost; (iii) increased step length asymmetry is associated with increased oxygen O2 cost during walking in women with hip OA. We evaluated 24 women with unilateral hip OA using motion analysis as participants walked on a treadmill at self-selected speeds. Kinematic data were collected to compute step length asymmetry and mechanical energy exchange through the motion of COM. We also used a portable metabolic system to measure the energy cost of walking simultaneously. We used Pearson correlations and linear regression to test our hypotheses. We found that more asymmetric step lengths were associated with lower mechanical energy exchange (R2 = 0.231, p = 0.017). More mechanical energy exchange was associated with lower O2 cost during gait (R2 = 0.284, p = 0.009). Mechanical energy exchange predicted 54.5% of the variance in O2 cost after adjusting for self-selected walking speed. Findings suggest that modifying step length asymmetry could enhance metabolic gait efficiency indirectly by improving mechanical energy exchange in participants with hip OA.

Chapter Open for the Excited-State Intramolecular Thiol Proton Transfer in the Room-Temperature Solution.

We report here, for the first time, the experimental observation on the excited-state intramolecular proton transfer (ESIPT) reaction of the thiol proton in room-temperature solution. This phenomenon is demonstrated by a derivative of 3-thiolflavone (3TF), namely, 2-(4-(diethylamino)phenyl)-3-mercapto-4H-chromen-4-one (3NTF), which possesses an -S-H···O═ intramolecular H-bond (denoted by the dashed line) and has an S1 absorption at 383 nm. Upon photoexcitation, 3NTF exhibits a distinctly red emission maximized at 710 nm in cyclohexane with an anomalously large Stokes shift of 12 230 cm-1. Upon methylation on the thiol group, 3MeNTF, lacking the thiol proton, exhibits a normal Stokes-shifted emission at 472 nm. These, in combination with the computational approaches, lead to the conclusion of thiol-type ESIPT unambiguously. Further time-resolved study renders an unresolvable (<180 fs) ESIPT rate for 3NTF, followed by a tautomer emission lifetime of 120 ps. In sharp contrast to 3NTF, both 3TF and 3-mercapto-2-(4-(trifluoromethyl)phenyl)-4H-chromen-4-one (3FTF) are non-emissive. Detailed computational approaches indicate that all studied thiols undergo thermally favorable ESIPT. However, once forming the proton-transferred tautomer, the lone-pair electrons on the sulfur atom brings non-negligible nπ* contribution to the S1' state (prime indicates the proton-transferred tautomer), for which the relaxation is dominated by the non-radiative deactivation. For 3NTF, the extension of π-electron delocalization by the diethylamino electron-donating group endows the S1' state primarily in the ππ* configuration, exhibiting the prominent tautomer emission. The results open a new chapter in the field of ESIPT, covering the non-canonical sulfur intramolecular H-bond and its associated ESIPT at ambient temperature.

Walking energetics and fatigue are associated with physical activity in people with knee osteoarthritis.

BACKGROUND: Aberrant biomechanics may influence osteoarthritis-associated physical activity limitations. Our purpose was to evaluate the association of walking energetics, fatigue, and fatigability on physical activity in people with knee osteoarthritis. We hypothesized that using increased energy for walking, experiencing more fatigue, or being more fatigable are associated with less activity, and that fatigue and fatigability mediate the relationships between walking energetics and physical activity. METHODS: We tested our hypothesis in 30 people with knee osteoarthritis (age 58 ± 9 years, 10 Male/20 Female). Physical activity was assessed using the University of California Los Angeles score. We used a six-minute walk test to predict VO2max. Next we used a portable oxygen exchange system to measure relative energy used (100 * VO2rate/VO2max) and VO2cost during walking at preferred speeds. We used the Knee injury and Osteoarthritis Outcome Score subscale to quantify pain, and the Patient Reported Outcome Measurement Instrument System Fatigue survey and a treadmill-based fatigability test to assess fatigue and fatigability. Spearman correlations, regression, and mediation analysis were used to test our hypotheses. FINDINGS: Greater energy used during walking, fatigue, and fatigability were all associated with lower physical activity (rho = -0.585 to -0.379, P = 0.001 to 0.043). These associations persisted when incorporating pain into the models. Fatigue and fatigability mediated the associations between walking energetics and physical activity. INTERPRETATION: Walking energetics could be a useful target to promote physical activity in people with osteoarthritis. Further, the effect of walking energetics on physical activity may work through its impact on fatigability.

Characterization of stem cell-like property in cancer cells based on single-cell impedance measurement in a microfluidic platform.

Investigation of stem cell-like property in cancer cells is important for the development of new therapeutic drugs targeting at malignant tumors. Currently, the standard approach for identifying cancer stem cell-like cells relies on the recognition of stem cell surface markers. However, the reliability remains controversial among biologists. In the current work, a dielectrophoretic and impedimetric hybrid microfluidic platform was developed for capturing single cells and characterizing their stem cell-like property. Single cells were captured in 20 µm trapping wells by dielectrophoretic force and their impedance spectra were measured by an impedance analyzer. The result showed that different cancer cell lines could be differentiated by impedance magnitude ranging between 2 and 20 kHz. Moreover, cancer cells and cancer stem cell-like cells could be categorized by a 2-dimensional graph of the impedance magnitudes at 2 and 20 kHz. The stem cell-like property in cancer cells was verified by stem cell surface markers and single-cell derived colony assay. Comparing with bio-chemical approach, i.e., surface markers, bio-physical approach, i.e., cell impedance, is a label-free technique to identify cancer stem cell-like cells.

Risk of Breast Cancer in Females With Hypothyroidism: A Nationwide, Population-Based, Cohort Study.

OBJECTIVES: The results of studies investigating the relationship between breast cancer and hypothyroidism vary greatly from study to study. In this study, we analyzed a large and reliable, population-based database to gain a better understanding of the correlation. METHODS: This retrospective cohort study analyzed patients with hypothyroidism between January 1, 2000 and December 31, 2012 (hypothyroidism cohort) from the Longitudinal Health Insurance Database 2000 in Taiwan. For each woman with hypothyroidism, 1 woman without a history of breast cancer was randomly selected from the Longitudinal Health Insurance Database 2000 and frequency matched (1:4) with women without hypothyroidism by age and index year of hypothyroidism. The study outcome was the diagnosis of breast cancer during a 12-year follow-up period. RESULTS: In this study, 6665 women with hypothyroidism and 26 660 women without hypothyroidism were identified. The hypothyroidism cohort had a significantly higher risk of breast cancer than the nonhypothyroidism cohort (adjusted hazard ratio [aHR] 1.69 [95% CI, 1.15-2.49]; P = .01), especially in the group aged 40 to 64 years (aHR 2.07 [95% CI, 1.32-3.23]; P = .01). Women in the hypothyroidism cohort taking levothyroxine for a duration ˃588 days showed a significantly decreased risk of breast cancer (aHR 0.37 [95% CI, 0.19-0.71]; P = .003). CONCLUSION: Women with hypothyroidism are at a higher risk of breast cancer than those without hypothyroidism. Levothyroxine may reduce the risk of breast cancer in a woman with hypothyroidism.