Participants with hemophilia A received B-domain–deleted factor VIII gene therapy delivered in an AAV5 vector. A decrease in annualized bleeding rates was maintained for 2 years despite declining ...factor VIII levels.
Introduction: Faculty and Residents are trained in peripheral nerve blocks guided by blind technique, Peripheral Neuro Stimulator (PNS) or Ultrasound (USG) guided technique. But due to unavailability ...of USG machine in all institutes and requiring special training, techniques used for peripheral nerve blocks vary from institute to institute. Aim: To analyse the effect of anaesthesiologists’ experience on preferred technique and Local Anaesthetic (LA) volume used for brachial plexus nerve block retrospectively. Materials and Methods: In this retrospective observational study, 129 adults American Society of Anesthesiologists (ASA) grade I and II patients requiring brachial plexus nerve block for upper limb orthopaedic surgical anaesthesia for both elective and emergency surgery were divided into three groups for each year depending on technique for nerve block used. Group A: Received USG guided (Micromaxx Sonosite Inc, USA) brachial plexus nerve block. Group B: Received peripheral nerve stimulator (Inmed) guided brachial plexus nerve block. Group C: Received brachial plexus nerve block by traditional anatomical landmark based paraesthesia elicitation blind technique. Patients with inadequate surgical analgesia were given general anaesthesia and were categorised as failure rate. Year wise demographic data, type of technique used for giving brachial plexus nerve block, volume of drug used, failure rate, complications observed were collected and analysed by Student’s t-test and Chi-square test. Results: USG guided technique was the most prefered technique in both years (57.6%, n=38 in year 2018 and 49.2%, n=31 in year 2019). In remaining nearly half of the patients PNS and blind technique was used (PNS 24.2%, n=16 in year 2018 and 20.6%, n=13 in year 2019; blind technique 18.2%, n=12 in year 2018 and 30.2%, n=19 in year 2019). Significantly, less volume of LA drug (mL) was used in group A in year 2019 (16.43±6.07) than in year 2018 (22.34±4.75) (p<0.001). Failure rate in group A in year 2019 (3.2%) was significantly less than in year 2018 (5.2%), but the difference was insignificant in all three groups. In group A, no complications were observed in year 2019 while one incidence of hemidiaphragm paralysis was observed in year 2018, while in group B and C, complications were observed in both years. Conclusion: USG guided nerve block was the most preferred technique for nerve block in the study institute. In 24 months observation period, with increasing experience with USG there was significant increase in success rate and decrease in the volume of LA administered and complications.
Introduction: For successful management of difficult paediatric airway intubation, proper preparation of airway along with a calm and sedated child with titrated doses of sedative agents is ...paramount. Aim: To compare two different classes of sedative agents (Dexmedetomidine vs Fentanyl) regarding intubating conditions and comfort score of paediatric population at the time of awake fiberoptic intubation. Materials and Methods: This retrospective study was carried out among 40 paediatric patients, aged between 5-14 years those who underwent surgery for Temporo-Mandibular Joint (TMJ) ankylosis. Clinical data relevant for this study was collected from the pre-format sheets of anaesthesia technique, attached with case files of the patients. Inj. dexmetedomidine bolus of 1 mcg/kg for 10 minutes followed by infusion at the rate 0.6 mcg/kg/hr in group A and Inj. fentanyl bolus dose of 2 mcg/kg followed by infusion 1 mcg/kg/hr in group B were compared in terms of intubating conditions and patient co-operation. For data analysis Statistical Package for the Social Sciences (SPSS) version 20 (IBM Inc.) was used. Patient characteristics in the two groups were compared using mean±SD and chi-square test. Results: All the patients had successful intubation in first attempt in both the groups. In terms of airway preparation, out of total, 14 (35%) patients in group A had no secretions as compare to 4 (10%) patients of group B (p-value was 0.002). In terms of cough score, 13 (32.5%) patients in group A had no cough as compared to 3 (7.5%) patients in group B. Patients in group A were more comfortable at the time of insertion of Flexible Fiberoptic Bronchoscopy (FOB) with no or less resistance to FOB insertion (p-value was 0.043). Vocal cord conditions were favourable in both the groups and there was no difference. Conclusion: Fiberoptic nasal intubation was found to be easier and safe in terms of patient comfort and preservation of patent airway with the use of dexmedetomidine, in paediatric TMJ ankylosis.
Data about prevalence of hepatitis E virus infection in persons who inject drugs are limited. Among 18-40-year-old persons who inject drugs in California, USA, prevalence of antibodies against ...hepatitis E virus was 2.7%. This prevalence was associated with age but not with homelessness, incarceration, or high-risk sexual behavior.
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DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: Ultrasound (USG) guided Internal jugular venous (IJV) cannulation is preferred than traditional approach due to increase in success rate, reduction in time taken and attempts of ...successful cannulation and less complications. The purpose of our study was to observe and compare three different real time 2-dimensional US-guided approaches and to determine which approach improves rate of successful cannulation, decreases complications along with shorter average time taken for the procedure. Primary outcomes of the study were venous access time, catheterization time and success rate. Secondary outcomes were number of patients requiring second attempt and complications observed.Methods: 120 adult patients were randomly divided into three groups according to real time US guided cannulation done with SAX-OP approach, LAX-IP approach and OAX-IP approach. Parameters like venous access time, catheterization time, number of patients requiring second attempt and complications were noted.Results: Venous access time was shortest in LAX group 21.84±3.67 seconds which was just significant statistically. Catheterization time was shortest in LAX group 241±123 seconds. Cannulation success rate was highest in LAX group 98% and was statistically significant. Patients requiring second attempt was least in LAX group 2.5%. Posterior IJV wall puncture was observed in 10% patients in SAX group and none in LAX and OAX group which was statistically significant.Conclusions: LAX-IP showed better performance in terms of higher cannulation success, lesser average venous access time and catheterization time and lesser complications. On toggling USG probe, both IJV and carotid artery can be differentiated and carotid puncture could be avoided. Hence LAX approach is safer and effective approach.
Most sexually active people will be infected with a sexually transmitted infection (STI) at some point in their lives. The number of STIs in the United States was previously estimated in 2000. We ...updated previous estimates to reflect the number of STIs for calendar year 2008.
We reviewed available data and literature and conservatively estimated incident and prevalent infections nationally for 8 common STIs: chlamydia, gonorrhea, syphilis, herpes, human papillomavirus, hepatitis B, HIV, and trichomoniasis. Where available, data from nationally representative surveys such as the National Health and Nutrition Examination Survey were used to provide national estimates of STI prevalence or incidence. The strength of each estimate was rated good, fair, or poor, according to the quality of the evidence.
In 2008, there were an estimated 110 million prevalent STIs among women and men in the United States. Of these, more than 20% of infections (22.1 million) were among women and men aged 15 to 24 years. Approximately 19.7 million incident infections occurred in the United States in 2008; nearly 50% (9.8 million) were acquired by young women and men aged 15 to 24 years. Human papillomavirus infections, many of which are asymptomatic and do not cause disease, accounted for most of both prevalent and incident infections.
Sexually transmitted infections are common in the United States, with a disproportionate burden among young adolescents and adults. Public health efforts to address STIs should focus on prevention among at-risk populations to reduce the number and impact of STIs.
Millions of cases of sexually transmitted infections (STIs) occur in the United States each year, resulting in substantial medical costs to the nation. Previous estimates of the total direct cost of ...STIs are quite dated. We present updated direct medical cost estimates of STIs in the United States.
We assembled recent (i.e., 2002-2011) cost estimates to determine the lifetime cost per case of 8 major STIs (chlamydia, gonorrhea, hepatitis B virus, human immunodeficiency virus (HIV), human papillomavirus, genital herpes simplex virus type 2, trichomoniasis and syphilis). The total direct cost for each STI was computed as the product of the number of new or newly diagnosed cases in 2008 and the estimated discounted lifetime cost per case. All costs were adjusted to 2010 US dollars.
Results indicated that the total lifetime direct medical cost of the 19.7 million cases of STIs that occurred among persons of all ages in 2008 in the United States was $15.6 (range, $11.0-$20.6) billion. Total costs were as follows: chlamydia ($516.7 $258.3-$775.0 million), gonorrhea ($162.1 $81.1-$243.2 million), hepatitis B virus ($50.7 $41.3-$55.6 million), HIV ($12.6 $9.5-$15.7 billion), human papillomavirus ($1.7 $0.8-$2.9 billion), herpes simplex virus type 2 ($540.7 $270.3-$811.0 million), syphilis ($39.3 $19.6-$58.9 million), and trichomoniasis ($24.0 $12.0-$36.0 million). Costs associated with HIV infection accounted for more than 81% of the total cost. Among the nonviral STIs, chlamydia was the most costly infection.
Sexually transmitted infections continue to impose a substantial cost burden on the payers of medical care in the United States. The burden of STIs would be even greater in the absence of STI prevention and control efforts.
Epidermal growth factor receptor (EGFR) is a therapeutic target in colorectal cancer (CRC). The benefit from EGFR inhibitors appears to be limited to a subset of patients with CRC. Mechanisms of ...resistance to EGFR inhibitors are being identified. KRAS codon 12 activating mutation is a predominate mechanism of resistance to EGFR inhibitors in around 40% of patients with advanced CRC. Other potential mechanisms of resistance include ligand expression, increased EGFR number, mutations of BRAF and activation of alternate signaling pathways.
Background. The number of deaths in hepatitis C virus (HCV)–infected persons recorded on US death certificates has been increasing, but actual rates and causes of death in these individuals have not ...been well elucidated. Methods. Disease-specific, liver-related, and non-liver-related mortality data for HCV-infected patients in an observational cohort study, the Chronic Hepatitis Cohort Study (CHeCS) at 4 US healthcare systems, were compared with multiple cause of death (MCOD) data in 12 million death certificates in 2006–2010. Premortem diagnoses, liver biopsies, and FIB-4 scores (a noninvasive measure of liver damage) were examined. Results. Of 2 143 369 adult patients seen at CHeCS sites in 2006–2010, 11 703 (0.5%) had diagnosed chronic HCV infection, and 1590 (14%) died. The majority of CHeCS decedents were born from 1945 to 1965 (75%), white (50%), and male (68%); mean age of death was 59 years, 15 years younger than MCOD deaths. The age-adjusted mortality rate for liver disease in CHeCS was 12 times higher than the MCOD rate. Before death, 63% of decedents had medical record evidence of chronic liver disease, 76% had elevated FIB-4 scores, and, among those biopsied, 70% had moderate or worse liver fibrosis. However, only 19% of all CHeCS decedents and only 30% of those with recorded liver disease had HCV listed on their death certificates. Conclusions. HCV infection is greatly underdocumented on death certificates. The 16 622 persons with HCV listed in 2010 may represent only one-fifth of about 80 000 HCV-infected persons dying that year, at least two-thirds of whom (53 000 patients) would have had premortem indications of chronic liver disease.
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Introduction. Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is an adeno-associated virus gene therapy that transfers a B-domain deleted factor VIII (FVIII) cDNA to hepatocytes. The open-label, ...single-arm, multicenter phase 3 GENEr8-1 trial (NCT03370913) evaluated valoctocogene roxaparvovec in 134 men with severe hemophilia A (HA) and demonstrated an 83.8% reduction in annualized treated bleeding rate (ABR) and superiority to FVIII prophylaxis (P <0.001). The relationship between baseline FVIII activity and ABR was estimated in congenital HA (den Uijl, et al. Haemophilia 2011;171:41-4); it is unknown if a similar relationship exists after gene transfer. We present here post-hoc analyses of transgene-derived FVIII activity and bleeds in GENEr8-1.
Methods. Men ≥18 years of age with severe HA previously on FVIII prophylaxis who were negative for FVIII inhibitors and anti-AAV5 antibodies received one 6x10 13 vg/kg infusion of valoctocogene roxaparvovec. FVIII activity was measured by chromogenic substrate (CSA; lower limit of quantitation LLOQ, 3.0 IU/dL) and one stage assays (OSA; LLOQ, 1.0 IU/dL); median FVIII activity in every 4- or 6-week window was assessed. Self-reported treated bleeds were counted after week 4, when routine prophylaxis was scheduled to end. The relationship between number of treated joint bleeds and matched median FVIII activity levels in each 4- or 6-week window was modeled using negative binomial regression.
Results. As of the data cut date, mean follow-up was 71.6 weeks; 1 participant was lost to follow-up at week 66. At weeks 49-52 (latest time with data for all participants; intent-to-treat population), 9% (12/134) had CSA FVIII activity <3 IU/dL, 3% (4/134) had median FVIII activity ≥3-<5 IU/dL, 17% (23/134) had median FVIII activity ≥5-<15 IU/dL, and 71% (95/134) had median FVIII activity ≥15 IU/dL.
While on FVIII prophylaxis prior to gene transfer, 32% of participants (43/134) had an ABR of 0. Following gene transfer, 75% of participants (101/134) were bleed-free through their last follow-up prior to the data cut. The remaining 33 participants reported 149 treated bleeds total, 62% (93/149) as traumatic and 38% (56/149) as spontaneous. By location, 53% (79/149) occurred in joints, 19% (28/149) in muscle, 14% (21/149) in soft tissue, and 14% (21/149) in other or unspecified locations.
Relative to FVIII level, 54% of treated bleeds (80/149) occurred when CSA FVIII was <3 IU/dL (LLOQ), 12% (18/149) when FVIII was ≥3-<5 IU/dL, 23% (35/149) when FVIII was ≥5-<15 IU/dL, and 11% (16/149) when FVIII was ≥15 IU/dL. Of 16 treated bleeds that occurred when FVIII was ≥15 IU/dL, 13 were traumatic.
Treated joint bleeds followed a similar pattern: 51% (40/79) occurred when FVIII was <3 IU/dL, 15% (12/79) when FVIII was ≥3-<5 IU/dL, 27% (21/79) when FVIII was ≥5-<15 IU/dL, and 8% (6/79) when FVIII was ≥15 IU/dL. A negative binomial regression model based on these data and matched FVIII activity levels predicts <1 treated joint bleed in 2 years for individuals treated with valoctocogene roxaparvovec with FVIII activity ≥15 IU/dL (CSA; Figure).
Clinical value of the CSA at low FVIII levels is limited by its LLOQ of 3 IU/dL. Of 12 participants with median FVIII levels below the CSA LLOQ at weeks 49-52, 9 had improved or the same ABR post-gene therapy relative to prophylaxis. The OSA, with its LLOQ of 1 IU/dL, provided important information here. By OSA, 1 had FVIII <1 IU/dL, 5 had FVIII ≥1-<5 IU/dL, and 3 had FVIII ≥5 IU/dL. The remaining 3 participants who had increased ABR after gene transfer had FVIII levels by OSA of 0, 2.1, and 4.8 IU/dL. For participants with OS FVIII <5 IU/dL at week 52 (n = 11), median (IQR) ABR was 1.2 (0-7.9), similar to the median (IQR) ABR of 1.6 (0.6-3.5) reported for people with moderate HA (Abdi, et al. J Throm Haemost 2020;1812:3203-10).
Conclusions. Gene transfer with valoctocogene roxaparvovec led to sustained endogenous FVIII production and reduced ABR in this phase 3 trial. After gene transfer, the majority of bleeds were traumatic. When FVIII was ≥15 IU/dL, reports of treated bleeds, including joint bleeds, were rare. CSA FVIII activity was predictive of bleeding risk post-gene transfer, as for epidemiologic congenital HA results. At FVIII levels below the CSA LLOQ, the OSA provided clinically relevant information; bleeding with OSA FVIII <5 IU/dL was similar to observations in people with moderate HA, though further exploration with more data is needed.
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Pipe: Biomarin: Consultancy, Other: Clinical trial investigator; Regeneron/ Intellia: Consultancy; uniQure: Consultancy, Other; Spark Therapeutics: Consultancy; Takeda: Consultancy; Sanofi: Consultancy, Other; Sangamo Therapeutics: Consultancy; Roche/Genentech: Consultancy, Other; Pfizer: Consultancy; Novo Nordisk: Consultancy; Freeline: Consultancy, Other: Clinical trial investigator; HEMA Biologics: Consultancy; CSL Behring: Consultancy; Catalyst Biosciences: Consultancy; Genventiv: Consultancy; Grifols: Consultancy; Bayer: Consultancy; ASC Therapeutics: Consultancy; Apcintex: Consultancy; Octapharma: Consultancy; Shire: Consultancy. Ozelo: BioMarin Pharmaceutical Inc.: Consultancy, Other: Clinical trial investigator, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Other: Clinical trial investigator, Travel support, Speakers Bureau; Pfizer: Consultancy, Other: Clinical trial investigator, Research Funding; Roche: Consultancy, Other: Clinical trial investigator, Travel support, Research Funding, Speakers Bureau; Sanofi: Consultancy, Other: Clinical trial investigator; Takeda: Consultancy, Other: Clinical trial investigator, Travel support, Research Funding, Speakers Bureau; Grifols: Other: Grants review. Kenet: Takeda: Consultancy; Roche: Consultancy; Novo Nordisk: Consultancy; Shire: Research Funding; Pfizer: Consultancy, Research Funding; Opko Biologics: Research Funding; Bayer: Consultancy, Research Funding; Alnylam: Consultancy, Research Funding. Reding: Bayer, CSL Behring, Sanofi Genzyme, Takeda: Speakers Bureau; Bayer, Biomarin (institutional research funding): Research Funding; Bayer, CSL Behring, NovoNordisk, Sanofi Genzyme, Takeda: Honoraria; Bayer, CSL Behring, NovoNordisk, Sanofi Genzyme, Takeda (advisory committees): Membership on an entity's Board of Directors or advisory committees. Mason: BioMarin Pharmaceutical Inc.: Other: Participation as a clinical trial investigator; Roche: Other: Participation as a clinical trial investigator, Travel support, Speakers Bureau. Leavitt: Syntimmune: Research Funding; Sangamo Therapeutics: Research Funding; Pfizer: Research Funding; Merck: Consultancy; CSL DOVA: Consultancy; Catalys: Consultancy; BioMarin: Consultancy, Research Funding; BPL: Consultancy; Behring: Consultancy; HEMA Biologics: Consultancy; Rigel: Consultancy. Laffan: Shire: Membership on an entity's Board of Directors or advisory committees; Leo-Pharma: Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Speakers Bureau; AstraZeneca: Consultancy; Sobi: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Bayer: Other: Travel support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BioMarin Pharmaceutical Inc.: Research Funding. Quon: Orthopaedic Institute for Children: Current Employment. von Drygalski: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hematherix, Inc: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Super FVa; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biomarin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; uniQure: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Chou: Bayer: Other: Clinical trial investigator, Speakers Bureau; Novo Nordisk: Consultancy, Other: Clinical trial investigator, Speakers Bureau; BioMarin: Other: Clinical trial investigator; Sanofi: Consultancy, Other: Clinical trial investigator, Speakers Bureau; Chugai: Consultancy, Other: Clinical trial investigator, Speakers Bureau; Pfizer: Other: Clinical trial investigator, Speakers Bureau; CSL: Consultancy, Other: Clinical trial investigator, Speakers Bureau. Shapiro: Sobi: Consultancy; Shire: Consultancy; Pfizer: Consultancy, Speakers Bureau; Bayer: Other: Travel support, Speakers Bureau; Takeda: Speakers Bureau; Roche: Speakers Bureau; CSL Behring: Other: travel support. Dunn: Genentech/Roche: Consultancy, Speakers Bureau; ATHN: Research Funding; Biomarin: Consultancy, Research Funding; Freeline: Research Funding; Takeda: Research Funding; World Federation of Hemophilia USA: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy; Uniqure: Consultancy; Sanofi: Research Funding; Kedrion: Consultancy. Wang: Bioverativ: Consultancy, Other: Clinical trial investigator; CSL Behring: Consultancy, Other: Clinical trial investigator; Novo Nordisk: Consultancy, Other: Clinical trial investigator; Genentech: Consultancy, Other: Clinical trial investigator; Takeda: Consultancy, Other: Clinical trial investigator; Hema Biologics: Consultancy, Other: Clinical trial
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