Background Ataxia-telangiectasia (A-T) is a rare genetic disease caused by germline biallelic mutations in the ataxia-telangiectasia mutated gene (ATM) that result in partial or complete loss of ATM ...expression or activity. The course of the disease is characterized by neurologic manifestations, infections, and cancers. Objective We studied A-T progression and investigated whether manifestations were associated with the ATM genotype. Methods We performed a retrospective cohort study in France of 240 patients with A-T born from 1954 to 2005 and analyzed ATM mutations in 184 patients, along with neurologic manifestations, infections, and cancers. Results Among patients with A-T, the Kaplan-Meier 20-year survival rate was 53.4%; the prognosis for these patients has not changed since 1954. Life expectancy was lower among patients with mutations in ATM that caused total loss of expression or function of the gene product (null mutations) compared with that seen in patients with hypomorphic mutations because of earlier onset of cancer (mainly hematologic malignancies). Cancer (hazard ratio, 2.7; 95% CI, 1.6-4.5) and respiratory tract infections (hazard ratio, 2.3; 95% CI, 1.4-3.8) were independently associated with mortality. Cancer (hazard ratio, 5.8; 95% CI, 2.9-11.6) was a major risk factor for mortality among patients with null mutations, whereas respiratory tract infections (hazard ratio, 4.1; 95% CI, 1.8-9.1) were the leading cause of death among patients with hypomorphic mutations. Conclusion Morbidity and mortality among patients with A-T are associated with ATM genotype. This information could improve our prognostic ability and lead to adapted therapeutic strategies.
Previously we showed that the relative biological efficiency for induced cell killing by the 76-MeV beam used at the Institut Curie Proton Therapy Center in Orsay increased with depth throughout the ...spread-out Bragg peak (SOBP). To investigate the repair pathways underlying this increase, we used an isogenic human cell model in which individual DNA repair proteins have been depleted, and techniques dedicated to precise measurements of radiation-induced DNA single-strand breaks (SSBs) and double-strand breaks (DSBs).
The 3-Gy surviving fractions of HeLa cells individually depleted of Ogg1, XRCC1, and PARP1 (the base excision repair/SSB repair pathway) or of ATM, DNA-PKcs, XRCC4, and Artemis (nonhomologous end-joining pathway) were determined at the 3 positions previously defined in the SOBP. Quantification of incident SSBs and DSBs by the alkaline elution technique and 3-dimensional (3D) immunofluorescence of γ-H2AX foci, respectively, was performed in SQ20 B cells.
We showed that the amount of SSBs and DSBs depends directly on the particle fluence and that the increase in relative biological efficiency observed in the distal part of the SOBP is due to a subset of lesions generated under these conditions, leading to cell death via a pathway in which the Artemis protein plays a central role.
Because therapies like proton or carbon beams are now being used to treat cancer, it is even more important to dissect the mechanisms implicated in the repair of the lesions generated by these particles. Additionally, alteration of the expression or activity of the Artemis protein could be a novel therapeutic tool before high linear energy transfer irradiation treatment.
To investigate the relationship between human papillomavirus (HPV) genotype and outcome after radiation therapy and intrinsic radiosensitivity.
HPV genotyping was performed on cervix biopsies by ...polymerase chain reaction using SPF-10 broad-spectrum primers, followed by deoxyribonucleic acid enzyme immunoassay and genotyping by reverse hybridization line probe assay (LiPA25) (version 1) (n=202). PapilloCheck and quantitative reverse transcription-polymerase chain reaction were used to genotype cervix cancer cell lines (n=16). Local progression-free survival after radiation therapy alone was assessed using log-rank and Cox proportionate hazard analyses. Intrinsic radiosensitivity was measured as surviving fraction at 2 Gy (SF2) using clonogenic assays.
Of the 202 tumors, 107 (53.0%) were positive for HPV16, 29 (14.4%) for HPV18, 9 (4.5%) for HPV45, 23 (11.4%) for other HPV genotypes, and 22 (10.9%) were negative; 11 (5.5%) contained multiple genotypes, and 1 tumor was HPV X (0.5%). In 148 patients with outcome data, those with HPVα9-positive tumors had better local progression-free survival compared with α7 patients in univariate (P<.004) and multivariate (hazard ratio 1.54, 95% confidence interval 1.11-1.76, P=.021) analyses. There was no difference in the median SF2 of α9 and α7 cervical tumors (n=63). In the cell lines, 9 were α7 and 4 α9 positive and 3 negative. There was no difference in SF2 between α9 and α7 cell lines (n=14).
The reduced radioresponsiveness of α7 cervical tumors is not related to intrinsic radiosensitivity.
Our scientific knowledge of bullous pemphigoid (BP) has dramatically progressed in recent years. However, despite the availability of various therapeutic options for the treatment of inflammatory ...diseases, only a few multicenter controlled trials have helped to define effective therapies in BP. A major obstacle in sharing multicenter-based evidences for therapeutic efforts is the lack of generally accepted definitions for the clinical evaluation of patients with BP. Common terms and end points of BP are needed so that experts in the field can accurately measure and assess disease extent, activity, severity, and therapeutic response, and thus facilitate and advance clinical trials. These recommendations from the International Pemphigoid Committee represent 2 years of collaborative efforts to attain mutually acceptable common definitions for BP and proposes a disease extent score, the BP Disease Area Index. These items should assist in the development of consistent reporting of outcomes in future BP reports and studies.
Background Data used for evaluating quality of medical care need to be of high reliability to ensure valid quality assessment and benchmarking. The American College of Surgeons National Surgical ...Quality Improvement Program (ACS NSQIP) has continually emphasized the collection of highly reliable clinical data through its program infrastructure. Study Design We provide a detailed description of the various mechanisms used in ACS NSQIP to assure collection of high quality data, including training of data collectors (surgical clinical reviewers) and ongoing audits of data reliability. For the 2005 through 2008 calendar years, inter-rater reliability was calculated overall and for individual variables using percentages of agreement between the data collector and the auditor. Variables with > 5% disagreement are flagged for educational efforts to improve accurate collection. Cohen's kappa was estimated for selected variables from the 2007 audit year. Results Inter-rater reliability audits show that overall disagreement rates on variables have fallen from 3.15% in 2005 (the first year of public enrollment in ACS NSQIP) to 1.56% in 2008. In addition, disagreement levels for individual variables have continually improved, with 26 individual variables demonstrating > 5% disagreement in 2005, to only 2 such variables in 2008. Estimated kappa values suggest substantial or almost perfect agreement for most variables. Conclusions The ACS NSQIP has implemented training and audit procedures for its hospital participants that are highly effective in collecting robust data. Audit results show that data have been reliable since the program's inception and that reliability has improved every year.
Mucous membrane pemphigoid encompasses a group of autoimmune bullous diseases with a similar phenotype characterized by subepithelial blisters, erosions, and scarring of mucous membranes, skin, or ...both. Although knowledge about autoimmune bullous disease is increasing, there is often a lack of clear definitions of disease, outcome measures, and therapeutic end points. With clearer definitions and outcome measures, it is possible to directly compare the results and data from various studies using meta-analyses. This consensus statement provides accurate and reproducible definitions for disease extent, activity, outcome measures, end points, and therapeutic response for mucous membrane pemphigoid and proposes a disease extent score, the Mucous Membrane Pemphigoid Disease Area Index.
Background The benefits of the National Breast and Cervical Cancer Early Detection Program (NBCCEDP) on cervical cancer screening for participating uninsured low-income women have never been ...measured. Purpose To estimate the benefits in life-years (LYs) gained; quality-adjusted life-years (QALYs) gained; and deaths averted. Methods A cervical cancer simulation model was constructed based on an existing cohort model. The model was applied to NBCCEDP participants aged 18–64 years. Screening habits for uninsured low-income women were estimated using National Health Interview Survey data from 1990 to 2005 and NBCCEDP data from 1991 to 2007. The study was conducted during 2011–2012 and covered all 68 NBCCEDP grantees in 50 states, the District of Columbia, five U.S. territories, and 12 tribal organizations. Separate simulations were performed for the following three scenarios: (1) women who received NBCCEDP (Program) screening; (2) women who received screening without the program (No Program); and (3) women who received no screening (No Screening). Results Among 1.8 million women screened in 1991–2007, the Program added 10,369 LYs gained compared to No Program, and 101,509 LYs gained compared to No Screening. The Program prevented 325 women from dying of cervical cancer relative to No Program, and 3,829 relative to No Screening. During this time period, the Program accounted for 15,589 QALYs gained when compared with No Program, and 121,529 QALYs gained when compared with No Screening. Conclusions These estimates suggest that NBCCEDP cervical cancer screening has reduced mortality among medically underserved low-income women who participated in the program.
Background The National Breast and Cervical Cancer Early Detection Program (NBCCEDP) provides breast cancer screening to medically underserved, low-income women aged 40–64 years. No study has ...evaluated NBCCEDP's effect on breast cancer mortality. Purpose This study estimates life-years saved by NBCCEDP breast cancer screening compared with screening in the absence of NBCCEDP and with no screening. Methods A breast cancer simulation model based on existing Cancer Intervention and Surveillance Modeling Network models was constructed. The screening module from these models was modified to reflect screening frequency for NBCCEDP participants. Screening data for uninsured women represented what would have happened without the program. Separate simulations were performed for women who received NBCCEDP (Program) screening, women who potentially received screening without the program (No Program), and women who received no screening (No Screening). The impact of NBCCEDP was estimated as the difference in life-years between the Program and No Program, and the Program and No Screening scenarios. The analysis was performed in 2008–2009. Results Among 1.8 million women who were screened between 1991 and 2006, the Program saved 100,800 life-years compared with No Program and 369,000 life-years compared with No Screening. Per woman screened, the Program saved 0.056 life-years (95% CI=0.031, 0.081) compared with No Program and 0.206 life-years (95% CI=0.177, 0.234) compared with No Screening. Per woman with invasive breast cancer and screen-detected invasive cancer, the Program saved 0.41 and 0.71 life-years, respectively, compared with No Program. Conclusions These estimates suggest that NBCCEDP breast cancer screening has reduced mortality among medically uninsured and underinsured low-income women.
Exercise is critical for health maintenance in late life. The COVID-19 shelter in place and social distancing orders resulted in wide-scale interruptions of exercise therapies, placing older adults ...at risk for the consequences of decreased mobilization. The purpose of this paper is to describe rapid transition of the Gerofit facility-based group exercise program to telehealth delivery. This Gerofit-to-Home (GTH) program continued with group-based synchronous exercise classes that ranged from 1 to 24 Veterans per class and 1 to 9 classes offered per week in the different locations. Three hundred and eight of 1149 (27%) Veterans active in the Gerofit facility-based programs made the transition to the telehealth delivered classes. Participants’ physical performance testing continued remotely as scheduled with comparisons between most recent facility-based and remote testing suggesting that participants retained physical function. Detailed protocols for remote physical performance testing and sample exercise routines are described. Translation to remote delivery of exercise programs for older adults could mitigate negative health effects.
Background There has been a long-standing desire to implement a multi-institutional, multispecialty program to address surgical quality improvement for children. This report documents results of the ...initial phase of the American College of Surgeons National Surgical Quality Improvement Program Pediatric. Study Design From October 2008 to December 2009, patients from 4 pediatric referral centers were sampled using American College of Surgeons National Surgical Quality Improvement Program methodology tailored to children. Results A total of 7,287 patients were sampled, representing general/thoracic surgery (n = 2,237; 30.7%), otolaryngology (n = 1,687; 23.2%), orthopaedic surgery (n = 1,367; 18.8%), urology (n = 893; 12.3%), neurosurgery (n = 697; 9.6%), and plastic surgery (n = 406; 5.6%). Overall mortality rate detected was 0.3% and 287 (3.9%) patients had postoperative occurrences. After accounting for demographic, preoperative, and operative factors, occurrences were 4 times more likely in those undergoing inpatient versus outpatient procedures (odds ratio OR = 4.71; 95% CI, 3.01−7.35). Other factors associated with higher likelihood of postoperative occurrences included nutritional/immune history, such as preoperative weight loss/chronic steroid use (OR = 1.49; 95% CI, 1.03−2.15), as well as physiologic compromise, such as sepsis/inotrope use before surgery (OR = 1.68; 95% CI, 1.10−1.95). Operative factors associated with occurrences included multiple procedures under the same anesthetic (OR = 1.58; 95% CI, 1.21−2.06) and American Society of Anesthesiologists classification category 4/5 versus 1 (OR = 5.74; 95% CI, 2.94−11.24). Specialty complication rates varied from 1.5% for otolaryngology to 9.0% for neurosurgery (p < 0.001), with specific procedural groupings within each specialty accounting for the majority of complications. Although infectious complications were the predominant outcomes identified across all specialties, distribution of complications varied by specialty. Conclusions Based on this initial phase of development, the highly anticipated American College of Surgeons National Surgical Quality Improvement Program Pediatric has the potential to identify outcomes of children's surgical care that can be targeted for quality improvement efforts.
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