ACVR1-activating mutation causes neuropathic pain and sensory neuron hyperexcitability in humans.

ABSTRACT: Altered bone morphogenetic protein (BMP) signaling is associated with many musculoskeletal diseases. However, it remains unknown whether BMP dysfunction has direct contribution to debilitating pain reported in many of these disorders. Here, we identified a novel neuropathic pain phenotype in patients with fibrodysplasia ossificans progressiva (FOP), a rare autosomal-dominant musculoskeletal disorder characterized by progressive heterotopic ossification. Ninety-seven percent of these patients carry an R206H gain-of-function point mutation in the BMP type I receptor ACVR1 (ACVR1 R206H ), which causes neofunction to Activin A and constitutively activates signaling through phosphorylated SMAD1/5/8. Although patients with FOP can harbor pathological lesions in the peripheral and central nervous system, their etiology and clinical impact are unclear. Quantitative sensory testing of patients with FOP revealed significant heat and mechanical pain hypersensitivity. Although there was no major effect of ACVR1 R206H on differentiation and maturation of nociceptive sensory neurons (iSNs) derived from FOP induced pluripotent stem cells, both intracellular and extracellular electrophysiology analyses of the ACVR1 R206H iSNs displayed ACVR1-dependent hyperexcitability, a hallmark of neuropathic pain. Consistent with this phenotype, we recorded enhanced responses of ACVR1 R206H iSNs to TRPV1 and TRPA1 agonists. Thus, activated ACVR1 signaling can modulate pain processing in humans and may represent a potential target for pain management in FOP and related BMP pathway diseases.

Prevalent coinfection and associated factors for Hepatitis B, Hepatitis C, and Human Immunodeficiency Virus in patients submitted to renal replacement therapy: A cross-sectional study of 21 dialysis units in the State of Mexico.

BACKGROUND: Chronic kidney disease (CKD) predispose to viral coinfections in patients submitted to renal replacement therapy (RRT); nevertheless, few reports have been performed to elucidate the current epidemiology within this population in Mexico. AIM: To estimate the prevalence of HBV, HCV, and HIV coinfection and to explore factors associated with prevalent coinfection in patients living with renal failure undergoing to RRT. METHODS: A multicenter cross-sectional recruitment across 21 units at the Mexican Institute of Social Security (IMSS) at the State of Mexico was performed during 2019. A standardized clinical questionnaire was performed to elucidate individual and relatives-related conditions. A treatment facility questionnaire was applied to the chief responsible of each unit to explore treatment facility variables. Serological testing, clinical, biochemical, and anthropometrical parameters were extracted from clinical records. RESULT: In 1,304 patients (57.5% male, mean age 45.5 (SD: 15.6) years, and 95.8% in hemodialysis), the prevalence of any viral coinfection was 3.14% (95% CI: 2.32%-4.23%). The highest viral coinfection prevalence were for HCV, HBV, and HIV, in which men and subjects diagnosed after 2010's had the highest rates. We identify that being submitted to peritoneal dialysis, being treated in a surrogated dialysis center and living with a close relative with prior hepatitis coinfection were associated factors for any viral coinfection. CONCLUSION: In patients submitted to RRT, the prevalence of viral coinfection remains high compared with general population. Screening strategies, medical awareness and targeted public healthcare policies should prioritize better care practices within patients submitted to RRT in Mexico.

Reproductive Justice: A Case-Based, Interactive Curriculum.

Introduction: Reproductive injustices such as forced sterilization, preventable maternal morbidity and mortality, restricted access to family planning services, and policy-driven environmental violence undermine reproductive autonomy and health outcomes, with disproportionate impact on historically marginalized communities. However, curricula focused on reproductive justice (RJ) are lacking in medical education. Methods: We designed a novel, interactive, case-based RJ curriculum for postclerkship medical students. This curriculum was created using published guidelines on best practices for incorporating RJ in medical education. The session included a prerecorded video on the history of RJ, an article, and four interactive cases. Students engaged in a 2-hour small-group session, discussing key learning points of each case. We evaluated the curriculum's impact with a pre- and postsurvey and focus group. Results: Sixty-eight students participated in this RJ curriculum in October 2020 and March 2021. Forty-one percent of them completed the presurvey, and 46% completed the postsurvey. Twenty-two percent completed both surveys. Ninety percent of respondents agreed that RJ was relevant to their future practice, and 87% agreed that participating in this session would impact their clinical practice. Most respondents (81%) agreed that more RJ content is needed. Focus group participants appreciated the case-based, interactive format and the intersectionality within the cases. Discussion: This interactive curriculum is an innovative and effective way to teach medical students about RJ and its relevance to clinical practice. Walking alongside patients as they accessed reproductive health care in a case-based curriculum improved students' comfort and self-reported knowledge on several RJ topics.

Active Observation of Biochemical Recurrence without Treatment following Radical Prostatectomy: Long-Term Analysis of Outcomes.

Biochemical recurrence (BCR) following radical prostatectomy (RP) is an unreliable predictor of prostate cancer (PC) progression. This study was a retrospective cohort analysis of prospectively collected data (407/1895) of men with BCR at a tertiary referral center. Patients were assessed for active observation (AO) compared with a treatment group (TG) utilizing doubling time (DT) kinetics. Risk assessment was based on the initial DT (>12 vs. <12 months), then based on the DT pattern (changed over time). Those with unstable, rapidly decreasing DTs received treatment. Those with increasing and slowly decreasing DTs prompted observation. The primary outcome was PC mortality, safety, and efficacy of observations based on DT kinetics. The secondary outcome was BCR patients managed with or without treatment. The median follow-up was 7.5 years (IQR 3.9−10.7). The PCSM in TG and AO was 10.7% and 0%, respectively (p < 0.001). The initial DT was >12 months in 73.6% of AO versus 22.6% of TG (p < 0.001). An increasing DT pattern was observed in 71.5% of AO versus 32.7% of TG (p < 0.001). Utilizing the Cleveland Clinic's PCSM nomogram, at 10 years, predicted and observed PCSM was 8.6% and 9.5% (p = 0.78), respectively. In conclusion, one-third of patients with BCR post-RP were managed without treatment using DT kinetics, avoiding treatment-related complications, quality-of-life issues, and expenses.

Retrospective Concomitant Nonrandomized Comparison of "Touch" Cautery Versus Athermal Dissection of the Prostatic Vascular Pedicles and Neurovascular Bundles During Robot-assisted Radical Prostatectomy.

BACKGROUND: During robotic-assisted radical prostatectomy (RARP), the use of electrocautery near the neurovascular bundles (NVBs) frequently results in thermal injury to the cavernous nerves. The cut and "touch" monopolar cautery technique has been suggested to reduce desiccating thermal injury caused by bipolar energy when vessels are sealed. OBJECTIVE: To compare potency outcomes between an athermal technique (AT) and touch cautery (TC) to transect the prostatic vascular pedicles (PVPs) and dissect the NVBs. DESIGN, SETTING, AND PARTICIPANTS: A retrospective concomitant nonrandomized study of AT versus TC was performed in 733 men. A total of 323 undergoing AT had "thin" pedicles, easily suitable for suture ligation. TC was based on "thick" pedicles (n = 230) difficult to suture ligate. Men were excluded for an International Index of Erectile Function (IIEF-5) score of <15 or adjuvant therapies (n = 180). SURGICAL PROCEDURE: Single-surgeon RARP. MEASUREMENTS: Patient-reported outcomes with erectile function (EF) recovery defined as two affirmative answers to erections sufficient for intercourse (ESI; "are erections firm enough for penetration?" and "are the erections satisfactory?"), IIEF-5 scores 15-25, and a novel percent fullness score comparing pre- versus postoperative erection fullness. Logistic regression models assessed the correlation between cautery technique, covariates, and EF recovery. RESULTS AND LIMITATIONS: In an unadjusted analysis, preoperative IIEF-5, age, body mass index (BMI), and prostate weight were significant predictors of potency recovery. Follow-up was similar (AT 52.7 mo vs TC 54.6 mo, p = 0.534). In logistic regression, preoperative IIEF-5, age, and BMI were significant predictors of EF recovery, defined as IIEF-5 scores 15-25, ESI, and percent fullness >75%. Results were similar when IIEF-5 and percent fullness were assessed continuously. CONCLUSIONS: During transection of the PVPs and dissection of the NVBs, TC did not impact EF recovery significantly, compared with an AT. PATIENT SUMMARY: Electrocautery can be applied safely, with similar outcomes to those of an athermal technique.

Modeling the ACVR1R206H mutation in human skeletal muscle stem cells.

Abnormalities in skeletal muscle repair can lead to poor function and complications such as scarring or heterotopic ossification (HO). Here, we use fibrodysplasia ossificans progressiva (FOP), a disease of progressive HO caused by ACVR1R206H (Activin receptor type-1 receptor) mutation, to elucidate how ACVR1 affects skeletal muscle repair. Rare and unique primary FOP human muscle stem cells (Hu-MuSCs) isolated from cadaveric skeletal muscle demonstrated increased extracellular matric (ECM) marker expression, showed skeletal muscle-specific impaired engraftment and regeneration ability. Human induced pluripotent stem cell (iPSC)-derived muscle stem/progenitor cells (iMPCs) single-cell transcriptome analyses from FOP also revealed unusually increased ECM and osteogenic marker expression compared to control iMPCs. These results show that iMPCs can recapitulate many aspects of Hu-MuSCs for detailed in vitro study; that ACVR1 is a key regulator of Hu-MuSC function and skeletal muscle repair; and that ACVR1 activation in iMPCs or Hu-MuSCs may contribute to HO by changing the local tissue environment.

Patient-reported menstrual and obstetric outcomes following hysteroscopic adhesiolysis for Asherman syndrome.

OBJECTIVE: Review the menstrual and obstetric outcomes among Asherman syndrome patients when stratified by disease severity. DESIGN: Retrospective cohort study. SETTING: A community teaching hospital affiliated with a large academic medical center. PATIENTS: A total of 355 Asherman syndrome patients stratified by March classification who underwent hysteroscopic adhesiolysis. INTERVENTIONS: Telephone survey, analyzed with multivariable analysis. MAIN OUTCOME MEASURES: Return of menstruation. Pregnancy, miscarriage, and live birth rate. RESULTS: A total of 355 patients underwent hysteroscopic adhesiolysis. Of these, 150 (42.3%) patients completed the telephone survey with a mean follow-up of 2.21 years. Additionally, 40.7% had mild, 52.7% had moderate, and 6.6% had severe disease. Furthermore, 25.3% of patients reported amenorrhea at presentation, with mild disease patients having the highest rate of returning menstruation (93.8%) following treatment. The cumulative pregnancy rate was 81.9%, and the cumulative live birth rate was 51.2%, with no statistical differences identified by the classification group. CONCLUSION: Asherman syndrome disease severity predicted returning menstruation but not pregnancy or live birth rate.

Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells.

Macrophages have a key role in shaping the tumour microenvironment (TME), tumour immunity and response to immunotherapy, which makes them an important target for cancer treatment1,2. However, modulating macrophages has proved extremely difficult, as we still lack a complete understanding of the molecular and functional diversity of the tumour macrophage compartment. Macrophages arise from two distinct lineages. Tissue-resident macrophages self-renew locally, independent of adult haematopoiesis3-5, whereas short-lived monocyte-derived macrophages arise from adult haematopoietic stem cells, and accumulate mostly in inflamed lesions1. How these macrophage lineages contribute to the TME and cancer progression remains unclear. To explore the diversity of the macrophage compartment in human non-small cell lung carcinoma (NSCLC) lesions, here we performed single-cell RNA sequencing of tumour-associated leukocytes. We identified distinct populations of macrophages that were enriched in human and mouse lung tumours. Using lineage tracing, we discovered that these macrophage populations differ in origin and have a distinct temporal and spatial distribution in the TME. Tissue-resident macrophages accumulate close to tumour cells early during tumour formation to promote epithelial-mesenchymal transition and invasiveness in tumour cells, and they also induce a potent regulatory T cell response that protects tumour cells from adaptive immunity. Depletion of tissue-resident macrophages reduced the numbers and altered the phenotype of regulatory T cells, promoted the accumulation of CD8+ T cells and reduced tumour invasiveness and growth. During tumour growth, tissue-resident macrophages became redistributed at the periphery of the TME, which becomes dominated by monocyte-derived macrophages in both mouse and human NSCLC. This study identifies the contribution of tissue-resident macrophages to early lung cancer and establishes them as a target for the prevention and treatment of early lung cancer lesions.

Effects of Asherman Syndrome on Maternal and Neonatal Morbidity with Evaluation by Conception Method.

STUDY OBJECTIVE: Create a comprehensive summary of maternal and neonatal morbidities from patients previously treated for Asherman syndrome and evaluate for differences in perinatal outcomes based on conception method. DESIGN: Retrospective cohort. SETTING: Community teaching hospital affiliated with a large academic medical center. PATIENTS: Total of 43 singleton births identified from 40 patients previously treated at our institution for Asherman syndrome. INTERVENTIONS: Review of fertility and obstetric data to summarize the maternal and neonatal outcomes in singleton births from patients with Asherman syndrome who had been treated with hysteroscopic adhesiolysis. MEASUREMENTS AND MAIN RESULTS: Primary outcomes of maternal morbidity (i.e., hypertensive disease, gestational diabetes, ruptured membranes, postpartum hemorrhage, morbidly adherent placenta [MAP]) and secondary outcomes of neonatal morbidity (i.e., gestational age at birth, method of delivery, weight, length, 1- and 5-minute Apgar score oxygen requirement, anatomic malformations, length of neonatal admission) were evaluated. We identified 40 patients who completed successful treatment of Asherman syndrome and went on to carry a singleton gestation within our institution: 20 (50%) with mild disease, 18 (45%) with moderate disease, and 2 (5%) with severe disease under the March classification system. In total, 43 singleton births were examined, with 27 of 43 (62.8%) conceived without in vitro fertilization (IVF) (group A: non-IVF conception) and 16 of 43 (37.2%) conceived through IVF (group B: IVF conception). The overall rate of preterm birth in Asherman pregnancies was 11.6%, with no difference between the 2 conception groups. We documented 9.3% cases with intrauterine growth restriction, with no difference based on conception groups. The rate of MAP in patients with Asherman syndrome was 14.0%, and the rate of postpartum hemorrhage was 32.6%, with no differences between the conception groups. Newborn anatomic malformations of any cause were documented in 18.6% of all singleton births, with no difference between the conception groups. CONCLUSION: Our series indicates a higher incidence of intrauterine growth restriction, MAP, postpartum hemorrhage, and newborn anatomic malformations in Asherman syndrome pregnancies than that reported in pregnancies within the general population. However, we found no significant differences in the maternal and neonatal outcomes of patients with Asherman syndrome who conceived with or without IVF after being treated with hysteroscopic adhesiolysis.

Concomitant Adenomyosis among Patients with Asherman Syndrome.

STUDY OBJECTIVE: To characterize obstetric outcomes for concomitant Asherman syndrome and adenomyosis. DESIGN: A retrospective cohort study. SETTING: A community teaching hospital affiliated with a large academic medical center. PATIENTS: A total of 227 patients with Asherman syndrome with available hysteroscopy and pelvic ultrasound reports. INTERVENTIONS: Telephone survey to assess and compare the obstetric outcomes of patients with Asherman syndrome with concomitant adenomyosis (Group A) vs patients with Asherman syndrome without concomitant adenomyosis (Group B). MEASUREMENTS AND MAIN RESULTS: A telephone survey and confirmatory chart review were conducted to obtain information on patients' demographics, gynecologic and obstetric history, past medical and surgical history, and Asherman syndrome management. Adenomyosis was a common sonographic finding, detected in 39 patients with Asherman syndrome (17.2%). In this cohort, 77 patients attempted pregnancy and produced 87 pregnancies. Age (odds ratio [OR] 0.67; 95% confidence intervals [CI], 0.52-0.86) was negatively associated with a pregnancy outcome. Age (OR 0.83; 95% CI, 0.73-0.95) and severe Asherman disease (OR 0.06; 95% CI, <0.01-0.99) were negatively associated with a live birth outcome. Adenomyosis was not an independent predictor of pregnancy rate, miscarriage rate, or live birth rate among patients with Asherman syndrome. CONCLUSION: Adenomyosis is relatively common in patients with Asherman syndrome. Adenomyosis does not seem to add any distinct detriment to fertility among patients with Asherman syndrome.

Endometrial thickness measurements among Asherman syndrome patients prior to embryo transfer.

STUDY QUESTION: Is there an association between endometrial thickness (EMT) measurement and clinical pregnancy rate among Asherman syndrome (AS) patients utilizing IVF and embryo transfer (ET)? SUMMARY ANSWER: EMT measurements may not be associated with successful clinical pregnancy among AS patients undergoing IVF. WHAT IS KNOWN ALREADY: Clinical pregnancy rate after IVF is significantly lower in patients with a thin endometrium, defined as a maximum EMT of <7 mm. However, AS patients often have a thin EMT measurement due to intrauterine scarring, with a paucity of data and no guidance on what EMT cutoff is appropriate when planning an ET among these patients. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort study of 45 AS patients treated at a specialized advanced hysteroscopic clinic from 1 January 2015, to 1 March 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: Review of EMT measurements prior to a total of 90 ETs, among 45 AS patients. The impact of the maximum EMT measurement prior to ET on clinical pregnancy rate was analyzed. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 25/45 (55.6%) AS patients ultimately went on to have ≥1 clinical pregnancy following a mean ± SD of 2.00 ± 1.26 ET attempts. There was a total of 90 ETs among the 45 AS patients, with 29/90 (32.2%) ETs resulting in a clinical pregnancy. Younger patient age (P = 0.05) and oocyte donation (P = 0.01) were the only variables identified to be significant predictors for a positive clinical pregnancy outcome on bivariate analysis. The mean EMT measurement prior to all ETs among AS patients was 7.5 ± 1.6 mm. EMT measurement prior to ET did not predict a positive clinical pregnancy on either bivariate (P = 0.84) or multivariable analysis (odds ratio 0.91, P = 0.60). 31.8% of EMT measurements measured <7.0 mm. In this small cohort, no difference in the clinical pregnancy rate was detected when comparing ETs with EMT measurements of <7.0 mm versus ≥7.0 mm (P = 0.83). The mean EMT measurement decreased with increasing AS disease severity; 8.0 ± 1.6 mm for mild disease, 7.0 ± 1.4 mm for moderate disease and 5.4 ± 0.1 mm for severe disease. LIMITATIONS, REASONS FOR CAUTION: Our small sample size limits our ability to draw any definitive conclusions. In addition, patients utilized various infertility clinics. This limits our ability to evaluate the consistency of EMT measurements and the IVF care that was received. WIDER IMPLICATIONS OF THE FINDINGS: EMT measurement cutoff values should be used with caution if canceling a scheduled ET in AS patients. STUDY FUNDING/COMPETING INTEREST(S): This study was not funded. K.I. reports personal fees from Karl Stroz and personal fees from Medtronics outside the submitted work. The other authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Miocardiopatía periparto: afección subvalorada / Peripartum cardiomyopathy: An undervalued disease

Resumen: El embarazo es un estado que impone un verdadero reto para el sistema cardiovascular materno. Existe remodelamiento cardiaco, que, junto con el incremento de la masa miocárdica y del tamaño del ventrículo izquierdo y la contractilidad miocárdica disminuida agravada por los cambios del embarazo, pueden condicionar insuficiencia cardiaca aguda durante el periodo periparto. Se considera miocardiopatía periparto cuando la función sistólica del ventrículo izquierdo y los síntomas de insuficiencia cardiaca ocurren en el último mes del embarazo y en los cinco meses posteriores al parto con incidencia de 1 por cada 1300 a 15,000 embarazos. Se comunica el caso de una paciente de 26 años, con antecedente de catarata congénita, que tuvo embarazo normoevolutivo, con parto eutócico, durante el puerperio tuvo disnea y datos de hipoperfusión, mediante evaluación ultrasonográfica pulmonar y cardiaca mostró datos de miocardiopatía dilatada periparto, fue trasladada a un hospital de tercer nivel, donde a pesar del tratamiento intensivo multidisciplinario, falleció. La miocardiopatía periparto es una enfermedad subvalorada con alta mortalidad materna y perinatal; sin embargo, la detección oportuna puede mejorar el tratamiento y el pronóstico. Con la comunicación de este caso, se pretende demostrar la importancia de la detección temprana de una afección poco diagnosticada, como es la miocardiopatía periparto.

Abstract: Pregnancy is a state that imposes a real challenge for the maternal cardiovascular system. There is a cardiac remodeling, which along with an increase in myocardial mass, in left ventricular size and decreased myocardial contractility aggravated by changes in pregnancy, can condition acute heart failure during the peripartum period. Peripartum cardiomyopathy is when the systolic function of the left ventricle and the symptoms of heart failure occur in the last month of pregnancy and in the five months after delivery with an incidence ranging from 1/1300 to 1/15,000 pregnancies. This paper reports the case of a 26-year-old female patient, who had a history of congenital cataract, with normal pregnancy and eutocic delivery; during the puerperium patient showed dyspnea, hypoperfusion data and pulmonary and cardiac ultrasonographic evaluation of peripartum dilated cardiomyopathy, being transferred at a third level, where despite intensive multidisciplinary treatment, the patient died. Peripartum cardiomyopathy is an undervalued disease that has a high maternal and perinatal mortality; however, a timely detection can improve treatment and prognosis. The purpose of this case report is to demonstrate the importance of early detection of a poorly diagnosed entity, such as peripartum cardiomyopathy.

Effect of donor variation on osteogenesis and vasculogenesis in hydrogel cocultures.

To introduce a functional vascular network into tissue-engineered bone equivalents, human endothelial colony forming cells (ECFCs) and multipotent mesenchymal stromal cells (MSCs) can be cocultured. Here, we studied the impact of donor variation of human bone marrow-derived MSCs and cord blood-derived ECFCs on vasculogenesis and osteogenesis using a 3D in vitro coculture model. Further, to make the step towards cocultures consisting of cells derived from a single donor, we tested how induced pluripotent stem cell (iPSC)-derived human endothelial cells (iECs) performed in coculture models. Cocultures with varying combinations of human donors of MSCs, ECFCs, or iECs were prepared in Matrigel. The constructs were cultured in an osteogenic differentiation medium. Following a 10-day culture period, the length of the prevascular structures and osteogenic differentiation were evaluated for up to 21 days of culture. The particular combination of MSC and ECFC donors influenced the vasculogenic properties significantly and induced variation in osteogenic potential. In addition, the use of iECs in the cocultures resulted in prevascular structure formation in osteogenically differentiated constructs. Together, these results showed that close attention to the source of primary cells, such as ECFCs and MSCs, is critical to address variability in vasculogenic and osteogenic potential. The 3D coculture model appeared to successfully generate prevascularized constructs and were sufficient in exceeding the ~200 µm diffusion limit. In addition, iPSC-derived cell lineages may decrease variability by providing a larger and potentially more uniform source of cells for future preclinical and clinical applications.

NF-κB/MAPK activation underlies ACVR1-mediated inflammation in human heterotopic ossification.

BACKGROUND: Inflammation helps regulate normal growth and tissue repair. Although bone morphogenetic proteins (BMPs) and inflammation are known contributors to abnormal bone formation, how these pathways interact in ossification remains unclear. METHODS: We examined this potential link in patients with fibrodysplasia ossificans progressiva (FOP), a genetic condition of progressive heterotopic ossification caused by activating mutations in the Activin A type I receptor (ACVR1/ALK2). FOP patients show exquisite sensitivity to trauma, suggesting that BMP pathway activation may alter immune responses. We studied primary blood, monocyte, and macrophage samples from control and FOP subjects using multiplex cytokine, gene expression, and protein analyses; examined CD14+ primary monocyte and macrophage responses to TLR ligands; and assayed BMP, TGF-ß activated kinase 1 (TAK1), and NF-κB pathways. RESULTS: FOP subjects at baseline without clinically evident heterotopic ossification showed increased serum IL-3, IL-7, IL-8, and IL-10. CD14+ primary monocytes treated with the TLR4 activator LPS showed increased CCL5, CCR7, and CXCL10; abnormal cytokine/chemokine secretion; and prolonged activation of the NF-κB pathway. FOP macrophages derived from primary monocytes also showed abnormal cytokine/chemokine secretion, increased TGF-ß production, and p38MAPK activation. Surprisingly, SMAD phosphorylation was not significantly changed in the FOP monocytes/macrophages. CONCLUSIONS: Abnormal ACVR1 activity causes a proinflammatory state via increased NF-κB and p38MAPK activity. Similar changes may contribute to other types of heterotopic ossification, such as in scleroderma and dermatomyositis; after trauma; or with recombinant BMP-induced bone fusion. Our findings suggest that chronic antiinflammatory treatment may be useful for heterotopic ossification.

Predictores de mortalidad en pacientes con sepsis obstétrica mediante uso de score de sepsis obstétrica y evaluación secuencial de falla orgánica-obstétrica / Predictors of mortality in patients with obstetric sepsis using sepsis obstetric score and sequential organ failure assessment-obstetrics / Preditores de mortalidade em pacientes com sepse obstétrica usando Escore de Sepse Obstétrica e Avaliação Seqüencial de Falha Orgânico-Obstétrica

Resumen: Objetivo: Determinar los predictores de mortalidad en pacientes con sepsis obstétrica mediante score de sepsis obstétrica (SOS) y evaluación secuencial de falla orgánica-obstétrica (SOFA-O). Material y métodos: Se realizó un estudio observacional, retrospectivo, descriptivo, donde se recabaron los datos de pacientes que ingresaron a una Unidad de Cuidados Intensivos de hospitales de segundo nivel, en el periodo 30 de junio de 2015 al 30 de junio de 2017 y que tuvieron diagnóstico de sepsis obstétrica, donde se aplicaron instrumentos mediante escala SOS y SOFA-O, correlacionándose las variables con mortalidad materna. Resultados: De un universo de 284 pacientes que ingresaron a UCI de Hospitales de segundo nivel se seleccionaron 51, quienes tenían criterios de inclusión para sepsis, correlacionándose con variables de escala de SOS y SOFA-O, encontrando como mayor factor de riesgo para el desarrollo de sepsis ser multigesta, tener preeclampsia, anemia, cesárea, mal control prenatal y tener procedimientos invasivos. Las variables cuantitativas relacionadas con muerte materna fueron creatinina, relación PaO2/FiO2, frecuencia cardiaca, lactato, saturación venosa, con un puntaje de SOS mínimo y máximo para muerte materna (7-22) y para SOFA-O (10-18) puntos. Hubo una mortalidad de 7.8% (cuatro pacientes) de la población estudiada. Conclusiones: La incidencia de sepsis obstétrica se encuentra en aumento, por lo que el reconocimiento rápido de ésta y la terapia adecuada impactarán en la supervivencia de la paciente.

Abstract: Objective: To determine the predictors of mortality in patients with obstetric sepsis using Sepsis Obsessional Score (SOS) and Sequential Organ Failure Assessment-Obstetric (SOFA-O). Material and methods: An observational, retrospective, descriptive study was carried out, where data were collected from patients who entered an intensive care unit of second level hospitals in the period June 30 2015, to June 30 2017, who had a diagnosis of sepsis Obstetric, where SOS and SOFA-O instruments were applied, correlating the variables with maternal mortality. Results: From a universe of 284 patients who entered the ICU of second level hospitals, 51 patients were selected who had inclusion criteria for sepsis, correlating with SOS and SOFA-O scale variables, finding it to be a major risk factor for development of sepsis being multigested, having preeclampsia, anemia, cesarean section, prenatal poor control and having invasive procedures, the quantitative variables related to maternal death were: creatinine, PaO2/FiO2 ratio, heart rate, lactate, venous saturation. With a minimum and maximum SOS score for maternal death (7-22) and SOFA-O (10-18) points. There was a mortality of 7.8% (four patients) of the study population. Conclusions: The incidence of obstetric sepsis is increasing, so rapid recognition and appropriate therapy will impact patient survival.

Resumo: Objetivo: Determinar os preditores de mortalidade em pacientes com sepse obstétrica pelo Escore de Sepse Obstétrica (S.O.S.) e Avaliação Seqüencial de Falha Orgânico-Obstétrica (SOFA-O). Material e métodos: Foi realizado um estudo observacional, retrospectivo, descritivo, onde foram coletados dados de pacientes internados em uma unidade de terapia intensiva no período de 30 de junho de 2015 a 30 de junho de 2017 com diagnóstico de sepse obstétrica, onde foram aplicados instrumentos utilizando escalas S.O.S e SOFA-O, correlacionando as variáveis com a mortalidade materna. Resultados: De um universo de 284 pacientes internados na UTI, foram selecionados 51 pacientes que possuíam critérios de inclusão para sepse, correlacionando com as variáveis S.O.S e SOFA-O, encontrando como um importante fator de risco para o desenvolvimento da sepse ser multigesta, apresentar pré-eclâmpsia, anemia, cesárea, controle pré-natal deficiente e procedimentos invasivos. As variáveis quantitativas relacionadas ao óbito materno foram creatinina, relação PaO2/FiO2, frequência cardíaca, lactato, saturação venosa. Com um escore de S.O.S mínimo e máximo para morte materna (7-22) e para SOFA-O (10-18). Houve uma mortalidade de 7.8% (4 pacientes) da população estudada. Conclusões: A incidência de sepse obstétrica está aumentando, portanto o reconhecimento rápido e a terapia adequada terão impacto na sobrevida do paciente.

Clinical-pathological correlations in three patients with fibrodysplasia ossificans progressiva.

OBJECTIVE: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder in which heterotopic bone forms in the soft tissues. This often occurs in response to injury or inflammation, leading to joint immobilization and significant disability. There are currently no definitive treatment options for this devastating disease. Although the most dramatic phenotype in FOP is the episodic and progressive heterotopic ossification, patients report a number of symptoms that affect other organ systems. Post-mortem examination of FOP patients may contribute to our understanding of the underlying pathophysiology and complications of this disease. Here, we present the autopsy findings from three patients with FOP. FINDINGS: Autopsy findings in two of the three patients confirmed that the cause of death was cardiorespiratory failure in the setting of severe thoracic insufficiency from heterotopic ossification. Both of these patients also had evidence of right ventricular dilatation likely secondary to thoracic insufficiency. The third patient died from complications of a traumatic head injury after a fall but also had post-mortem evidence of thoracic insufficiency syndrome. All three patients had extensive, widespread heterotopic ossification and joint deformities consistent with FOP. There was extensive ossification of the spinal ligament in these patients, which may contribute to cervical spine rigidity. One patient was diagnosed post-mortem with a brainstem malformation. No additional significant abnormalities were noted in the other organ systems. Finally, we also demonstrate that cadaveric skin fibroblasts can be isolated for use as a potential source for future in vitro cell culture studies. CONCLUSIONS: This autopsy case series provides valuable information about the underlying complications of FOP and contributes significantly to our knowledge of this rare yet debilitating disorder. Thoracic insufficiency syndrome, right heart dysfunction, widespread heterotopic ossification, spinal ligament ossification, and CNS malformations were clearly evident; however, most other non-bone tissues appeared to be spared from gross malformations. Finally, the ability to isolate live cells from cadaveric skin is an important technique that will facilitate future studies, particularly as induced pluripotent stem cells and other cell-based technologies evolve. This case series highlights the importance of post-mortem examinations and their contribution to our current knowledge of disease pathophysiology and comorbidities.

Predictores de la mortalidad en pacientes con sepsis obstétrica mediante el uso de una puntuación de sepsis obstétrica y evaluación secuencial de falla orgánica-obstétrica / Predictors of mortality in patients with obstetric sepsis using the Sepsis in Obstetrics Score and Sequential Organ Failure Assessment-Obstetrics / Preditores da mortalidade em pacientes com sepse obstétrica usando escore de sepse obstétrica e evaluação sequencial da falha orgânica obstétrica

Resumen Objetivo Determinar los predictores de mortalidad en pacientes con sepsis obstétrica mediante puntuación de sepsis obstétrica (SOS) y evaluación secuencial de falla orgánica-obstétrica (SOFA-O). Material y métodos Se realizó un estudio observacional, retrospectivo, descriptivo, donde se recabaron los datos de las pacientes que ingresaron a unidades de cuidados intensivos de hospitales de segundo nivel con diagnóstico de sepsis obstétrica en el periodo del 30 de junio de 2015 al 30 de junio de 2017; se aplicaron los instrumentos SOS (sepsis en obstetricia) y SOFA-O (evaluación secuencial de falla orgánica-obstétrica), y se correlacionaron las variables con la mortalidad materna. Resultados De un universo de 284 pacientes que ingresaron a las UCI de hospitales de segundo nivel, se seleccionaron 51 que tenían criterios de inclusión para sepsis, correlacionándose con variables de las escalas SOS y SOFA-O. Se encontró como mayor factor de riesgo para el desarrollo de sepsis ser multigesta, tener preeclampsia, anemia, cesárea, mal control prenatal y haber sido sometida a procedimientos invasivos. Las variables cuantitativas relacionadas con muerte materna fueron creatinina, relación PaO2/FiO2, frecuencia cardiaca, lactato, saturación venosa. El puntaje de SOS mínimo y máximo para muerte materna fue 7-22 y de SOFA-O, 10-18 puntos. Hubo una mortalidad de 7.8% (cuatro pacientes) de la población estudiada. Conclusiones La incidencia de sepsis obstétrica se encuentra en aumento, por lo que su reconocimiento rápido y la terapia adecuada impactarán en la supervivencia de la paciente.

Abstract Objective To determine the predictors of mortality in patients with obstetric sepsis using the Sepsis in Obstetrics Score (SOS) and the Sequential Organ Failure Assessment-Obstetrics (SOFA-O). Material and methods An observational, retrospective, descriptive study was carried out, where data were collected from patients who entered intensive care units of second-level hospitals with a diagnosis of obstetric sepsis in the period from June 30, 2015 to June 30, 2017. The SOS and SOFA-O instruments were applied, correlating the variables with maternal mortality. Results From a universe of 284 patients who entered the ICU of second level hospitals, 51 were selected who had inclusion criteria for sepsis, correlating with SOS and SOFA-O variables. We found that major risk factors for the development of sepsis were multigestation, having preeclampsia, anemia, cesarean section, poor prenatal control and been subject of invasive procedures. The quantitative variables related to maternal death were creatinine, PaO2/FiO2 ratio, heart rate, lactate, venous saturation. The minimum and maximum SOS scores for maternal death were 7-22, and SOFA-O, 10-18 points. There was a mortality of 7.8% (four patients) of the study population. Conclusions The incidence of obstetric sepsis is increasing; therefore, rapid recognition and appropriate therapy will impact patient's survival.

Resumo Objetivo Determinar os preditores de mortalidade em pacientes com sepse obstétrica por meio do escore de sepse obstétrica (S.O.S) e Avaliação Sequencial da falha orgânica-obstétrica (SOFA-O). Material e métodos Foi realizado um estudo observacional, retrospectivo e descritivo, onde foram coletados dados de todas as pacientes que ingressaram na unidade de terapia intensiva, no período de 30 de junho de 2015 a 30 de junho de 2017, com diagnóstico de sepse obstétrica, onde foram aplicadas escalas S.O.S e SOFA-O, correlacionando as variáveis com a mortalidade materna. Resultados De um universo de 284 pacientes que ingressaram na UTI, selecionaram-se 51 pacientes que apresentaram critérios de inclusão para sepse, correlacionando-se com variáveis de escala S.O.S e SOFA-O, encontrando como maior fator de risco para desenvolvimento da sepse ser: multigesta, apresentar pré-eclâmpsia, anemia, cesariana, controle pré-natal deficiente e procedimentos invasivos. As variáveis quantitativas relacionadas à morte materna foram: creatinina, relação PaO2/FIO2, freqüência cardíaca, lactato, saturação venosa. Com um escore mínimo e máximo de S.O.S para morte materna 7-22 e SOFA-O 10-18 pontos. Houve uma mortalidade de 7.8% (4 pacientes) da população estudada. Conclusões A incidência de sepse obstétrica está aumentando, de modo que reconhecimento rápido e uma terapia apropriada afetará a sobrevivência do paciente.

Analysis of Accessory Pudendal Artery Transection on Erections During Robot-Assisted Radical Prostatectomy.

PURPOSE: To compare the recovery of erections and potency following the transection of accessory pudendal arteries (APAs) in men undergoing robot-assisted radical prostatectomy (RARP) compared with men with normal vascular anatomy. MATERIALS AND METHODS: A total of 880 consecutive patients who underwent RARP from January 1, 2007 to December 31, 2014 were included with prospectively collected data in cross-sectional analysis. Erectile function (EF) was assessed preoperatively and postoperatively at 3, 6, 12, and 24 months using the International Index of Erectile Function (IIEF)-5, a percent erection fullness compared to preoperative status, and two Expanded Prostate Cancer Index (EPIC) questions: (1) are erections firm enough for penetration and (2) are they satisfactory? RESULTS: Two hundred thirty-one (33.1%) men had APAs transected. There were no significant differences in baseline demographics or clinical characteristics in men with or without APAs transected. Multivariate analyses demonstrated that age (confidence interval [95% CI]: 0.94, 0.99) and baseline IIEF-5 (95% CI: 1.15, 1.26) strongly correlated with recovery of erections and potency. Transection of APAs was not a significant predictor of erectile dysfunction (ED). CONCLUSION: Good surgical technique dictates the preservation of APAs. However, when preservation is questioned, we found that APA transection had no measurable effect on recovery of erections or potency regardless of age, preoperative ED, or number of APAs transected.