Gut bacteria-derived serotonin promotes immune tolerance in early life.

The gut microbiota promotes immune system development in early life, but the interactions between the gut metabolome and immune cells in the neonatal gut remain largely undefined. Here, we demonstrate that the neonatal gut is uniquely enriched with neurotransmitters, including serotonin, and that specific gut bacteria directly produce serotonin while down-regulating monoamine oxidase A to limit serotonin breakdown. We found that serotonin directly signals to T cells to increase intracellular indole-3-acetaldehdye and inhibit mTOR activation, thereby promoting the differentiation of regulatory T cells, both ex vivo and in vivo in the neonatal intestine. Oral gavage of serotonin into neonatal mice resulted in long-term T cell-mediated antigen-specific immune tolerance toward both dietary antigens and commensal bacteria. Together, our study has uncovered an important role for specific gut bacteria to increase serotonin availability in the neonatal gut and identified a function of gut serotonin in shaping T cell response to dietary antigens and commensal bacteria to promote immune tolerance in early life.

Analytical Performance Evaluation of Three Point-of-Care CBC Analyzers for Management of Clozapine Therapy in Ambulatory Psychiatry Clinics.

BACKGROUND: Clozapine is a first-line therapy and the only FDA-approved drug for patients with treatment-resistant schizophrenia (TRS). However, frequent measurement of absolute neutrophil count (ANC) is required to monitor for potential adverse severe neutropenia from clozapine therapy. We evaluated 3 point-of-care (POC) instruments that perform the complete blood count (CBC) with differential to assess their analytical performance and potential to meet the clinical need for clozapine therapy management. METHODS: A CBC with differential was performed on 104 residual whole blood specimens using 3 CBC analyzers (Sight OLO, PixCell HemoScreen, and Sysmex pocH-100i) to assess analytical precision, linearity, and accuracy vs the ADVIA 2120i and manual differential reference methods. Clinical concordance of ANC between POC devices and manual differential at medical decision points for mild, moderate, or severe neutropenia, and the threshold for clozapine therapy discontinuation (1.0 × 109/L) were determined. RESULTS: For CBC parameters, a CV ≤ 6.4% was observed on the OLO, CV ≤ 6.2% for the HemoScreen, and CV ≤ 5.1% with the pocH-100i. Each device accurately identified ANC with the greatest mean bias ±0.42 × 109/L using the pocH-100i vs manual differential. For results near the medical decision points (ANC <1.5 × 109/L), clinical concordance of ANC results was 55.6% for the OLO, 89.5% for the HemoScreen, and 82.4% for the pocH-100i. CONCLUSIONS: The HemoScreen device demonstrated the best clinical concordance in ANC values at medical decision thresholds for clozapine therapy management.

Myocardial brain-derived neurotrophic factor regulates cardiac bioenergetics through the transcription factor Yin Yang 1.

AIMS: Brain-derived neurotrophic factor (BDNF) is markedly decreased in heart failure patients. Both BDNF and its receptor, tropomyosin-related kinase receptor (TrkB), are expressed in cardiomyocytes; however, the role of myocardial BDNF signalling in cardiac pathophysiology is poorly understood. Here, we investigated the role of BDNF/TrkB signalling in cardiac stress response to exercise and pathological stress. METHODS AND RESULTS: We found that myocardial BDNF expression was increased in mice with swimming exercise but decreased in a mouse heart failure model and human failing hearts. Cardiac-specific TrkB knockout (cTrkB KO) mice displayed a blunted adaptive cardiac response to exercise, with attenuated upregulation of transcription factor networks controlling mitochondrial biogenesis/metabolism, including peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α). In response to pathological stress (transaortic constriction, TAC), cTrkB KO mice showed an exacerbated heart failure progression. The downregulation of PGC-1α in cTrkB KO mice exposed to exercise or TAC resulted in decreased cardiac energetics. We further unravelled that BDNF induces PGC-1α upregulation and bioenergetics through a novel signalling pathway, the pleiotropic transcription factor Yin Yang 1. CONCLUSION: Taken together, our findings suggest that myocardial BDNF plays a critical role in regulating cellular energetics in the cardiac stress response.

SARS CoV-2 detected in neonatal stool remote from maternal COVID-19 during pregnancy.

BACKGROUND: In utero transmission of SARS coronavirus 2 (SARS-CoV-2) has not been fully investigated. We investigated whether newborns of mothers with COVID-19 during pregnancy might harbor SARS-CoV-2 in the gastrointestinal tract. METHODS: This cohort study investigated stool from 14 newborns born at 25-41 weeks admitted at delivery to our urban academic hospital whose mothers had COVID-19 during pregnancy. Eleven mothers had COVID-19 resolved more than 10 weeks before delivery. Newborn stool was evaluated for SARS-CoV-2 RNA, Spike protein, and induction of inflammatory cytokines interleukin-6 (IL-6) and interferon-γ (IFN-γ) in macrophages. RESULTS: Despite negative SARS CoV-2 nasal PCRs from all newborns, viral RNAs and Spike protein were detected in the stool of 11 out of 14 newborns as early as the first day of life and increased over time in 6. Stool homogenates from all 14 newborns elicited elevated inflammatory IL-6 and IFN-γ from macrophages. Most newborns were clinically well except for one death from gestational autoimmune liver disease and another who developed necrotizing enterocolitis. CONCLUSIONS: These findings suggest in utero transmission of SARS-CoV-2 and possible persistent intestinal viral reservoirs in the newborns. Further investigation is required to understand the mechanisms and their clinical implications. IMPACT: SARS-CoV-2 RNAs or Spike protein was detected in the stool of 11 out of 14 preterm newborns born to mothers with resolved COVID-19 weeks prior to delivery despite negative newborn nasal PCR swabs. These novel findings suggest risk of in utero SARS-CoV-2 transmission to the fetal intestine during gestation. The presence of SARS-CoV-2 RNAs and Spike protein in the intestines of newborns may potentially impact the development of the gut microbiome and the immune system; the long-term health impact on the preterm infants should be further investigated.

Machine Learning Classifies Ferroptosis and Apoptosis Cell Death Modalities with TfR1 Immunostaining.

Determining cell death mechanisms occurring in patient and animal tissues is a longstanding goal that requires suitable biomarkers and accurate quantification. However, effective methods remain elusive. To develop more powerful and unbiased analytic frameworks, we developed a machine learning approach for automated cell death classification. Image sets were collected of HT-1080 fibrosarcoma cells undergoing ferroptosis or apoptosis and stained with an anti-transferrin receptor 1 (TfR1) antibody, together with nuclear and F-actin staining. Features were extracted using high-content-analysis software, and a classifier was constructed by fitting a multinomial logistic lasso regression model to the data. The prediction accuracy of the classifier within three classes (control, ferroptosis, apoptosis) was 93%. Thus, TfR1 staining, combined with nuclear and F-actin staining, can reliably detect both apoptotic and ferroptotis cells when cell features are analyzed in an unbiased manner using machine learning, providing a method for unbiased analysis of modes of cell death.

Neonatal management and outcomes during the COVID-19 pandemic: an observation cohort study.

BACKGROUND: The risk of vertical and perinatal transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, which causes COVID-19), the most appropriate management, and the neonate's risk of developing COVID-19 during the perinatal period are unknown. Therefore, we aimed to elucidate best practices regarding infection control in mother-newborn dyads, and identify potential risk factors associated with transmission. METHODS: In this observational cohort study, we identified all neonates born between March 22 and May 17, 2020, at three New York Presbyterian Hospitals in New York City (NY, USA) to mothers positive for SARS-CoV-2 at delivery. Mothers could practice skin-to-skin care and breastfeed in the delivery room, but had to wear a surgical mask when near their neonate and practice proper hand hygiene before skin-to-skin contact, breastfeeding, and routine care. Unless medically required, neonates were kept in a closed Giraffe isolette in the same room as their mothers, and were held by mothers for feeding after appropriate hand hygiene, breast cleansing, and placement of a surgical mask. Neonates were tested for SARS-CoV-2 by use of real-time PCR on nasopharyngeal swabs taken at 24 h, 5-7 days, and 14 days of life, and were clinically evaluated by telemedicine at 1 month of age. We recorded demographics, neonatal, and maternal clinical presentation, as well as infection control practices in the hospital and at home. FINDINGS: Of 1481 deliveries, 116 (8%) mothers tested positive for SARS-CoV-2; 120 neonates were identified. All neonates were tested at 24 h of life and none were positive for SARS-CoV-2. 82 (68%) neonates completed follow-up at day 5-7 of life. Of the 82 neonates, 68 (83%) roomed in with the mothers. All mothers were allowed to breastfeed; at 5-7 days of life, 64 (78%) were still breastfeeding. 79 (96%) of 82 neonates had a repeat PCR at 5-7 days of life, which was negative in all; 72 (88%) neonates were also tested at 14 days of life and none were positive. None of the neonates had symptoms of COVID-19. INTERPRETATION: Our data suggest that perinatal transmission of COVID-19 is unlikely to occur if correct hygiene precautions are undertaken, and that allowing neonates to room in with their mothers and direct breastfeeding are safe procedures when paired with effective parental education of infant protective strategies. FUNDING: None.

Transferrin Receptor Is a Specific Ferroptosis Marker.

Ferroptosis is a type of regulated cell death driven by the iron-dependent accumulation of oxidized polyunsaturated fatty acid-containing phospholipids. There is no reliable way to selectively stain ferroptotic cells in tissue sections to characterize the extent of ferroptosis in animal models or patient samples. We address this gap by immunizing mice with membranes from lymphoma cells treated with the ferroptosis inducer piperazine erastin and screening ∼4,750 of the resulting monoclonal antibodies generated for their ability to selectively detect cells undergoing ferroptosis. We find that one antibody, 3F3 ferroptotic membrane antibody (3F3-FMA), is effective as a selective ferroptosis-staining reagent. The antigen of 3F3-FMA is identified as the human transferrin receptor 1 protein (TfR1). We validate this finding with several additional anti-TfR1 antibodies and compare them to other potential ferroptosis-detecting reagents. We find that anti-TfR1 and anti-malondialdehyde adduct antibodies are effective at staining ferroptotic tumor cells in multiple cell culture and tissue contexts.

Use of Antimetastatic SOD3-Mimetic Albumin as a Primer in Triple Negative Breast Cancer.

Of the deaths attributed to cancer, 90% are due to metastasis. Treatments that prevent or cure metastasis remain elusive. Low expression of extracellular superoxide dismutase (EcSOD or SOD3) has been associated with poor outcomes and increased metastatic potential in multiple types of cancer. Here, we characterize the antimetastatic therapeutic mechanisms of a macromolecular extracellular SOD3-mimetic polynitroxyl albumin (PNA, also known as VACNO). PNA is macromolecular human serum albumin conjugated with multiple nitroxide groups and acts as an SOD-mimetic. Here we show that PNA works as a SOD3-mimetic in a highly metastatic 4T1 mouse model of triple negative breast cancer (TNBC). In vitro, PNA dose dependently inhibited 4T1 proliferation, colony formation, and reactive oxygen species (ROS) formation. In vivo, PNA enhanced reperfusion time in the hypoxic cores of 4T1 tumors as measured by ultrasound imaging. Furthermore, PNA enhanced ultrasound signal intensity within the cores of the 4T1 tumors, indicating PNA can increase blood flow and blood volume within the hypoxic cores of tumors. Lung metastasis from 4T1 flank tumor was inhibited by PNA in the presence or absence of doxorubicin, a chemotherapy agent that produces superoxide and promotes metastasis. In a separate study, PNA increased the survival of mice with 4T1 flank tumors when used in conjunction with three standard chemotherapy drugs (paclitaxel, doxorubicin, and cyclophosphamide), as compared to treatment with chemotherapy alone. In this study, PNA-increased survival was also correlated with reduction of lung metastasis. These results support the hypothesis that PNA works through the inhibition of extracellular superoxide/ROS production leading to the conversion of 4T1 cells from a metastatic tumorigenic state to a cytostatic state. These findings support future clinical trials of PNA as an antimetastatic SOD3-mimetic drug to increase overall survival in TNBC patients.

Blood group A mothers are more likely to develop anemia during antenatal intravenous immunoglobulin treatment of fetal and neonatal alloimmune thrombocytopenia.

BACKGROUND: Incompatibility between parental platelet (PLT) antigens may lead to sensitization of mother and development of fetal and neonatal alloimmune thrombocytopenia (FNAIT) resulting in fetal thrombocytopenia. Intravenous immunoglobulin (IVIG) with or without prednisone is the most effective, evidence-based antenatal treatment for subsequent FNAIT-affected pregnancies. IVIG infusion causes hemolysis in other settings, the degree depending upon patient blood groups (BGs). STUDY DESIGN AND METHODS: In ClinicalTrials.gov NCT00194987, 102 pregnant women received randomized antenatal treatment: Arm A received 2 g/kg/week IVIG; Arm B received 1 g/kg/week IVIG + 0.5 mg/kg/day prednisone. This post hoc analysis explored BG and anemia in 69 FNAIT mothers treated with Arm A or Arm B without salvage treatment to explore the effects of IVIG and steroid treatment on development of anemia in these women. Mothers whose treatment changed, for example, those with insufficient or unknown fetal PLT response who received salvage therapy, were excluded. RESULTS: For Arm A, 17 of 21 (hemoglobin [Hb] < 10 g/dL) mothers with anemia but only three of 15 mothers without anemia had BG-A and/or BG-B (p = 0.0005). BG was unrelated to anemia in Arm B; only nine of 33 Arm B mothers became anemic during treatment. The mean decrease in Hb level in women with BG-non-O was 1.9 g/dL and in women with BG-O was 1.1 g/dL (p = 0.004). Anemia was not caused by iron deficiency; the lowest mean corpuscular volume was 79. CONCLUSION: FNAIT women with BG-non-O more frequently develop anemia secondary to high-dose IVIG infusion (2 g/kg/week), quite possibly from isohemagglutinin-mediated hemolysis; maternal Hb requires monitoring. IVIG at 1 g/kg/week did not cause anemia in women with BG-non-O; concomitant prednisone likely alleviated the IVIG effect. Maternal BG could influence selection of antenatal treatment for FNAIT.

Omission of fetal sampling in treatment of subsequent pregnancies in fetal-neonatal alloimmune thrombocytopenia.

BACKGROUND: Fetal-neonatal alloimmune thrombocytopenia affects approximately 1 of 1000 live births, most of which are not severely thrombocytopenic. Despite effective treatment with intravenous gammaglobulin and/or prednisone, antenatal management of a subsequent affected pregnancy is complicated by the risks associated with fetal blood sampling. Furthermore, there are no biomarker(s) of high risk other than the occurrence of intracranial hemorrhage in a previous sibling. Management of these high-risk pregnancies requires intensive treatment initiated at 12 weeks of gestation. OBJECTIVE: The objective of the study was to evaluate whether empiric escalation of therapy at 32 weeks allows the omission of fetal blood sampling in all fetal-neonatal alloimmune thrombocytopenia-affected patients. Specifically, we sought to determine whether intensive intravenous gammaglobulin-based regimens for the treatment of a subsequent fetal-neonatal alloimmune thrombocytopenia-affected pregnancy followed by empirically escalated intravenous gammaglobulin and prednisone treatment would increase the fetal platelet count and thus safely allow omission of fetal blood sampling in the antepartum management of these patients. STUDY DESIGN: In this prospective, multicenter, randomized controlled study, 99 women with fetal-neonatal alloimmune thrombocytopenia whose prior affected child did not have an intracranial hemorrhage were randomized to receive an intensive intravenous gammaglobulin-based regimen: 2 g/kg per week or intravenous gammaglobulin 1 g/kg per week plus prednisone 0.5 mg/kg per day, starting at 20-30 weeks of gestation. Escalated therapy (intravenous gammaglobulin 2 g/kg per week plus prednisone 0.5 mg/kg per day) was recommended and usually initiated at 32 weeks when fetal counts were <50,000/mL(3) or when fetal blood sampling was not performed. The preliminary report of this study from 2007 demonstrated the efficacy of both intravenous gammaglobulin-based regimens in most patients. Most patients who underwent fetal sampling had adequate fetal counts and therefore did not have their treatment escalated. This post hoc analysis describes the 29 fetuses who had their treatment escalated either because they had low counts at 32 weeks or when sampling was not performed. This study explored whether the empiric escalation of treatment at 32 weeks was sufficiently effective in increasing fetal platelet counts in these patients. RESULTS: Mean fetal and birth counts of fetuses randomized to each of the 2 initial treatment groups were all >100,000/mL(3). Three neonates had an intracranial hemorrhage; all 3 were grade 1 and all had birth platelet counts >130,000/mL(3). In a post hoc analysis, 19 fetuses undergoing fetal blood sampling at 32 weeks had fetal platelet counts <50,000/mL(3) despite their initial treatment. Of these 19, birth platelet counts were >50,000/mL(3) in 11 of 13 fetuses who received escalated treatment compared with only 1 of 6 of those who did not (P = .01); only 3 fetuses that received initial therapy followed by escalated treatment had birth platelet counts <50,000/mL(3) and none had an intracranial hemorrhage. The platelet counts of 14 of 15 fetuses that received empirically escalated treatment without sampling were >50,000/mL(3) at birth. In addition, none of these had an intracranial hemorrhage. CONCLUSION: The 2 recommended protocols of intensive initial treatment followed by empiric escalation of therapy at 32 weeks of gestation are reasonably safe, effective in increasing fetal platelet counts, and allow omission of fetal blood sampling by increasing the fetal platelet count in almost all cases.

Anatomic Alignment and Integrity of the Sustentaculum Tali in Intra-Articular Calcaneal Fractures: Is the Sustentaculum Tali Truly Constant?

BACKGROUND: In an intra-articular calcaneal fracture, the sustentaculum tali is generally thought to remain tightly bound to the talus by the interosseous talocalcaneal ligaments, spring ligament, and deltoid ligament, providing a "constant" fragment that remains anatomically aligned. The extensile lateral approach is commonly used for reduction based on this assumption, but because it provides only limited access to the medial aspect of the calcaneus, indirect fracture reduction is required to restore an anatomic relationship of these fragments to the sustentacular fragment. The purpose of this study was to determine the prevalence and displacement of sustentacular fractures in patients with an intra-articular calcaneal fracture, and thus determine whether the sustentacular fragment can be accurately considered as constant and can be consistently relied on to maintain anatomic alignment. METHODS: All patients with an intra-articular calcaneal fracture who presented to two level-I trauma centers from 2006 to 2012 were included in the study if computed tomography scanning was performed. The presence or absence of a sustentacular fracture was documented, along with the displacement and the comminution of any such fracture and the subluxation or dislocation of the sustentaculum tali. RESULTS: Sustentacular fractures were present in ninety-four (44.3%) of the 212 patients who met the inclusion criteria. Seventy-two (76.6%) of the sustentacular fractures were nondisplaced, eleven (11.7%) were displaced, and ten (10.6%) were comminuted. The articulation between the sustentaculum tali and the talus was anatomically aligned in 166 (78.3%) of the calcaneal fractures, subluxated in forty-three (20.3%), and dislocated in two (0.9%). CONCLUSIONS: This study provides a detailed description of the frequency of sustentacular fractures, the displacement of such fractures, and articular subluxation or dislocation associated with intra-articular calcaneal fractures. Fixation by means of a lateral approach may be compromised when the sustentaculum tali is fractured or subluxated. A medial approach or combined medial and lateral approaches may be considered in such circumstances. Special attention should be paid to the integrity and alignment of the sustentacular fragment prior to surgical fixation. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Peripheral nerve repair in rats using composite hydrogel-filled aligned nanofiber conduits with incorporated nerve growth factor.

Repair of peripheral nerve defects with current synthetic, tubular nerve conduits generally shows inferior recovery when compared with using nerve autografts, the current gold standard. We tested the ability of composite collagen and hyaluronan hydrogels, with and without the nerve growth factor (NGF), to stimulate neurite extension on a promising aligned, nanofiber poly-L-lactide-co-caprolactone (PLCL) scaffold. In vitro, the hydrogels significantly increased neurite extension from dorsal root ganglia explants. Consistent with these results, the addition of hydrogels as luminal fillers within aligned, nanofiber tubular PLCL conduits led to improved sensory function compared to autograft repair in a critical-size defect in the sciatic nerve in a rat model. Sensory recovery was assessed 3 and 12 weeks after repair using a withdrawal assay from thermal stimulation. The addition of hydrogel did not enhance recovery of motor function in the rat model. The NGF led to dose-dependent improvements in neurite out-growth in vitro, but did not have a significant effect in vivo. In summary, composite collagen/hyaluronan hydrogels enhanced sensory neurite outgrowth in vitro and sensory recovery in vivo. The use of such hydrogels as luminal fillers for tubular nerve conduits may therefore be useful in assisting restoration of protective sensation following peripheral nerve injury.

Risk factors for subtrochanteric and diaphyseal fractures: the study of osteoporotic fractures.

CONTEXT: Patients on long-term bisphosphonate therapy may have an increased incidence of low-energy subtrochanteric and diaphyseal (SD) femoral fractures. However, the incidence and risk factors associated with these fractures have not been well defined. OBJECTIVE: The objective of the study was to determine the incidence of and risk factors for low-energy SD fractures in the Study of Osteoporotic Fractures (SOF). DESIGN: Low-energy SD fractures were identified from a review of radiographic reports obtained between 1986 and 2010 in women in the SOF. Among the SD fractures, pathological, periprosthetic, and traumatic fractures were excluded. We assessed risk factors for SD fractures as well as risk factors for femoral neck (FN) and intertrochanteric (IT) hip fractures using both age-adjusted and multivariate time-dependent proportional hazards models. During this follow-up, only a small minority had ever used bisphosphonates. RESULTS: Forty-five women sustained low-energy subtrochanteric/diaphyseal femoral fractures over a total follow-up of 140 000 person-years. The incidence of SD fracture was 3.2 per 10 000 person-years compared with a total hip fracture incidence of 110 per 10 000 person-years. A total of about 12% of women reported bisphosphonate use at 1 or more visits. In multivariate analyses, age, total hip bone mineral density (BMD), bisphosphonate use, and history of diabetes emerged as independent risk factors for SD fractures. Risk factors for FN and IT fractures included age, BMD, and history of falls or prior fractures. Bisphosphonate use was protective against FN fractures, whereas there was an increased risk of SD fractures (hazard ratio 2.58, P = .049) with bisphosphonate use after adjustment for other risk factors for fracture. CONCLUSIONS: In SOF, low-energy SD fractures were rare occurrences, far outnumbered by FN and IT fractures. Typical risk factors were associated with FN and IT fractures, whereas only age, total hip BMD, and history of diabetes were independent risk factors for SD fractures. In addition, bisphosphonate use was a marginally significantly predictor although the SOF study has limited ability to assess this association.

Functional motor recovery after peripheral nerve repair with an aligned nanofiber tubular conduit in a rat model.

AIM: Current synthetic tubular conduits are inferior to nerve autograft for the repair of segmental peripheral nerve injuries. We examined motor outcomes with the use of longitudinally aligned poly (L-lactide-co-caprolactone) nanofiber conduits for repair of nerve gap injury in a rat model. METHODS: Ten-millimeter segments of sciatic nerve were resected in 44 Lewis rats. The gaps were either left unrepaired (n = 6), repaired with nerve autograft (n = 19), or repaired with conduit (n = 19). After 12 weeks, nerve conduction latency, compound muscle action potential amplitude, muscle force and muscle mass were measured. The numbers of axons and axon diameters both within the grafts and distally were determined. RESULTS: After 12 weeks, gastrocnemius isometric tetanic force and muscle mass for the conduit group reached 85 and 82% of autograft values, respectively. Nerve conduction and compound muscle action potential were not significantly different between these two groups, although the latter approached significance. There was no recovery in the unrepaired group. CONCLUSION: Muscle recovery for the animals treated with this aligned nanofiber conduit approached that of autograft, suggesting the importance of internal conduit structure for nerve repair.

Are women with thicker cortices in the femoral shaft at higher risk of subtrochanteric/diaphyseal fractures? The study of osteoporotic fractures.

CONTEXT: Femoral shaft cortical thickening has been mentioned in reports of atypical subtrochanteric and diaphyseal (S/D) femur fractures, but it is unclear whether thickening precedes fracture or results from a preceding stress fracture and what role bisphosphonates might play in cortical thickening. OBJECTIVE: Our objective was to examine the relationship of cortical thickness to S/D fracture risk as well as establish normal reference values for femoral cortical thickness in a large population-based cohort of older women. DESIGN: Using pelvic radiographs obtained in 1986-1988, we measured femoral shaft cortical thickness 3 cm below the lesser trochanter in women in the Study of Osteoporotic Fractures. We measured this in a random sample and in those with S/D fractures and femoral neck and intertrochanteric fractures. Low-energy S/D fractures were identified from review of radiographic reports obtained between 1986 and 2010. Radiographs to evaluate atypia were not available. Analysis used case-cohort, proportional hazards models. OUTCOMES: Cortical thickness as a risk factor for low-energy S/D femur fractures as well as femoral neck and intertrochanteric fractures in the Study of Osteoporotic Fractures, adjusting for age and bone mineral density in proportional hazards models. RESULTS: After age adjustment, women with thinner medial cortices were at a higher risk of S/D femur fracture, with a relative hazard of 3.94 (95% confidence interval = 1.23-12.6) in the lowest vs. highest quartile. Similar hazard ratios were seen for femoral neck and intertrochanteric fractures. Medial or total cortical thickness was more strongly related to fracture risk than lateral cortical thickness. CONCLUSIONS: In primarily bisphosphonate-naive women, we found no evidence that thick femoral cortices placed women at higher risk for low-energy S/D femur fractures; in fact, the opposite was true. Women with thin cortices were also at a higher risk for femoral neck and intertrochanteric fractures. Whether cortical thickness among bisphosphonate users plays a role in atypical S/D fractures remains to be determined.