Recommendations for the diagnosis and management of vaccine-induced immune thrombotic thrombocytopenia.

There have recently been safety concerns regarding an increased risk of vaccine-induced immune thrombotic thrombocytopenia (VITT) following administration of SARS-CoV-2 adenoviral vector vaccines. The Southern African Society of Thrombosis and Haemostasis reviewed the emerging literature on this idiosyncratic complication. A draft document was produced and revised by consensus agreement by a panel of professionals from various specialties. The recommendations were adjudicated by independent international experts to avoid local bias. We present concise, practical guidelines for the clinical management of VITT.

Effectiveness of first-line treatments in metastatic squamous non-small-cell lung cancer.

Background: Commonly used first-line (1L) chemotherapies for patients with advanced squamous-cell lung cancer (scc) include gemcitabine-platinum (gp), nab-paclitaxel-carboplatin (nabpc), and sb-paclitaxel-carboplatin (sbpc) regimens. However, no head-to-head trials have compared those treatments. In the present study, we compared the efficacy of 1L gp, nabpc, and sbpc in patients with scc and in patients with scc who subsequently received second-line (2L) immunotherapy. Methods: Medical records of patients who initiated the 1L treatments of interest between June 2014 and October 2015 were reviewed by 132 participating physicians. Kaplan-Meier curves were used to evaluate overall survival (os), progression-free survival (pfs), and treatment discontinuation (td), and then Cox proportional hazards regression was used to compare the results between the cohorts. Results: Medical records of 458 patients with scc receiving gp (n = 139), nabpc (n = 159), or sbpc (n = 160) as 1L therapy were reviewed. Median os was longer with nabpc (23.9 months) than with gp (16.9 months; adjusted hazard ratio vs. nabpc: 1.55; p < 0.05) and with sbpc (18.3 months; adjusted hazard ratio: 1.42; p = 0.10). No differences were observed in pfs (median pfs: 8.8, 8.0, and 7.6 months for gp, nabpc, and sbpc respectively; log-rank p = 0.76) or in td (median td: 5.5, 5.7, and 4.6 months respectively; p = 0.65). For patients who subsequently received 2L immunotherapy, no differences in os were observed (median os: 27.3, 25.0, and 23.0 months respectively; p = 0.59). Conclusions: In a nationwide sample of scc patients, longer median os was associated with 1L nabpc than with gp and sbpc. Median os for all 1L agents considered was similar in the subgroup of patients who sequenced to a 2L immunotherapy.

[Systemic safety following intravitreal injections of anti-VEGF]. / Tolérance systémique des injections intravitréennes d'anti-VEGF.

The goal of this manuscript is to assess data suggesting that intravitreal injection of anti-vascular endothelial growth factors (anti-VEGFs) could result in systemic adverse events (AEs). The class-specific systemic AEs should be similar to those encountered in cancer trials. The most frequent AE observed in oncology, hypertension and proteinuria, should thus be the most common expected in ophthalmology, but their severity should be lower because of the much lower doses of anti-VEGFs administered intravitreally. Such AEs have not been frequently reported in ophthalmology trials. In addition, pharmacokinetic and pharmacodynamic data describing systemic diffusion of anti-VEGFs should be interpreted with caution because of significant inconsistencies reported. Thus, safety data reported in ophthalmology trials and pharmacokinetic/pharmacodynamic data provide robust evidence that systemic events after intravitreal injection are very unlikely. Additional studies are needed to explore this issue further, as much remains to be understood about local and systemic side effects of anti-VEGFs.

Multicentre study of short-course radiotherapy and transanal endoscopic microsurgery for early rectal cancer.

BACKGROUND: Organ-preserving treatment for early-stage rectal cancer may avoid the substantial perioperative morbidity and functional sequelae associated with total mesorectal excision (TME). The initial results of an organ-preserving approach using preoperative short-course radiotherapy (SCRT) and transanal endoscopic microsurgery (TEMS) are presented. METHODS: Patients with cT1-2N0 rectal cancers staged using high-quality MRI and endorectal ultrasonography received SCRT, with TEMS 8-10 weeks later, at four regional referral centres between 2007 and 2013. Patients were generally considered high risk for TME surgery (a small number refused TME). RESULTS: Following SCRT and TEMS, 60 (97 per cent) of 62 patients had an R0 resection. Histopathological staging identified 20 ypT0 tumours, 23 ypT1, 18 ypT2 and one ypT3. Preoperative uT category was significantly associated with a complete pathological response, which was achieved in 13 of 27 patients with uT0/uT1 disease and in five of 29 with uT2 (P = 0·010). Acute complications affected 19 patients, the majority following TEMS. No fistulas occurred and no stomas were formed. Surveillance detected four intraluminal local recurrences at a median follow-up of 13 months, all in patients with tumours staged as ypT2. Salvage TME achieved R0 resection in three patients and a stent was placed in one patient owing to co-morbidities. CONCLUSION: SCRT with TEMS was effective in the majority of patients considered high risk for (or who refused) TME surgery.

Aspirin-triggered resolvin D1 is produced during self-resolving gram-negative bacterial pneumonia and regulates host immune responses for the resolution of lung inflammation.

Bacterial pneumonia is a leading cause of morbidity and mortality worldwide. Host responses to contain infection and mitigate pathogen-mediated lung inflammation are critical for pneumonia resolution. Aspirin-triggered resolvin D1 (AT-RvD1; 7S,8R,17R-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid) is a lipid mediator (LM) that displays organ-protective actions in sterile lung inflammation, and regulates pathogen-initiated cellular responses. Here, in a self-resolving murine model of Escherichia coli pneumonia, LM metabololipidomics performed on lungs obtained at baseline, 24, and 72 h after infection uncovered temporal regulation of endogenous AT-RvD1 production. Early treatment with exogenous AT-RvD1 (1 h post infection) enhanced clearance of E. coli and Pseudomonas aeruginosa in vivo, and lung macrophage phagocytosis of fluorescent bacterial particles ex vivo. Characterization of macrophage subsets in the alveolar compartment during pneumonia identified efferocytosis by infiltrating macrophages (CD11b(Hi) CD11c(Low)) and exudative macrophages (CD11b(Hi) CD11c(Hi)). AT-RvD1 increased efferocytosis by these cells ex vivo, and accelerated neutrophil clearance during pneumonia in vivo. These anti-bacterial and pro-resolving actions of AT-RvD1 were additive to antibiotic therapy. Taken together, these findings suggest that the pro-resolving actions of AT-RvD1 during pneumonia represent a novel host-directed therapeutic strategy to complement the current antibiotic-centered approach for combatting infections.

Lipoxin B4 promotes the resolution of allergic inflammation in the upper and lower airways of mice.

Chronic mucosal inflammation is the hallmark of important and common airway diseases, such as allergic rhinitis (AR) and asthma. Lipoxin A4 (LXA4) is an endogenous pro-resolving mediator for mucosal inflammation that decreases allergic and asthmatic responses. Lipoxin B4 (LXB4) is a structurally distinct member of the lipoxin family that signals in a manner distinct from LXA4. LXB4 is generated by mucosal tissues, but its actions in allergic inflammation are unknown. Here, we used murine models of AR and asthma to investigate LXB4's activity in mucosal inflammation. In the upper airway, LXB4 significantly decreased nasal mucosal leukocytes and degranulation of mast cells (MCs) and eosinophils. In the lower airway, LXB4 significantly decreased airway inflammation, mucus metaplasia, and hyper-responsiveness. Inhibition of MC degranulation in vivo by LXB4 was more potent than dexamethasone, and these agents displayed unique profiles for cytokine regulation; however, their overall anti-inflammatory actions were comparable. LXB4 decreased eotaxin-dependent eosinophil chemotaxis, IgE-mediated MC degranulation, and expression of type 2 cytokine receptors. Together, these findings indicate that LXB4 carries cell type selective and mucosal protective actions that broaden the lipoxin family's therapeutic potential for upper and lower airway catabasis.

Hysteroscopic sterilization: 10-year retrospective analysis of worldwide pregnancy reports.

STUDY OBJECTIVE: To identify factors that might contribute to pregnancies reported after hysteroscopic sterilization worldwide. DESIGN: Retrospective review of commercial data compiled from the MAUDE database, medical literature, and manufacturer reports received during commercial distribution of hysteroscopic sterilization micro-inserts from 2001 through 2010 (Canadian Taskforce classification III descriptive study). MEASUREMENTS AND MAIN RESULTS: From 2001 through 2010, 497 305 hysteroscopic sterilization kits were distributed worldwide, and 748 pregnancies were reported, i.e., 0.15% of the estimated user population based on the number of distributed kits. The data were sufficient to enable analysis of 508 pregnancies for potential contributing factors and showed most to be associated with patient or physician noncompliance (n = 264) or misinterpreted confirmation tests (n = 212). Conceptions deemed to have occurred within 2 weeks of the procedure and therefore too early for detection were identified in 32 cases. CONCLUSION: Although there are limitations to the dataset and the study design is retrospective, it represents the largest body of cumulative hysteroscopic sterilization data available to date. Of the 748 pregnancies reported, it is apparent that some might have been prevented with greater patient and clinician attention to interim contraceptive use and counseling and with more rigorous evaluation and informed interpretation of the procedure confirmation tests. Although the estimated pregnancy rate based on such a dataset is likely an underestimation, it does suggest that the evaluable field performance of hysteroscopic sterilization micro-inserts is consistent with the labeled age-adjusted effectiveness of 99.74% at 5 years.

Transanal endoscopic microsurgery: a new technique for completion proctectomy.

AIM: Following subtotal colectomy, the retained rectal stump is a potential source of morbidity. Although restorative ileal pouch-anal anastomosis is the gold standard for ulcerative colitis, up to 14% of patients will opt for a permanent ileostomy and undergo completion proctectomy, traditionally by an abdomino-perineal approach, which itself carries significant morbidity. We describe a new technique of perineal proctectomy using transanal endoscopic microsurgery (TEMS) equipment. To our knowledge, this technique has not previously been described in the literature. METHOD: Twelve patients, mean (SD) age 66 (±13) years, underwent TEMS proctectomy, performed by a single surgeon between January 2007 and October 2011. Excision began with an intersphincteric dissection following which the TEMS (WOLF) proctoscope was inserted and close rectal dissection was performed, entering the peritoneal cavity (if the top of the stump was intraperitoneal). Following perineal extraction of the specimen, the external sphincter and skin were closed with an absorbable suture. RESULTS: Nine patients had inflammatory bowel disease, two had neoplasia and one had intractable radiation proctitis. The mean (SD) rectal stump length was 17.8 (±6.1) cm and the peritoneal cavity was entered in nine patients, with no small-bowel injury. The median postoperative hospital stay was 5.5 days. In four patients there was delayed healing of the perineal wound. There was no perioperative mortality. CONCLUSION: TEMS perineal proctectomy is a novel, but safe, technique that may avoid the need for a traditional abdominoperineal approach in selected patients.

[Genic and cellular therapy for peripheral arterial diseases]. / Thérapie génique et cellulaire dans le traitement des pathologies ischémiques des membres inférieurs.

Late evolution of peripheral arterial disease consists in the apparition of critical limb ischemia. Surgical treatments allow to treat these patients during long time; however, in most patients, especially the diabetic ones, there a very few options and the clinical evolution is rapidly dramatic. For these reasons, the critical limb ischemia is one of the first diseases treated by genic or cellular therapies aiming to improve blood flow perfusion in the lower-limbs. In this short review, we describe the main clinical trials of genic therapy; most of them have been abandoned because serious side effects, modest effects and major risks. Different types of stem cells are now used for cell therapy: endothelial progenitor cells, early or late, activated or not, mesenchymal stem cells, embryonic stem cells and human induced pluripotent stem cells. Problems of characterization are described and the results of the most important clinical trials are reported.

Aspirin-triggered resolvin D1 reduces mucosal inflammation and promotes resolution in a murine model of acute lung injury.

Acute lung injury (ALI) is a severe illness with excess mortality and no specific therapy. Protective actions were recently uncovered for docosahexaenoic acid-derived mediators, including D-series resolvins. Here, we used a murine self-limited model of hydrochloric acid-induced ALI to determine the effects of aspirin-triggered resolvin D1 (AT-RvD1; 7S,8R,17R-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid) on mucosal injury. RvD1 and its receptor ALX/FPR2 were identified in murine lung after ALI. AT-RvD1 (~0.5-5 µg kg(-1)) decreased peak inflammation, including bronchoalveolar lavage fluid (BALF) neutrophils by ~75%. Animals treated with AT-RvD1 had improved epithelial and endothelial barrier integrity and decreased airway resistance concomitant with increased BALF epinephrine levels. AT-RvD1 inhibited neutrophil-platelet heterotypic interactions by downregulating both P-selectin and its ligand CD24. AT-RvD1 also significantly decreased levels of BALF pro-inflammatory cytokines, including interleukin (IL)-1ß, IL-6, Kupffer cells, and tumor necrosis factor-α, and decreased nuclear factor-κB-phosphorylated p65 nuclear translocation. Taken together, these findings indicate that AT-RvD1 displays potent mucosal protection and promotes catabasis after ALI.

[The impact of early cranioplasty on cerebral blood flow and its correlation with neurological and cognitive outcome. Prospective multi-centre study on 24 patients]. / Impact de la cranioplastie sur l'hémodynamique cérébrale comme facteur pronostic de l'amélioration clinique chez les patients craniectomisés pour traumatisme crânien grave.

INTRODUCTION: Cranioplasty after decompressive craniectomy in patients suffering from severe head injury often leads to a functional improvement although, to date, the pathophysiology of this phenomenon remains unclear. A few hypotheses have been proposed. The impact of cranioplasty on cerebral perfusion could be one explanation. We have evaluated the impact of cranioplasty on the functional status of patients undergoing decompressive craniectomy for severe head injury with its influence on cerebral perfusion. MATERIALS AND METHODS: Twenty-four patients undergoing craniectomy for severe head injury were included in this multi-centric and prospective study. All of them had a cranioplasty within 12 weeks following decompressive craniectomy. A clinical and radiological evaluation was performed prior to and after cranioplasty. Neurological and cognitive evaluation was performed with the Glasgow Outcome Score (GOS), the Frontal Assessment Battery (FAB) and the Mini Mental State Examination (MMSE). Radiological evaluation was performed by perfusion CT scan and transcranial Doppler. RESULTS: A statistically significant neurological and cognitive improvement was observed in 92% of patients at 6 months follow-up (F-U). Brain perfusion was improved at 6 weeks F-U, predominantly in the affected hemisphere. Systolic and diastolic blood velocity flow were improved in both middle cerebral arteries. CONCLUSION: Cranioplasty after decompressive craniectomy for patients suffering from severe head injury probably improves the functional outcome of these patients, thanks to a global improvement of cerebral perfusion.

[Left atrial appendage as a source of stroke: to close (and how), or not to close (and why)]. / La orejuela izquierda como fuente de accidentes cerebrovasculares: cerrar (y cómo), o no cerrar (y por qué).

The left atrial appendage is considered the main source of emboli in strokes in patients with atrial fibrillation. Oral anticoagulant therapy significantly reduces the risk of cerebral embolic events compared to aspirin, but it is associated with bleeding complications, and is not always used. Closure of the left atrial appendage reduces the rate of thromboembolic events, and it is currently recommended in patients with atrial fibrillation submitted to mitral valve surgery. However, the formation of emboli in these patients may be due to other causes, as the role of the atrial appendage could be less important than is assumed. Moreover, not all patients are candidates for oral anticoagulation, and not all are kept in a proper therapeutic range, which could justify the formation of atrial thrombi. There are several methods for performing the closure of the appendage: direct suture in concomitant mitral surgery, epicardial exclusion by stapling or clips, or endovascular occlusion by percutaneous application. However, the results seem inconclusive with regards to their effectiveness for complete occlusion of the appendage, safety, and efficacy in preventing cerebral embolic events. To add to the confusion, some authors reveal no clear benefit in suture closure, and even describe an increased risk of thromboembolism. We present a review of left atrial appendage closure for the prevention of strokes, as well as the different procedures described above.

Bladder injuries in emergency/expedited laparoscopic surgery in the absence of previous surgery: a case series.

INTRODUCTION: The use of laparoscopy as a diagnostic and therapeutic tool is being used increasingly in the emergency setting with many of these procedures being performed by trainees. While the incidence of iatrogenic injuries is reported to be low, we present six emergency or expedited cases in which the bladder was perforated by the suprapubic trocar. CASES: Three cases were related to the management of appendicitis, two to negative diagnostic laparoscopies for lower abdominal pain and one to an ectopic pregnancy. Management of the bladder injuries varied from a urinary catheter alone to laparotomy with debridement of the abdominal wall due to sepsis and later reconstruction. Four of the six cases were performed by registrars. CONCLUSIONS: Although the incidence of bladder injury is low, its importance is highlighted by the large number of laparoscopies being performed. In addition to catheterisation of the patient, care must be taken with the insertion of low suprapubic ports and consideration should be made regarding alternative sites. Adequate laparoscopic supervision and training in port site planning is required for surgical trainees.

Intra-operative oxygen delivery in infusion volume-optimized patients undergoing laparoscopic colorectal surgery within an enhanced recovery programme: the effect of different analgesic modalities.

AIM: Patients undergoing major open surgery who have an indexed oxygen delivery (DO(2) I) > 600 ml/min/m(2) have been shown to have a lower incidence of morbidity and mortality compared with those whose DO(2) I is below this level. Laparoscopy and Trendelenburg positioning cause a reduction in DO(2) I. We aimed to quantify the effect of the type of analgesia on DO(2) I and to correlate the DO(2) I achieved with the incidence of anastomotic leakage in patients undergoing laparoscopic surgery. METHOD: Following ethical approval, patients were randomized to receive spinal anaesthesia (Group S), epidural analgesia (Group E) or intravenous morphine (Group P) followed by postoperative patient-controlled analgesia (PCA). In addition to standard monitoring, oesophageal Doppler monitoring of the stroke volume allowed directed intravenous fluid therapy. The mean DO(2) I was compared with the anastomotic leakage rate. RESULTS: Seventy-five patients were recruited (Group S, 27; Group E, 23; Group P, 25). The mean (range) DO(2) I for all patients was 490 (230-750) ml/min/m(2) . The analgesic modality had no effect on DO(2) I. Of the 18 patients with a DO(2) I of < 400 ml/min/m(2) , four (22%) developed anastomotic leakage compared with one (%) of the 57 patients with a DO(2) I of > 400 ml/min/m(2) (P = 0.01). CONCLUSION: The analgesic modality used had no effect on the DO(2) I achieved. Anastomotic leakage was significantly higher in patients with a DO(2) I of < 400 ml/min/m(2) . A further study assessing the outcome after raising the DO(2) I with inotropes is required.

Optimizing patient outcomes in laparoscopic surgery.

There is increasing recognition that the entire peri-operative care delivered plays a vital role in determining patient's outcome. Optimisation of this care helps to prevent complications beyond immediate morbidity and mortality. Of the 20 factors described in Enhanced Recovery Programmes, some have a greater impact than others, with analgesia and fluid therapy being two of the main factors. 1 Analgesia - The main analgesic regimes used so far for laparoscopic colorectal surgery have been continuous thoracic epidural and patient controlled analgesia. There is a growing body of opinion that epidural analgesia may not be required for laparoscopic surgery. 2 Individualised goal directed therapy - It is now recognized that measuring flow rather than pressure within the cardiovascular system is more important. Fluid therapy impacts on the outcome by minimizing fluid shifts, optimizing stroke volume and restricting the salt load given whilst maintaining normovolaemia. Analgesia and fluid therapy, together with the remaining enhanced recovery criteria have led to the development of the trimodal approach.

Randomized clinical trial of epidural, spinal or patient-controlled analgesia for patients undergoing laparoscopic colorectal surgery.

BACKGROUND: Epidural analgesia is considered fundamental in enhanced recovery protocols (ERPs). However, its value in laparoscopic colorectal surgery is unclear. The aim of this study was to examine the effects of different analgesic regimens on outcomes following laparoscopic colorectal surgery in fluid-optimized patients treated within an ERP. METHODS: Ninety-nine patients were randomized to receive epidural, spinal or patient-controlled (PCA) analgesia. The primary endpoints were time until medically fit for discharge and length of hospital stay. Secondary endpoints included return of bowel function, pain scores, and changes in pulmonary function and quality of life. RESULTS: Ninety-one patients completed the study. The median length of hospital stay was 3.7 days following epidural analgesia, significantly longer than that of 2.7 and 2.8 days for spinal analgesia and PCA respectively (P = 0.002 and P < 0.001). There was also a slower return of bowel function with epidural analgesia than with spinal analgesia and PCA. Epidural analgesia did not offer better preservation of pulmonary function or quality of life, although pain scores were higher in the PCA group in the early postoperative period. CONCLUSION: Many of the outcomes in the epidural analgesia group were significantly worse than those in the spinal analgesia and PCA groups, suggesting that either of these two modalities could replace epidural analgesia.

Health advantage for black women: patterns in pre-menstrual dysphoric disorder.

BACKGROUND: Pre-menstrual dysphoric disorder (PMDD) is commonly studied in white women; consequently, it is unclear whether the prevalence of PMDD varies by race. Although a substantial proportion of black women report symptoms of PMDD, the Biocultural Model of Women's Health and research on other psychiatric disorders suggest that black women may be less likely than white women to experience PMDD in their lifetimes. METHOD: Multivariate multinomial logistic regression modeling was used with a sample of 2590 English-speaking, pre-menopausal American women (aged 18-40 years) who participated in the Collaborative Psychiatric Epidemiology Surveys in 2001-2003. The sample consisted of 1672 black women and 918 white women. The measure of PMDD yields a provisional diagnosis of PMDD consistent with DSM-IV criteria. RESULTS: Black women were significantly less likely than white women to experience PMDD [odds ratio (OR) 0.44, 95% confidence interval (CI) 0.25-0.79] and pre-menstrual symptoms (OR 0.64, 95% CI 0.47-0.88) in their lifetimes, independently of marital status, employment status, educational attainment, smoking status, body mass index, history of oral contraceptive use, current age, income, history of past-month mood disorder, and a measure of social desirability. The prevalence of PMDD was 2.9% among black women and 4.4% among white women. CONCLUSIONS: This study showed for the first time that black women were less likely than white women to experience PMDD and pre-menstrual symptoms, independently of relevant biological, social-contextual and psychological risk factors. This suggests that PMDD may be an exception to the usual direction of racial disparities in health. Further research is needed to determine the mechanisms that explain this health advantage.

SNP microarray-based 24 chromosome aneuploidy screening demonstrates that cleavage-stage FISH poorly predicts aneuploidy in embryos that develop to morphologically normal blastocysts.

Although selection of chromosomally normal embryos has the potential to improve outcomes for patients undergoing IVF, the clinical impact of aneuploidy screening by fluorescence in situ hybridization (FISH) has been controversial. There are many putative explanations including sampling error due to mosaicism, negative impact of biopsy, a lack of comprehensive chromosome screening, the possibility of embryo self-correction and poor predictive value of the technology itself. Direct analysis of the negative predictive value of FISH-based aneuploidy screening for an embryo's reproductive potential has not been performed. Although previous studies have found that cleavage-stage FISH is poorly predictive of aneuploidy in morphologically normal blastocysts, putative explanations have not been investigated. The present study used a single nucleotide polymorphism (SNP) microarray-based 24 chromosome aneuploidy screening technology to re-evaluate morphologically normal blastocysts that were diagnosed as aneuploid by FISH at the cleavage stage. Mosaicism and preferential segregation of aneuploidy to the trophectoderm (TE) were evaluated by characterization of multiple sections of the blastocyst. SNP microarray technology also provided the first opportunity to evaluate self-correction mechanisms involving extrusion or duplication of aneuploid chromosomes resulting in uniparental disomy (UPD). Of all blastocysts evaluated (n = 50), 58% were euploid in all sections despite an aneuploid FISH result. Aneuploid blastocysts displayed no evidence of preferential segregation of abnormalities to the TE. In addition, extrusion or duplication of aneuploid chromosomes resulting in UPD did not occur. These findings support the conclusion that cleavage-stage FISH technology is poorly predictive of aneuploidy in morphologically normal blastocysts.