COVID-19 vaccination and breakthrough infections in patients with cancer.

BACKGROUND: Vaccination is an important preventive health measure to protect against symptomatic and severe COVID-19. Impaired immunity secondary to an underlying malignancy or recent receipt of antineoplastic systemic therapies can result in less robust antibody titers following vaccination and possible risk of breakthrough infection. As clinical trials evaluating COVID-19 vaccines largely excluded patients with a history of cancer and those on active immunosuppression (including chemotherapy), limited evidence is available to inform the clinical efficacy of COVID-19 vaccination across the spectrum of patients with cancer. PATIENTS AND METHODS: We describe the clinical features of patients with cancer who developed symptomatic COVID-19 following vaccination and compare weighted outcomes with those of contemporary unvaccinated patients, after adjustment for confounders, using data from the multi-institutional COVID-19 and Cancer Consortium (CCC19). RESULTS: Patients with cancer who develop COVID-19 following vaccination have substantial comorbidities and can present with severe and even lethal infection. Patients harboring hematologic malignancies are over-represented among vaccinated patients with cancer who develop symptomatic COVID-19. CONCLUSIONS: Vaccination against COVID-19 remains an essential strategy in protecting vulnerable populations, including patients with cancer. Patients with cancer who develop breakthrough infection despite full vaccination, however, remain at risk of severe outcomes. A multilayered public health mitigation approach that includes vaccination of close contacts, boosters, social distancing, and mask-wearing should be continued for the foreseeable future.

Synthetic peptide optimization improves the inhibition of dengue NS2B-NS3 protease and dengue replication in vitro.

Dengue virus (DENV) infection is one of the most widely-spread flavivirus infections with no effective antiviral drugs available. Peptide inhibitors have been considered as one of the best drug candidates due to their high specificity, selectivity in their interactions and minimum side effects. In this study, we employed computational studies using YASARA, HADDOCK server and PyMOL software to generate short and linear peptides based on a reference peptide, CP5-46A, to block DENV NS2B-NS3 protease. The inhibition potencies of the peptides were evaluated using in-house DENV2 serine protease and fluorogenic peptide substrates. In vitro analyses were performed to determine the peptides cytotoxicity and the inhibitory effects against DENV2 replication in WRL-68 cells. Our computational analyses revealed that the docking energy of AYA3, a 16 amino acid (aa) (-81.2 ± 10.6 kcal/mol) and AYA9, a 15 aa peptide (-83.8 ± 6.8 kcal/mol) to DENV NS2B-NS3 protease were much lower than the reference peptide (46 aa; -70.9 ± 7.8 kcal/mol) and the standard protease inhibitor, aprotinin (58 aa; -48.2 ± 10.6 kcal/mol). Both peptides showed significant inhibition against DENV2 NS2B-NS3 protease activity with IC50 values of 24 µM and 23 µM, respectively. AYA3 and AYA9 peptides also demonstrated approximately 68% and 83% of viral plaque reduction without significantly affecting cell viability at 50 µM concentration. In short, we generated short linear peptides with lower cytotoxic effect and substantial antiviral activities against DENV2. Further studies are required to investigate the inhibitory effects of these peptides in vivo. Keywords: peptide inhibitors; dengue virus; NS2B-NS3 protease; plaque reduction.

A rare partnership: patient community and industry collaboration to shape the impact of real-world evidence on the rare disease ecosystem.

People with rare lysosomal storage diseases face challenges in their care that arise from disease complexity and heterogeneity, compounded by many healthcare professionals being unfamiliar with these diseases. These challenges can result in long diagnostic journeys and inadequate care. Over 30 years ago, the Rare Disease Registries for Gaucher, Fabry, Mucopolysaccharidosis type I and Pompe diseases were established to address knowledge gaps in disease natural history, clinical manifestations of disease and treatment outcomes. Evidence generated from the real-world data collected in these registries supports multiple stakeholders, including patients, healthcare providers, drug developers, researchers and regulators. To maximise the impact of real-world evidence from these registries, engagement and collaboration with the patient communities is essential. To this end, the Rare Disease Registries Patient Council was established in 2019 as a partnership between the Rare Disease Registries and global and local patient advocacy groups to share perspectives on how registry data are used and disseminated. The Patient Council has resulted in a number of patient initiatives including patient representation at Rare Disease Registries advisory boards; development of plain language summaries of registry publications to increase availability of real-world evidence to patient communities; and implementation of digital innovations such as electronic patient-reported outcomes, and patient-facing registry reports and electronic consent (in development), all to enhance patient engagement. The Patient Council is building on the foundations of industry-patient advocacy group collaboration to fully integrate patient communities in decision-making and co-create solutions for the rare disease community.

Granulomatosis with polyangiitis and pregnancy: A case report and review of the literature.

The association of granulomatosis with polyangiitis and pregnancy is rare and therapeutic options are limited by the risk of teratogenicity and fetotoxicity. There is a paucity of published literature to guide clinical decision-making in these cases. We report the case of a 26-year-old woman with no medical history who presented at 21 weeks of gestation with a bilateral sudden loss of hearing and erosive rhinitis. The diagnosis of granulomatosis with polyangiitis was confirmed radiologically and biologically. Corticosteroids were not enough to stabilize the disease and she received intravenous immunoglobulins with remission. A successful delivery of a healthy male newborn was done at 36 weeks. A review of all published literature on granulomatosis with polyangiitis in pregnancy between 1970 and 2017 is presented. Trial registration: Not applicable.

Removal and recovery of U(VI) from aqueous effluents by flax fiber: Adsorption, desorption and batch adsorber proposal.

Flax fiber (Linen fiber), a valuable and inexpensive material was used as sorbent material in the uptake of uranium ion for the safe disposal of liquid effluent. Flax fibers were characterized using BET, XRD, TGA, DTA and FTIR analyses, and the results confirmed the ability of flax fiber to adsorb uranium. The removal efficiency reached 94.50% at pH 4, 1.2 g adsorbent dose and 100 min in batch technique. Adsorption results were fitted well to the Langmuir isotherm. The recovery of U (VI) to form yellow cake was investigated by precipitation using NH4OH (33%). The results show that flax fibers are an acceptable sorbent for the removal and recovery of U (VI) from liquid effluents of low and high initial concentrations. The design of a full scale batch unit was also proposed and the necessary data was suggested.

Id3 induces a caspase-3- and -9-dependent apoptosis and mediates UVB sensitization of HPV16 E6/7 immortalized human keratinocytes.

Inhibitor of differentiation/DNA binding (Id) proteins comprise a class of helix-loop-helix transcription factors involved in proliferation, differentiation, apoptosis, and carcinogenesis. We have shown that while Id2 is induced by UVB in primary keratinocytes, Id3 is upregulated only in immortalized cells. We have now determined that the consequences of ectopic expression of Id3 protein are strikingly different between immortalized and primary keratinocytes. Overexpression of Id3 induces a significant increase in apoptotic cells as revealed by Annexin V positivity as well as proteolytic processing of caspase-3 in immortalized, but not in primary keratinocytes. Id3-green fluorescent protein (GFP)-positive cells exhibited a fivefold increase in apoptotic nuclear fragmentation compared to Id3-GFP-negative cells. These apoptotic responses were accompanied by activation of caspase-3, as shown by immunocytochemical staining with antibodies to active caspase-3. Immunostaining with antibodies to the active form of caspase-9 as well as to the active form of Bax further revealed that induction of apoptosis in Id3-overexpressing keratinocytes occurred via a mitochondrial-caspase-9-mediated pathway. Coexpression of dominant-negative caspase-9 with Id3 significantly suppressed apoptotic nuclear fragmentation, indicating that caspase-9 activation is essential for Id3-induced cell death. This response was also markedly attenuated by coexpression with the Bax antagonist antiapoptotic protein Bcl2, confirming a role for Bax activation in this apoptotic response. Id3-induced Bax activation may result from increased expression of Bax protein. Furthermore, reduction of Id3 expression by small interfering RNAs abrogated the UVB-induced proteolytic activation of caspase-3 in these cells. These data together suggest that UVB-induced apoptosis of immortalized keratinocytes is at least in part due to Id3 upregulation in these cells.

Comparative effects of glibenclamide and metformin on ambulatory blood pressure and cardiovascular reactivity in NIDDM.

OBJECTIVE: To compare the effects of chronic glibenclamide and metformin therapy on blood pressure (BP) and cardiovascular responsiveness in patients with NIDDM. RESEARCH DESIGN AND METHODS: Fourteen patients with NIDDM received metformin or glibenclamide for 1 month in a double-blind, randomized crossover study. At the end of each treatment period, patients were tested for forearm vascular responsiveness to intrabrachial arterial infusion of diazoxide (an ATP-sensitive potassium channel opener), acetylcholine, sodium nitroprusside, and norepinephrine, BP responses to intravenous infusions of NE and angiotensin II, BP responses to cold pressor testing and isometric exercise, and 24-h ambulatory BP monitoring. RESULTS: Metformin and glibenclamide produced similar glycemic control. Mean 24-h BPs did not differ between the two groups, but mean 24-h heart rates were significantly lower (75 +/- 6 bpm vs. 80 +/- 6 bpm) on glibenclamide therapy than on metformin. Plasma norepinephrine levels were significantly higher on glibenclamide (6.41 +/- 1.77 vs. 4.26 +/- 1.54 mmol/l, P < 0.01), and systolic BP responses to intravenous norepinephrine and angiotensin II were significantly higher on glibenclamide than on metformin (P < 0.02 and P < 0.05, respectively). Systolic BP responses to cold pressor testing appeared higher on glibenclamide than on metformin, but the difference did not quite achieve statistical significance (P = 0.052). Baseline forearm vascular resistance did not differ between the two drugs, nor did forearm vascular resistance responses to diazoxide, acetylcholine, sodium nitroprusside, and norepinephrine differ. CONCLUSIONS: Glibenclamide therapy is accompanied by greater systolic BP responses to norepinephrine and angiotensin II and higher plasma norepinephrine levels than those that occur on metformin therapy. Lower heart rates on glibenclamide therapy despite evidence of greater sympathetic activity suggests that glibenclamide may have negative chronotropic effects.

Infective endocarditis in neonates.

We studied retrospectively the predisposing factors and signs of infective endocarditis (IE) in neonates and infants younger than 3 months of age, and we suggest diagnostic criteria. The charts of 16 infants less than 3 months of age, diagnosed with IE during a 5-year period, were reviewed for possible maternal and infant risk factors and for pathognomonic clinical and laboratory features. No apparent maternal risk factors were noted. Infant risk factors were congenital heart disease (4), patent ductus arteriosus (PDA) (5), and the use of central venous catheters (14). The main clinical findings were cardiac murmurs (12), petechiae (2), skin abscesses (7), arthritis (2), hepatomegaly (9), and splenomegaly (2). Echocardiography revealed a mass or vegetation in nine patients. Of the 27 microorganisms isolated from blood, the most common were staphylococci (15) and Candida sp. (6). Urine cultures were positive in six patients and cerebrospinal fluid cultures were positive in one. Other laboratory findings were not of diagnostic value. We conclude that the main risk factors for neonatal IE are central venous catheters and congenital heart disease, including PDA. The main causative microorganisms are staphylococci and Candida sp. The main investigations of diagnostic value are blood and urine cultures and echocardiography. We propose the diagnostic categories of definite, probable, and possible cases of neonatal IE, based primarily on clinical, blood culture, and echocardiographic data.

[Tubulo-papillary tumor of the kidney. Apropos of a case]. / Les tumeurs tubulo-papillaires du rein. A propos d'un cas.

Tubulopapillary tumors represent a particular group of the renal tumors. Beyond their characteristic histological features, these tumors can be distinguished from the other renal tumors by the frequency of stage I on histology and by a more favorable prognosis.

[Talus bipartitus]. / Talus bipartitus.

Talus bipartitus is an exceptional congenital malformation consisting in the presence of two non-fused bony talar fragments. We report the case of an adolescent girl who complained of mechanical pain in the left ankle which became increasingly invalidating. Plain radiographs, CT-scan and MRI led to the diagnosis of this congenital anomaly: talus bipartitus. Surgical correction by subtalar arthrodesis provided improvement at the cost of reduced ankle mobility. Surgical treatment should be proposed for talus bipartitus in patients with invalidating pain or stiffness when rehabilitation fails to provide sufficient improvement.

[Extra-intracranial shunts by venous grafts interposed on the carotid system]. / Pontages extra-intracrâniens par greffons veineux interposés sur le système carotidien.

Patients with occlusive arterial diseases, tumors invading the vascular structures of the skull base or giant aneurysms may benefit from an EICB. Most of the time this can be achieved using a scalp artery. But in cases of a thrombotic ECA, excessively short or thin scalp branches or destruction of those by prior cranial surgery, an interposed venous graft is needed. In the author's series, which consists of 16 patients, the bypass was performed for ICA occlusive diseases in 5, before complete removal of cavernous sinus tumours in 4 and prior to cervical internal carotid ligation for giant aneurysms in 7. The grafts were always harvested from the internal saphenous vein. The proximal site of implantation was CCA (2 cases), ECA (6 cases), ICA (1 case), superior thyroid A (2 cases)--i.e. 11 long grafts--and the trunk of the occipital A--i.e. short grafts in 5 cases. In this series, there was no mortality and no morbidity related to revascularization. The early patency rate, checked with arteriography, was 62.5% (10 cases) and the late one 56.2% (9 cases). Causes of failure, partially related to technical difficulties in 2 cases, were almost always due to an insufficient extra-intracranial pressure gradient (4 cases). Excepted in one case, there was no correlation between patency and the use or not of anti-aggregant and/or heparin. Literature data are summarized and discussed. They all confirm the importance--besides the absence of technical errors--of a sufficient extra-intracranial gradient for obtaining a good patency rate.

[Parasellar chondrosarcoma: report of a case operated on through a pteriono-temporal approach and review of the literature]. / Chondrosarcome parasellaire: rapport d'un cas opéré par voie ptériono-temporale et revue de la littérature.

Cartilaginous tumours represent 0.16% of all intracranial tumours; among them 14% are chondrosarcomas (Ch-S). A majority (56%) arise from the skull base, especially from the spheno-occipital and spheno-temporal synchondroses. The others develop at the level of the dura mater convexity, falx and choroid plexuses, probably from ectopic cartilages or mesenchymatous cells with multiple potentialities. Parasellar Ch-S originate from the spheno-temporal synchondrosis and expand inside the cavernous region. With 21 published cases, they represent 51.2% of the 41 skull base Ch-S and 28.7% of the whole 73 intracranial primary Ch-S. The authors report a recent case of such a parasellar Ch-S, revealed by a left progressive, and finally total, ophthalmoplegia. The responsible mass, which eroded the lateral part of the sella turcica, was shown partially calcified and not enhanced by contrast medium at CT-scan, and was avascular on angiogram. The tumour, which was identified as a low grade myxoid Ch-S, could be entirely removed through an intradural pteriono-temporal approach. After a two-year follow-up, the clinical status was unchanged (total ophthalmoplegia) and the CT-scan did not show any sign of recurrence. The 21 cases of parasellar Ch-S published in the literature are reviewed.

[Preliminary study on the feasibility of robot-assisted double mesh sacrocolpopexy in comparison to the laparoscopic approach]. / Étude préliminaire sur la faisabilité de la double promontofixation robotique comparée à la voie cœlioscopique.

OBJECTIVES: The aim of our study was to demonstrate the feasibility of the laparoscopic robot-assisted anterior and posterior mesh sacrocolpopexy compared to the laparoscopic approach. MATERIALS AND METHODS: Between November 2009 and August 2011, 36 women underwent sacrocolpopexy with anterior and posterior mesh, 16 by a robot-assisted approach and 20 by laparoscopy. The cases were systematically evaluated at 1 and 12 months postoperatively. All cases were contacted 6 months later to evaluate the functional results. RESULTS: Both groups were comparable in terms of age, ASA score, Body Mass Index, surgical history and grades of pelvic organ prolapse preoperatively. There was no difference in terms of hospital stay, per- and postoperative complications, especially concerning the rate of postoperative constipation. The mean operating time was significantly more important in the Robot group (P=0.001) with 318 min for the Robot group versus 260 min for the laparoscopic group. With a mean follow-up of 12 months, the anatomic result was satisfactory without recurrence in 97.2% of the cases. The urinary and sexual results, the restart of a sexual activity postoperatively, the surgical satisfaction and the return to daily activities were comparable between both groups. CONCLUSION: Robot-assisted laparoscopic sacrocolpopexy seems to be a reliable technique with morbidity, anatomic and functional outcomes comparable to that of laparoscopy.

[Uterine necrosis following pelvic arterial embolisation for postpartum haemorrhage: case report]. / Nécrose utérine après embolisation pelvienne pour hémorragie du postpartum : à propos d'un cas.

We report a case of uterine necrosis in a 38 year-old patient, who underwent a caesarean section for placenta praevia and an embolisation of the uterine arteries for postpartum haemorrhage. The pelvic embolisation was performed with absorbable gelatine sponge pledgets. This woman presented with abdominal pain and fever three weeks after delivery and a computed tomography scan revealed the presence of gas in the myometrium and endometrium and allowed the diagnosis of uterine necrosis. A total abdominal hysterectomy was performed with adnexal conservation and the diagnosis of uterine necrosis was confirmed histologically. The complications of pelvic embolization and the risks of surgical procedures for the management of intractable obstetric hemorrhage are described.

The role of popliteal vein incompetence in the diagnosis of saphenous-popliteal reflux using continuous wave doppler.

INTRODUCTION: continuous wave Doppler (CWD) has good discriminatory power at the groin in the assessment of saphenous femoral junction (SFJ); however, it is not as accurate as duplex ultrasound scanning (DUS) in the popliteal fossa for assessment of saphenous popliteal junction (SPJ) in patients with primary short saphenous vein incompetence. AIM: the aim of this study was to compare the findings of CWD with those of DUS at the SPJ and assess the role of popliteal vein incompetence in the accuracy of CWD. METHOD: prospective study of consecutive patients presenting to a vein clinic requiring a duplex scan of their SPJ. Each patient was examined by one surgeon using CWD and by one radiologist using DUS. Each observer was unaware of the other's findings. Additional information on the competence of the popliteal vein on DUS was also recorded. RESULTS: some 171 limbs in 128 patients with varicose veins were studied. One hundred and sixteen limbs had reflux at SPJ on CWD whilst 55 did not. Their mean age was 54 (range 18-85). Female to male ratio was 3:1. Spearman's rank correlation between CWD and DUS has 0.49 (p =0.0001). CWD has a sensitivity of 92% and specificity of 53% (PPV=62%, NPV=89%, accuracy=70%). Twenty-nine limbs had an incompetent popliteal vein (IPV). Of those, 12 limbs also had incompetence on CWD and competence on DUS at the SPJ, which represent 28% of the total number of limbs with these findings (n =43). CONCLUSION: CWD is sensitive in detecting incompetence at SPJ, though its specificity is low. In this study 17% (n =29) of all patients had incompetence of popliteal vein. Up to 25% ( n =12) of patients with SPJ incompetence on CWD (Doppler +) and competence on DUS (duplex -) had incompetence of the underlying popliteal vein, which may explain the low specificity. The presence of SPJ incompetence on CWD should be confirmed on DUS prior to surgery.

Effect of pre-conceptional external or internal irradiation of N5 male mice and the risk of leukemia in their offspring.

Male mice of the N5 strain were exposed to a unique external X-ray dose of 500 cGy, or to i.p. injections of tritiated water (HTO) over a 30 day period, which resulted in an estimated total internal exposure of 150 cGy. The paternal X-ray irradiation resulted in a marginally significant (P = 0.07) doubling of the leukemia/lymphoma rate in the offspring, over a 1 year observation period. The constitutive gene expression of granulocyte-macrophage colony stimulating factor (GM-CSF) and tumour necrosis factor (TNF) (two cytokines associated with hematopoiesis and immune response) spontaneously diminished between the ages of 6 months and 12 months in the bone marrows and in the spleens of these mice, and paternal X-ray exposure influenced the statistical significance of this diminution. Male exposure to HTO resulted in a statistically significant several-fold increase of leukemia incidence among the young offspring. However this increase tended to diminish as older mice were observed, and was no longer significant at 1 year of age. The overall leukemia incidence in the offspring of the HTO-exposed fathers was significantly dependent on the maturation stage of the sperm-forming cells during the HTO exposure, which suggests an influence of such an exposure.

Effects of exogenous nitric oxide on neutrophil oxidative function and viability.

Previous studies have suggested that nitric oxide (NO) can modulate neutrophil function. Exposure to inhaled NO for pulmonary vasodilation could thus potentially affect neutrophil involvement in lung inflammation and infection. We evaluated the effect of exogenous NO gas exposure at clinically relevant concentrations in vitro on the oxidative function of human neutrophils. Isolated neutrophils were exposed for 2 h to either room air (RA), 80% oxygen (O2), or NO at 20 or 5 ppm blended with room air (NO20/RA, NO5/RA) or blended with 80% oxygen (NO20/O2) (NO5/O2). Neutrophils were then evaluated for superoxide anion generation with the cytochrome c reduction assay, for oxygen consumption with the Clark oxygen electrode technique, and for myeloperoxidase (MPO) release by enzyme-linked immunosorbent assay (ELISA). Neutrophil viability was determined by both trypan blue dye exclusion and fluorescence viability/cytotoxicity assay. Neutrophils exposed to NO at 20 ppm demonstrated a significant decrease in superoxide anion generation in both NO20/RA (97 +/- 46 nmol/10(6) neutrophils) and NO20/O2 (102 +/- 54 nmol/10(6) neutrophils) groups as compared with RA (190 +/- 41 nmol/10(6) neutrophils) (mean +/- SEM, P < 0.005 by analysis of variance [ANOVA] and the Student-Newman-Keuls test). No significant difference was seen at 5 ppm NO exposure. Neutrophil oxygen consumption was decreased with NO20/O2 (6.5 +/- 1.2 nmol O2/ml/min/10(7) neutrophils) as compared with RA (13.7 +/- 3.9 nmol O2/ml/min/10(6) neutrophils) or O2 alone (11.6 +/- 3.1 nmol O2/ml/min/10(7) neutrophils) (P < 0.002). MPO levels were significantly decreased with NO20/O2 (2.3 +/- 0.4 microg/ml) as compared with RA (4.0 +/- 0.4 microg/ml, P < 0.005), and also with NO5/O2. Cell viability as reflected by trypan blue dye exclusion was decreased with O2 (70 +/- 2.3%), NO20/RA (61 +/- 4%), and NO20/O2 (58 +/- 2.5%) exposure as compared with RA control (84.4 +/- 0.9%) (P < 0.0001). Decreased neutrophil viability was confirmed by live/dead assay for O2 (80.8 +/- 2.8%), NO20/RA (62.8 +/- 6.1%), and NO20/O2 (31.7 +/- 5.6%) groups as compared with RA control (95.8 +/- 1.4%, P < 0.0001). Adjusting neutrophil superoxide anion generation, oxygen consumption, and MPO values for cell viability abolished differences between exposure groups. We conclude that exogenous NO exposure at clinically relevant concentrations decreases neutrophil oxidative function, primarily as a result of reduced cell viability. Further studies are necessary to determine if these effects serve an in vivo immunoregulatory or immunosuppressive role in neutrophil response to lung injury and infection.