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Catherine Kiwuka

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Yiran Li

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Takanori Sato

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Fulminant streptococcal infection with early immunoglobulin introduction resulting in a favourable outcome for both mother and new-born: A case reportTakanori Sato, Rie Oyama, Tsukasa BABADepartment of Obstetrics and GynecologyIwate Medical University2-1-1 Ididori, Yaba-cho, Shiwa-gunIwateTel: 81-19-613-7111028-3695, JapanCo-author: Rie Oyama.E mail: oyamariegm@gmail.comRunning title: Successful treatment of STSS with immunoglobulinCase reportStreptococcal toxic shock syndrome (STSS) is Group A Streptococcus infection that causes rapidly progressive sepsis, disseminated intravascular coagulation (DIC), and multiple organ failure. STSS is the most common cause of sepsis-related maternal mortality1. Early diagnosis and intervention are important, but few reports on immunoglobulin as an adjunctive therapy. The cytokine production is elevated during pregnancy2, suppressing the cytokine storm is more important in sepsis caused by STSS in pregnant women than non-pregnant women, and anti-inflammatory immunoglobulin will likely be useful as an adjunctive therapy to improve maternal and infant prognosis. We report a case of STSS possibility treated using antimicrobial agents and immunoglobulin as adjuvant therapy. This patient of case report provided informed consent. We report a case of the potential of STSS treated with antibiotics and immunoglobulins as adjuvant therapy, and indicate the mechanism of effect of immunoglobulins on cytokine storm.A 37-year-old pregnant woman (gravid 5, para3) woman with a history of WPW syndrome and chronic thyroiditis. The patient had sore throat and fever of 39 °C on 32 +1 weeks, who was admministred in our hospital. At 32 + 4 weeks, her blood pressure and pulse were 79/48 mmHg and 140bpm, SpO2, 98% (oxygen mask, 6 L/min). Cardiotocography revealed delayed transient bradycardia, and we suspected septic shock and foetal insufficiency. Blood tests: WBC 14,740/μL, platelet 9.2 ×104/μL, C-reactive protein 11.1 mg/dL. Her qSOFA score: 1 (respiratory rate: >22 breaths/min), but her National Early Warning Score was 9 (respiratory rate, ≥25; oxygen demand, systolic blood pressure 101-110, heart rate ≥131/min), which is a warning value and corresponds to symptoms of sepsis due to STSS. Therefore, the antimicrobial agent was changed from cefepime to a combination of piperacillin and clindamycin, and an emergency caesarean section was performed 3 houre after admmited at our department. The baby was 2320 g, Apgar score, 1points/3 points (1 minute/5 minutes),umbilical artery blood pH 7.28. Obstetric DIC score was 3 points. Placental histopathology revealed stage 1 chorioamnionitis, but noGroup A streptococcal aggregation in the interchorionic space. On the second postoperative day, we were informed that Group A Streptococcus was detected in pharyngeal and blood cultures at the previous hospital, and antibacterial therapy with piperacillin and clindamycin for STSS and immunoglobulin were continued. Noradrenaline was also started as she had trouble maintaining her blood pressure on the first postoperative day, and dobutamine was added on the third postoperative day. On the fourth postoperative day, her respiratory condition worsened and bilateral diffuse frosted glass shadows were observed on chest radiography. Bilateral pleural effusions and pleural thickening were observed on computed tomography. Respiratory therapy with nasal high flow (NHF) was initiated. The patient was weaned from the NHF and switched to nasal cannula oxygenation on postoperative day 7. Oxygen administration was discontinued on postoperative day 15, and the patient was discharged on postoperative day 21 with improved bilateral diffuse frosted margins on chest radiographyDiscussionIn this case, STSS developed during pregnancy, but early delivery of the baby, antimicrobial therapy, and concomitant use of immunoglobulin from the early postoperative period onward resulted in a good outcome for both the mother and baby. In the field of obstetrics, perinatal STSS was described as “a condition that develops in pregnant women in the last trimester of pregnancy due to hematogenous myometrial infection mainly originating from the upper respiratory tract that induces labour pain and rapidly progresses to septic shock, resulting in a high rate of foetal and maternal death” in 20013,4. There is a trend toward poor prognosis for both the mother and new-born. In Japan, 24 (7.5%) of 317 maternal deaths were due to sepsis, and 13 (53.4%) were due to Group A Streptococcus infection between 2010 and 2016. A 2019 proposal by the Division of Medical Safety of the Japanese Society of Obstetricians and Gynaecologists stated that a modified Centor score should be used for pregnant women to facilitate early medical intervention and reduce maternal deaths due to STSS5. Penicillin and clindamycin are the basic antimicrobial agents of choice for STSS, and combinations containing clindamycin effectively suppress exotoxins and TNF-α and promote phagocytosis by inhibiting M-protein synthesis6,7. Meta-analysis reported that adjunctive immunoglobulin administration was associated with a significant reduction in mortality in STSS patients treated with clindamycin in 20188.The mechanisms of cytokine production and perinatal STSS are shown in Figure 1. Antigens are normally absorbed by antigen-presenting cells, fragmented into peptides, then recognised by T-cell receptors via the major histocompatibility complex (MHC) class II, which activates T cells. In contrast, superantigens bind directly to MHC class II and T-cell receptors without being taken up by antigen-presenting cells and produce numerous cytokines9,10, causing a marked inflammatory reaction via exotoxin11 and leading to septic shock. The production of cytokines such as TNF and IL-1β is also elevated during pregnancy due to changes in monocyte subsets13, and cases of perinatal STSS are prone to cytokine storms.Immunoglobulins exert effects similar to those of opsonin, along with phagocytosis-promoting, superantigen-neutralizing, anti-inflammatory, and antibody-dependent cytotoxic effects, and suppresses proinflammatory cytokine production11,13,14. Immunoglobulins have become a standard anti-inflammatory therapy for Kawasaki disease15. In this case, maintaining blood pressure became difficult on the first postoperative day, and noradrenaline was initiated along with immunoglobulin to suppress the cytokine storm caused by perinatal STSS. Procalcitonin levels were elevated the day after the culture results were obtained from the previous physician (postoperative day 3), but quickly decreased thereafter, and immunoglobulin was discontinued on postoperative day 4. Procalcitonin is produced by endotoxins and proinflammatory cytokines such as TNF-α, IL-1, and IL-6 in cases of severe bacterial infection16,17, and thus indirectly reflects the inflammatory state in the body. Procalcitonin may be an indicator of inflammation reflecting hypercytokinemia in cases of Kawasaki disease, and effectively predicts immunoglobulin refractoriness18. In this case, the reduction in procalcitonin levels following concomitant immunoglobulin use reflected STSS control and cytokine storm suppression, suggesting that the concomitant use of immunoglobulin may have been effective.In this study, we encountered a case of a mother and infant whose lives were saved by delivering the infant early, combined with the use of maternal antimicrobial therapy and combined immunoglobulin administration. The usefulness of combined immunoglobulin administration in perinatal STSS should be studied to further improve maternal and infant prognosis.

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Yuval Shafir

and 8 more

INTRODUCTION: Transvenous Lead Extraction (TLE) is usually performed via a superior approach. Predictors and outcomes of TLE requiring femoral vein bailout are poorly defined. We aimed to analyze predictors and consequences of TLE requiring femoral bailout. METHODS: A single tertiary center cohort of 421 consecutive patients who underwent TLE between May 2010 and February 2020 were analyzed. Venography was routinely performed before system upgrade to identify occluded veins. Patients were divided into 2 groups according to their need for femoral bailout extraction. RESULTS: A total of 928 leads were extracted with femoral bailout approach was needed in 71 leads(7.7%) among 49 patients(11.6%). A higher proportion of right ventricular(RV) leads required femoral bailout approach compared with right atrial(RA) leads[51/499(10.2%) vs 18/326(5.5%);p=0.02]. Femoral bailout was more common among younger patients, longer lead dwell time, more pocket entries, higher number of extracted leads, presence of abandoned leads and among patients with vascular occlusion. Following multivariate analysis, presence of abandoned leads, vascular occlusion and younger age remained a significant predictor for femoral bailout. Femoral bailout resulted in higher rates of major complications [5/49(10.2%) vs 12/372(3.2%);p=0.05] without intra-procedural mortality and no additional 30-day mortality[2/49(4.1%) vs 33/377(8.8%);p=0.39]. CONCLUSION: TLE of abandoned leads, occluded veins and younger age were found to be predictors of femoral bailout requirement. Despite higher rates of major complications in femoral TLE bailout, mortality was not increased. Venography prior to TLE should be considered for procedure planning.

Manuel E. Izquierdo

and 21 more

Background:  Heterozygote carriers of potentially pathogenic variants in the cystic fibrosis transmembrane conductance regulator ( CFTR) gene have increased asthma risk. However, the frequency and impact of CFTR variation among individuals with asthma is unknown. Objective: To determine whether potentially pathogenic  CFTR variants associate with disease severity and whether individuals with two potentially pathogenic variants exist in a severe asthma-enriched cohort . Methods: We analyzed sequencing data spanning a 190.5Kb region of  CFTR in participants from the Severe Asthma Research Program (SARP1-3). Potentially pathogenic, rare  CFTR variants (frequency<0.05) were classified as CF-causing or of varying clinical consequences (VVCC) ( Regression-based models tested for association between  CFTR genotypes (0-2 potentially pathogenic variants) and severity outcomes. Results: Of 1401 participants, 9.5% (134) had one potentially pathogenic variant, occurring more frequently in non-Hispanic white (NHW, 10.1% [84 of 831]) compared to African American individuals (AA, 5.2% [22 of 426]). We found ≥2 potentially pathogenic  CFTR variants in 1.4% (19); 0.5% (4) of NHW and 2.8% (12) of AA. Potentially pathogenic  CFTR variant genotypes (≥1 or ≥2 variants) were not cumulatively associated with lung function or exacerbations. In NHW, we found three F508del compound heterozygotes with F508del and a VVCC (two 5T;TG12[c.1210-11T>G] and one Arg1070Trp) and a homozygote for the VVCC, 5T;TG12. Conclusions: We found potentially pathogenic  CFTR variants within a severe asthma-enriched cohort , including three compound heterozygote genotypes variably associated with CF in NHW individuals. These findings provide the rationale for  CFTR sequencing and phenotyping of CF-related traits in individuals with severe asthma.

Hanan Al-Abboh

and 2 more

A Novel MECOM Variant Associated with Congenital Amegakaryocytic Thrombocytopenia and Radioulnar Synostosis Hanan Al-Abboh1, Akmal Zahra1 and Adekunle Adekile1,2Pediatric Hematology Unit, Mubarak Hospital1 and Department of Pediatrics, Faculty of Medicine, Kuwait University2, Kuwait Address Correspondence to: Professor Adekunle Adekile Department of Pediatrics Faculty of Medicine Kuwait University PO Box 24923 Safat 13110 Kuwait Email: Tel: +96525319486To the EditorCongenital radioulnar synostosis (RUS) is a rare developmental anomaly of proximal fusion of the radius and ulna, resulting in limited pronation and supination of the forearm. It may accompany other abnormalities in the skeleton, kidney, heart and aneuploidy syndromes1,2. A subset of patients with RUS present with bone marrow failure (BMF) syndromes, characterized by amegakaryocytic thrombocytopenia (RUSAT), progressing to myelodysplasia and pancytopenia2,3. The hematological manifestations are quite variable, with some presenting with severe BMF in childhood, while others are mild and may not present until adulthood.Heterozygous germline variants in the homeobox A11 (HOXA11) gene were the first to be associated with RUS and designated RUSAT14, but lately, several families have been described with variants in the MDS1 and EVI1 complex (MECOM) locus, and referred to as RUSAT22,5,6. Many of these variants appear de novo , while others follow an autosomal dominant inheritance. We, hereby, report the case of a Kuwaiti patient who presented with congenital amegakaryocytic thrombocytopenia (CAMT) in the neonatal period and later noticed to have RUS. Whole exome sequencing revealed a novel MECOM variant.A.A. is a male Kuwaiti, the first child of consanguineous parents and was first seen at the age of 36 days, following antenatal ultrasound diagnosis of bilateral hydronephrosis and right renal cyst. He was a product of induced vaginal delivery with a birth weight of 2.3 kg. After delivery, he was kept under observation in the neonatal intensive care unit. His CBC showed isolated thrombocytopenia (Plt 34 x109/L). He received several platelet transfusions, as well as IVIG twice. Postnatal abdominal ultrasound showed multicystic right kidney, in addition to bilateral hydronephrosis. The mother had no history of thrombocytopenia during pregnancy and there was no other pertinent family history.Physical examination at presentation showed 2 café-au-lait spots, one on the back, measuring 1x2 cm and another over the left leg, that was less than 0.6 cm. There were no obvious dysmorphic features and other systems were unremarkable. CBC showed WBC 11.2 x109/L Hb 10.4 g/dL, MCV 83fl, Plt 49 x109/L, ANC 1.8 x109/L. Renal function tests were normal. Blood film showed no abnormal cells; there was true thrombocytopenia with giant forms. Antiplatelet antibody was negative. Abdominal ultrasound at age 1 month showed complete replacement of the right kidney by cystic changes with left moderate hydronephrosis. Skeletal survey was reportedly normal.Bone marrow biopsy showed normal distribution of granulocytic and erythroid precursors, with severe suppression of megakaryocytosis, consistent with a bone marrow failure syndrome. Chromosomal breakage study was normal. The patient was diagnosed with right undescended testis, as well as right inguinal hernia that were operated at age 1 year and 10 months. At the age 2 and a half years, A.A. was noticed to have limited bilateral arm movement supination and pronation. The mother volunteered that she has a similar defect. X-rays confirmed that the child had bilateral radioulnar synostosis. Whole exome sequencing showed that the patient is heterozygous for a previously-unreported MECOM gene, c.2282A>G mutation. Unfortunately, the parents have not been screened for these mutations.The patient has been under follow up for 4 years, his platelet count has been stable, ranging between 40-50 x109/L, with no bleeding tendency. In spite of his limited arm rotation, he currently functions normally in his daily activities, however, his hand writing skills and ability to engage in sports are yet to be observed since he is still pre-school age. Platelet transfusion is reserved only for severe bleeding, which he has not had. Bone marrow transplant may be considered in future if his bone marrow failure worsens and/or his marrow shows dysplastic changes.Dokal et al3 were the first to report an association between RUS and late-onset BMF, while Thompson et al described its association with CAMT and linked it to the c.872delA ,p.Asn291Thrfs3 variant of the HOXA11gene4,7. More recently, several germline mutations in the MECOM locus have been reported and appear to be the more common cause of RUSAT. Indeed, no other cases of HOXA11 mutations linked to RUSAT have been described since the initial report. Niihori et al8 reported the first 3 heterozygous MECOMmutations in 3 sporadic patients. These variants and those subsequently reported by Walne et al2 are in a highly conserved cluster within 10 amino acids (aa750-760) and impact on either the highly conserved Cys2His2 zinc finger motif (zinc finger 8, aa733-755) or the adjacent linker motif (aa756-760). It has been shown that removal of the 8th zinc finger causes granulopoiesis arrest while mutations and deletions in other parts of the complex, outside the 8th and 9th fingers, are associated with hematological disorders without RUS9.MECOM codes for a zinc finger transcription factor with important roles in normal development and oncogenesis and is involved in the regulation of embryonic development and hematopoietic stem-cell renewal. Hence the phenotype in individuals with these mutations is very variable ranging from BMF to different skeletal, cardiac, renal malformations, B cell deficiency and sensorineural deafness.Our patient showed a previously unreported variant in the region of the 8th zinc finger of the MECOM locus. This c.2282A>G missense variant results in the tyrosine to cysteine substitution at codon 761 (p.Tyr761Cys). The amino acid is in the Zinc finger, C2H2 and Zinc finger, C2H2-like protein domains and is highly evolutionarily conserved. Unfortunately, the parents were not screened for the mutation, however, the mother shows RUS, with normal blood counts. This is consistent with the marked variability in the clinical phenotype. The father is also physically and hematologically normal.Apart from thrombocytopenia, our patient also had renal abnormalities – hydronephrosis and multicystic kidney disease. The natural history of his condition is that he may develop pancytopenia and/or myelodysplasia in the future. He is under close follow up and will be considered for bone marrow transplantation if his condition worsens. In the meantime, he remains hypomegakaryocytic with a platelet count at 30 – 50 x 109/l while other blood cellular elements are normal. His renal function and hearing are being monitored, but still remain normal.AcknowledgementsWe thank the patient’s family for allowing us to report this case. The whole exome sequencing was done at the Laboratory of Genetics and Genomics, Cincinnati Children’s Hospital, Cincinnati, Ohio.References1. Rizzo R, Pavone V, Corsello G, Sorge G, Neri G, Opitz JM. Autosomal dominant and sporadic radio-ulnar synostosis. Am J Med Genet.1997;68(2):127-134.2. Walne A, Tummala H, Ellison A, et al. Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease. Haematologica. 2018;103(7):e284-e287.3. Dokal I, Ganly P, Riebero I, et al. Late onset bone marrow failure associated with proximal fusion of radius and ulna: a new syndrome.Br J Haematol. 1989;71(2):277-280.4. Thompson AA, Nguyen LT. Amegakaryocytic thrombocytopenia and radio-ulnar synostosis are associated with HOXA11 mutation. Nat Genet. 2000;26(4):397-398.5. Germeshausen M, Ancliff P, Estrada J, et al. MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia. Blood Adv. 2018;2(6):586-596.6. Ripperger T, Hofmann W, Koch JC, et al. MDS1 and EVI1 complex locus (MECOM): a novel candidate gene for hereditary hematological malignancies. Haematologica. 2018;103(2):e55-e58.7. Thompson AA, Woodruff K, Feig SA, Nguyen LT, Schanen NC. Congenital thrombocytopenia and radio-ulnar synostosis: a new familial syndrome.Br J Haematol. 2001;113(4):866-870.8. Niihori T, Ouchi-Uchiyama M, Sasahara Y, et al. Mutations in MECOM, Encoding Oncoprotein EVI1, Cause Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia. Am J Hum Genet.2015;97(6):848-854.9. Nielsen M, Vermont CL, Aten E, et al. Deletion of the 3q26 region including the EVI1 and MDS1 genes in a neonate with congenital thrombocytopenia and subsequent aplastic anaemia. J Med Genet.2012;49(9):598-600.

Hoda Abdelgawad

and 2 more

57-years old man presented with exertional dyspnea. An early systolic murmur was heard over the aortic areas 2D and 3D Echocardiography revealed unicuspid , unicommissural aortic valve (UAV) with a characteristic “teardrop” lateral orifice (Figure A) and moderate valve stenosis (3D planimetered aortic valve area (AVA) is 1.1cm2) (Figure B) Continuous wave Doppler across aortic valve (AV) showed high peak and mean systolic gradients of 85 and 60mmHg respectively.(Figure C). 2D /3D Transesophageal Echocardiography (TOE) revealed a subaortic ridge attached to the posterior annulus (Arrow) (Figure D) Further En-face viewing of the aortic valve from the left ventricular outflow tract (LVOT) perspective showed a shelf-like ridge extending from the commissure to the cusp (Arrow) (Figure E) Zoomed mode of the aortic- LVOT junction confirmed the presence of the subaortic ridge seen attached to the posterior aortic annulus near the commissural opening (Figure F) The patient was referred for surgical consultation .. Unicupid aortic valve (UAV) is a rare congenital anomaly that has.2 subtypes ; unicomissural and acommissural subtypes. Both can present with variable degrees of the aortic stenosis (AS) and/or aortic valve regurgitation (AR).UAV has more early, accelerated and severe valvular degeneration in addition to smaller orifice in comparison with bicuspid and tricuspid aortic valve. Echocardiography is the gold standard for diagnosis and evaluation of the AV morphology and function and the associated disorders such as ventricular septal defect , aortopathy and subaortic obstruction.. Surgical aortic valve replacement (AVR) and repair of the associated anomalies are the most common treatment modality .

Esin Isik

and 7 more

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