Animal and translational models of SARS-CoV-2 infection and COVID-19.

COVID-19 is causing a major once-in-a-century global pandemic. The scientific and clinical community is in a race to define and develop effective preventions and treatments. The major features of disease are described but clinical trials have been hampered by competing interests, small scale, lack of defined patient cohorts and defined readouts. What is needed now is head-to-head comparison of existing drugs, testing of safety including in the background of predisposing chronic diseases, and the development of new and targeted preventions and treatments. This is most efficiently achieved using representative animal models of primary infection including in the background of chronic disease with validation of findings in primary human cells and tissues. We explore and discuss the diverse animal, cell and tissue models that are being used and developed and collectively recapitulate many critical aspects of disease manifestation in humans to develop and test new preventions and treatments.

Clinical assessment of acellular dermal matrix (AlloDerm©) as an option in the replacement of the temporomandibular joint disc: A pilot study.

BACKGROUND: There is limited data available in the literature describing the utility of acellular dermal matrix (AlloDerm©) in the replacement of the temporomandibular joint disc. Few reports of clinicians using implantable AlloDerm to replace the disc do exist, however, this has been described for reconstruction after surgical resection of the entire temporomandibular joint complex to treat pathology, as opposed to isolated articular disc disorders. Moreover, there is a lack of description in the literature regarding associated perioperative outcomes after such a procedure. We sought to assess the immediate perioperative outcomes in the form of a pilot study, to determine whether this technique warrants further investigation in the form of prospective clinical studies. METHODS: The study team conducted a retrospective review of medical records for patients who underwent temporomandibular joint discectomy and replacement with AlloDerm© at a single tertiary care center, from 2011 to 2016. Perioperative outcomes of interest including pain levels and range of motion were recorded and descriptive statistics were utilized for statistical analysis. RESULTS: 15 patients met the inclusion criteria, of which 87% were females and 13% males. The mean age was 47.27±15.93 years. Preoperatively, 74% of the patients reported severe pain (VAS scores of 7-10); in contrast, 73% of the patients reported only mild pain (VAS scores of 1-3) during the postoperative visits, suggesting an overall reduction in pain intensity. Range of motion also improved from an average of 27.73±13.04mm, to an average of 38.60±6.08mm (P<0.01). CONCLUSIONS: Based on our preliminary data, patients with advanced TMJ articular disc disorders showed clinical improvement from discectomy and replacement with acellular dermal matrix (AlloDerm©). Further longitudinal studies evaluating long-term outcomes need to be conducted to validate this technique, in the form of larger sample sizes with a control group, as well as radiographic assessment of long-term clinical outcomes.

Pre-stroke glycemic control is associated with early neurologic deterioration in acute atrial fibrillation-related ischemic stroke.

BACKGROUND: It has been suggested that AF-related ischemic stroke (IS) that is accompanied by atherosclerotic burden have poorer outcomes. The aim of this study was to investigate the importance of pre-stroke glycemic control (PSGC) on the early neurologic deterioration (END) of patients with acute AF-related IS. METHODS: We retrospectively recruited 121 patients with AF-related IS who also had Diabetes mellitus (DM). The HbA1C level was measured in all subjects. END was defined as an increase in the National Institute of Health Stroke Scale (NIHSS) score of 4 NIHSS points within 7 days of symptom onset compared to the initial NIHSS score. RESULTS: In this study, 20.7% (25 patients) were classified as having a poor PSGC status with a HbA1C level above 8.0%. In the univariate analysis, a poor PSGC status (p < 0.01), smoking (p = 0.01), severe neurologic deficits at admission (p = 0.01), and a larger size of ischemic lesions on DWI (p < 0.01) were associated with the occurrence of END. In the multivariate model, a poor PSGC status (p = 0.02) and larger size of ischemic lesions on MRI (p < 0.01) were independent predictors of END in acute AF-related IS. CONCLUSION: The HbA1c level upon admission was independently associated with significant prediction of END in acute AF-related IS.

Effective therapeutic strategy for massive retroperitoneal hematoma after conization: arterial embolization and pigtail catheter insertion.

The loop electrosurgical excision procedure (LEEP) is commonly used to remove cervical intraepithelial neoplasia (CIN) because of its safety profile and likelihood of fewer complications. The authors report a rare case of massive retroperitoneal bleeding combined with hypovolemic shock after LEEP conization. Vessel injury was detected by angiographic computed tomography (CT) and embolization of the uterine artery was successfully performed to achieve hemostasis by an intervention radiologist. A pigtail catheter was subsequently inserted for the drainage of the large retroperitoneal hematoma. The patient did not show any further hemorrhage and recovered safely from hypovolemic shock. Th present case demonstrates a successful multidisciplinary and minimal invasive approach to manage retroperitoneal bleeding with uterine artery embolization. Thus, it should be considered a potential treatment option for hemostasis.

A pathogenic role for tumor necrosis factor-related apoptosis-inducing ligand in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a life-threatening inflammatory respiratory disorder, often induced by cigarette smoke (CS) exposure. The development of effective therapies is impaired by a lack of understanding of the underlining mechanisms. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine with inflammatory and apoptotic properties. We interrogated a mouse model of CS-induced experimental COPD and human tissues to identify a novel role for TRAIL in COPD pathogenesis. CS exposure of wild-type mice increased TRAIL and its receptor messenger RNA (mRNA) expression and protein levels, as well as the number of TRAIL(+)CD11b(+) monocytes in the lung. TRAIL and its receptor mRNA were also increased in human COPD. CS-exposed TRAIL-deficient mice had decreased pulmonary inflammation, pro-inflammatory mediators, emphysema-like alveolar enlargement, and improved lung function. TRAIL-deficient mice also developed spontaneous small airway changes with increased epithelial cell thickness and collagen deposition, independent of CS exposure. Importantly, therapeutic neutralization of TRAIL, after the establishment of early-stage experimental COPD, reduced pulmonary inflammation, emphysema-like alveolar enlargement, and small airway changes. These data provide further evidence for TRAIL being a pivotal inflammatory factor in respiratory diseases, and the first preclinical evidence to suggest that therapeutic agents that target TRAIL may be effective in COPD therapy.

Biochemical indicators of implantation success of tissue-engineered oral mucosa.

Real-time (RT) determination of the health of in vitro tissue-engineered constructs prior to grafting is essential for prediction of success of the implanted tissue-engineered graft. In addition, the US Food and Drug Administration requires specific release criteria in RT prior to the release of tissue-engineered devices for human use. In principle, assessing the viability and functionality of the cellular component can be achieved by quantifying the secretion of growth factors and chemokines of tissue-engineered constructs. Ex vivo-produced oral mucosa equivalents (EVPOMEs) were fabricated under thermally stressed conditions at 43 °C for 24 h to create a functionally compromised EVPOME. We used microchannel enzyme-linked immunosorbent assay to evaluate the functionality of the cellular component, oral keratinocytes, of stressed and unstressed EVPOMEs by measuring the release of vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), human ß-defensin 1 (hBD-1), and tissue inhibitor of metalloproteinase 1 and 2 (TIMP-1 and -2) into the spent medium, which was collected on the same day prior to graft implantation into severe combined immunodeficiency mice. Implanted EVPOMEs' histology on the seventh postimplantation day was used to correlate outcomes of grafting to secreted amounts of IL-8, hBD-1, VEGF, TIMP-1, and TIMP-2 from corresponding EVPOMEs. Our findings showed that significantly higher levels of IL-8, hBD-1, and TIMP-2 were secreted from controls than from thermally stressed EVPOMEs. We also found a direct correlation between secreted VEGF and IL-8 and blood vessel counts of implanted EVPOMEs. We concluded that measuring the constitutive release of these factors can be used as noninvasive predictors of healthy tissue-engineered EVPOMEs in RT, prior to their implantation.

Evaluation of a large-scale donation of Lifebox pulse oximeters to non-physician anaesthetists in Uganda.

Pulse oximetry is widely accepted as essential monitoring for safe anaesthesia, yet is frequently unavailable in resource-limited settings. The Lifebox pulse oximeter, and associated management training programme, was delivered to 79 non-physician anaesthetists attending the 2011 Uganda Society of Anaesthesia Annual Conference. Using a standardised assessment, recipients were tested for their knowledge of oximetry use and hypoxia management before, immediately following and 3-5 months after the training. Before the course, the median (IQR [range]) test score for the anaesthetists was 36 (34-39 [26-44]) out of a maximum of 50 points. Immediately following the course, the test score increased to 41 (38-43 [25-47]); p < 0.0001 and at the follow-up visit at 3-5 months it was 41 (39-44 [33-49]); p = 0.001 compared with immediate post-training test scores, and 75/79 (95%) oximeters were in routine clinical use. This method of introduction resulted in a high rate of uptake of oximeters into clinical practice and a demonstrable retention of knowledge in a resource-limited setting.

Tumor necrosis factor-related apoptosis-inducing ligand translates neonatal respiratory infection into chronic lung disease.

Respiratory infections in early life can lead to chronic respiratory disease. Chlamydia infections are common causes of respiratory disease, particularly pneumonia in neonates, and are linked to permanent reductions in pulmonary function and the induction of asthma. However, the immune responses that protect against early-life infection and the mechanisms that lead to chronic lung disease are incompletely understood. Here we identify novel roles for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in promoting Chlamydia respiratory infection-induced pathology in early life, and subsequent chronic lung disease. By infecting TRAIL-deficient neonatal mice and using neutralizing antibodies against this factor and its receptors in wild-type mice, we demonstrate that TRAIL is critical in promoting infection-induced histopathology, inflammation, and mucus hypersecretion, as well as subsequent alveolar enlargement and impaired lung function. This suggests that therapeutic agents that target TRAIL or its receptors may be effective treatments for early-life respiratory infections and associated chronic lung disease.

Constitutive production of IL-13 promotes early-life Chlamydia respiratory infection and allergic airway disease.

Deleterious responses to pathogens during infancy may contribute to infection and associated asthma. Chlamydia respiratory infections in early life are common causes of pneumonia and lead to reduced lung function and asthma. We investigated the role of interleukin-13 (IL-13) in promoting early-life Chlamydia respiratory infection, infection-induced airway hyperresponsiveness (AHR), and severe allergic airway disease (AAD). Infected infant Il13(-/-) mice had reduced infection, inflammation, and mucus-secreting cell hyperplasia. Surprisingly, infection of wild-type (WT) mice did not increase IL-13 production but reduced IL-13Rα2 decoy receptor levels compared with sham-inoculated controls. Infection of WT but not Il13(-/-) mice induced persistent AHR. Infection and associated pathology were restored in infected Il13(-/-) mice by reconstitution with IL-13. Stat6(-/-) mice were also largely protected. Neutralization of IL-13 during infection prevented subsequent infection-induced severe AAD. Thus, early-life Chlamydia respiratory infection reduces IL-13Rα2 production, which may enhance the effects of constitutive IL-13 and promote more severe infection, persistent AHR, and AAD.

Programming of the lung by early-life infection.

Many important human diseases, such as asthma, have their developmental origins in early life. Respiratory infections in particular may alter the course of asthma and may either protect against or promote the development of this disease. It is likely that the nature of the effects depends on the type and age of infection and is determined by the impact of infection on the immune and respiratory systems. Immunity in early life is plastic and can be moulded by antigen encounter, which may enhance or reinforce the asthmatic phenotype of early life, or induce protective responses. Chlamydial respiratory infections have specific effects and may increase asthma severity in early life by promoting systemic interleukin 13 responses and causing permanent changes in lung structure. Respiratory viral infections, such as those of respiratory syncytial virus and rhinovirus, promote pro-asthmatic responses in early life that contribute to the induction of asthma. By contrast, probiotics or infection or exposure to certain bacteria, such as Streptococcus pneumoniae, may have protective effects in asthma by increasing the numbers and activity of regulatory T cells. Here, we review the impact of infections on the developmental origins of asthma. Understanding these effects may lead to new therapeutic approaches for asthma that either target deleterious infections or utilize beneficial ones.

Neonatal respiratory infection and adult re-infection: effect on glucocorticoid and mineralocorticoid receptors in the hippocampus in BALB/c mice.

Stressful events during the perinatal period in both humans and animals have long-term consequences for the development and function of physiological systems and susceptibility to disease in adulthood. One form of stress commonly experienced in the neonatal period is exposure to bacterial and viral infections. The current study investigated the effects of live Chlamydia muridarum bacterial infection at birth followed by re-infection in adulthood on hippocampal glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) and stress response outcomes. Within 24 h of birth, neonatal mice were infected intranasally with C. muridarum (400 inclusion-forming units [ifu]) or vehicle. At 42 days, mice were re-infected (100 ifu) and euthanized 10 days later. In males, infection in adulthood alone had the most impact on the parameters measured with significant increases in GR protein compared to adult infection alone; and significant increases MR protein and circulating corticosterone compared to other treatment groups. Neonatal infection alone induced the largest alterations in the females with results showing reciprocal patterns for GR protein and TH protein. Perinatal infection resulted in a blunted response following adult infection for both males and females across all parameters. The present study demonstrates for the first time that males and females respond differently to infection based on the timing of the initial insult and that there is considerable sex differences in the hippocampal phenotypes that emerge in adulthood after neonatal infection.

Which MR imaging sequences are necessary in determining the need for radiation therapy for cord compression? A prospective study.

BACKGROUND AND PURPOSE: To determine which MR imaging sequences are necessary to assess for spinal metastases. METHODS: Hypothetical MR imaging interpretations and management plans were made prospectively for consecutive adult cases acquired retrospectively. Standardized MR imaging protocols were independently interpreted by 2 neuroradiologists. MR imaging protocol types varied: 1) T1-weighted images only; 2) T1-weighted and T2-weighted images; 3) T1-weighted and postcontrast T1-weighted images; and 4) T1- and T2-weighted images and postcontrast T1-weighted images. Hypothetical management plans were created by 2 radiation oncologists. Logit model was used to investigate the effect of MR imaging protocol type on the probability of recommending radiation therapy (RT). Mixed effect models were used to investigate whether median spinal level or total number of spinal levels of planned RT was associated with MR imaging protocol type. RESULTS: Thirty-one subjects were evaluated, each with multiple scan interpretations. Logit model showed that neither MR imaging protocol type nor neuroradiologist reader affected the probability that the oncologist would recommend RT (all P > .50). Mixed models showed that neither ML nor NL was affected by MR imaging protocol type or by neuroradiologist reader (all P > .12). CONCLUSION: Although MR imaging is known to be the most useful diagnostic test in suspected spinal cord compression, which particular MR images are necessary remain unclear. Compared with T1-weighted images alone, the additional use of T2-weighted and/or postcontrast T1-weighted sequences did not significantly affect the probability that RT would be recommended or the levels that would be chosen for RT in our study. Our data suggest that unenhanced T1-weighted images may be sufficient for evaluation of possible cord compression.

Endoscopic third ventriculostomy for tumor-related hydrocephalus in a pediatric population.

OBJECT: Endoscopic third ventriculostomy (ETV) has become a common alternative for managing hydrocephalus in select patients. Nevertheless, there is still controversy regarding the indications for ETV as the primary procedure, given its variable success rates. The purpose of this study is to review the authors' experience with ETV for a variety of patients. METHODS: A total of 43 children underwent ETV between July 1992 and June 2003. Their medical records, operative reports, and imaging studies, when available, were retrospectively reviewed with regard to outcome, complications, and patency rate. Treatment failure was defined as the need to place a shunt within 4 weeks of performing ETV in the patient. There were 20 male and 23 female patients with a mean age of 9.6 years (range 8 weeks-21 years). The overall success rate was 69.8%, and the mean follow-up duration was 24.6 months. Six patients underwent eight repeated ETVs at a mean interval of 25 months, with a patency rate of 62.5% after the second procedure. Only two surgeries were aborted for anatomical reasons. The highest success rates (100% in each instance) were achieved for obstructive hydrocephalus resulting from midbrain/tectal tumor (four patients) and pineal tumor (three patients). CONCLUSIONS: The ETV procedure is an effective management tool for obstructive hydrocephalus in children. It should be considered the primary procedure, rather than ventriculoperitoneal shunts, in carefully selected children. The success rate is dependent on the origin of the hydrocephalus.

Long-term follow-up of RTOG 92-10: cervical cancer with positive para-aortic lymph nodes.

PURPOSE: The purpose of this study was to evaluate the late toxicity and efficacy of twice-daily external irradiation to the pelvis and lumbar para-aortic region with brachytherapy and concurrent chemotherapy for carcinoma of the cervix with positive para-aortic lymph nodes. PATIENTS AND METHODS: This study was designed to administer twice-daily radiation doses of 1.2 Gy to the pelvis and lumbar para-aortic lymph nodes (simultaneously) at 4-6-h intervals, 5 days per week. The total external radiation doses were 24-48 Gy to the whole pelvis, 12-36 Gy parametrial boost, and 48 Gy to the lumbar para-aortic region with an additional boost to a total dose 54-58 Gy to the positive para-aortic lymph node(s). One or two intracavitary implants were performed to deliver a minimum total dose of 85 Gy to point A. Cisplatin (75 mg/m(2); Days 1, 22, and 43) and 5-fluorouracil (1,000 mg/m(2)/24 h x 4 consecutive days, beginning on Days 1, 22, and 43) were given for two or three cycles. RESULTS: Thirty patients with clinical Stages I-IV carcinoma of the cervix with biopsy-proven para-aortic lymph node metastases were enrolled in this study. Hyperfractionated external irradiation was completed in 87% (26 of 30). Brachytherapy was given in two implants to 47% (14 of 30) and in one implant to 33% (10 of 30); 13% (4 of 30) did not receive brachytherapy, 1 patient had three implants, and 1 had five high-dose-rate implants. Radiotherapy was completed per protocol in 70%. Three cycles of chemotherapy were given to 23% (7 of 30); 73% (22 of 30) received two cycles, and 1 patient did not receive chemotherapy. The acute toxicity from chemotherapy was Grade 1 in 3%, Grade 2 in 17%, Grade 3 in 48%, and Grade 4 in 28%. Acute toxicity from radiotherapy was Grade 1 in 7%, Grade 2 in 34%, Grade 3 in 21%, and Grade 4 in 28%. Late toxicity was Grade 1 in 10%, Grade 2 in 17%, Grade 3 in 7%, and Grade 4 in 17%. Grade 5 toxicity occurred in 1 patient during the course of therapy, but none had a late Grade 5 toxicity. The median follow-up time for the 7 patients alive at the time of last follow-up was 57 months. The overall survival estimates were 46% at 2 years and 29% at 4 years. The probability of local-regional failure was 40% at 1 year and 50% at 2 and 3 years. The probability of disease failure at any site was 46% at 1 year, 60% at 2 years, and 63% at 3 years. CONCLUSION: The results suggest that twice-daily external irradiation to the pelvis and lumbar para-aortic region with brachytherapy and concurrent chemotherapy resulted in an unacceptably high rate (17%, 5 of 29) of Grade 4 late toxicity. One patient died of acute complications of therapy. The survival estimates seem no better than standard fractionation irradiation without chemotherapy.

Welfare reform and "ineligibles": issue of constitutionality and recent court rulings.

In 1996 welfare legislation made lawful immigrants, with a few exemptions, categorically ineligible for most forms of public assistance. This legislation has led affected immigrants and their advocacy groups to file lawsuits to challenge the constitutionality of the Personal Responsibility and Work Opportunity Reconciliation Act. This article reviews recent court rulings that have upheld the act and examines court decisions in light of two constitutional principles (the Equal Protection and Supremacy clauses), which traditionally have been applied to the issue of aliens' eligibility for welfare benefits. The author finds inconsistent outcomes between federal and state legislation in the judicial review process. To resolve this inconsistency, the author suggests several policy changes in the distribution of welfare benefits concerning eligibility of lawful immigrants. The implications for social work practice are discussed.

Surgical removal of subfoveal choroidal neovascularization without removal of posterior hyaloid: a consecutive series in younger patients.

PURPOSE: Subfoveal choroidal neovascularization (CNV) remains a common and important cause of visual loss. Previous studies have suggested that submacular surgery may improve or maintain visual acuity, particularly in younger patients. The majority of reported cases included removal of the posterior hyaloid during vitrectomy. The authors present a consecutive series of patients age 55 or younger with subfoveal CNV removal without posterior hyaloid removal. METHODS: Seventeen patients without age-related macular degeneration (ARMD), with subfoveal CNV from choroiditis, presumed ocular histoplasmosis syndrome, myopia, or idiopathic causes, underwent a small retinotomy technique to extract the membranes after vitrectomy without posterior hyaloid removal. RESULTS: Median improvement in visual acuity was from 20/320 to 20/50. Eleven patients (65%) experienced an improvement of three or more lines of Snellen acuity (average 7.5), 4 (23%) were within two lines of preoperative acuity, and 2 (12%) had decreased acuity, with an average follow-up of 12 months (range 3-31). Choroidal neovascularization recurred in six patients (35%). Postoperative retinal detachment, epiretinal proliferation, or macular hole did not occur. CONCLUSIONS: In this series of younger patients with subfoveal CNV not from ARMD, visual acuity was improved in the majority after submacular membrane removal. Omission of removal of the posterior hyaloid did not adversely affect outcome.

Bmp6 and Bmp7 are required for cushion formation and septation in the developing mouse heart.

The mature heart valves and septa are derived from the cardiac cushions which initially form as local outgrowths of mesenchymal cells within the outflow tract and atrioventricular regions. Endocardial cells respond to signals from the overlying myocardium and undergo an epithelial-to-mesenchymal transformation to invade the intervening extracellular matrix. The molecules that can induce and maintain these cell populations are not known, but many candidates, including several TGFbetas and BMPs, have been proposed based on their expression patterns and activities in other systems. In the present study, we describe the expression of Bmp6 and Bmp7 in overlapping and adjacent sites, including the cardiac cushions during mouse embryonic development. Previous analyses demonstrate that neither of these BMPs is required during cardiogenesis, but analysis of Bmp6;Bmp7 double mutants uncovers a marked delay in the formation of the outflow tract endocardial cushions. A proportion of Bmp6;Bmp7 mutants also display defects in valve morphogenesis and chamber septation, and the embryos die between 10.5 and 15.5 dpc due to cardiac insufficiency. These data provide the first genetic evidence that BMPs are involved in the formation of the cardiac cushions.

Tumor shrinkage before intracavitary brachytherapy for cancer of the cervix: radiotherapy alone versus concurrent chemoradiotherapy.

PURPOSE: The purpose of this study was to compare the tumor shrinkage between radiotherapy alone and concurrent chemoradiotherapy before intracavitary brachytherapy (ICBT). MATERIALS AND METHODS: Nineteen consecutive patients (three stage IB2, nine stage IIB, seven stage IIIB) were selected for measurement of tumor regression. Ten patients underwent radiotherapy alone, and nine patients underwent concurrent cisplatin-based chemoradiotherapy. The average dose of pelvic radiation was given at 45 Gy over a 5-week period in both groups. Computed tomography-based tumor measurement before treatment was compared with measurement after treatment but before intracavitary brachytherapy. The largest width and thickness of the cervical mass were measured from the axial computed tomographic images. RESULTS: Tumor regression before intracavitary brachytherapy varied widely, ranging from 15% to 65%. However, the tumor regression in patients who underwent chemoradiotherapy was higher, ranging from 41% to 65% (mean, 55%), compared with radiotherapy alone, which ranged from 15% to 52% (mean, 38%). CONCLUSION: Our results show that significant tumor shrinkage occurs with concurrent chemoradiotherapy compared with radiotherapy alone. This finding supports the results of recent clinical trials demonstrating improvement of pelvic control and survival with concurrent chemoradiotherapy for advanced cancer of the cervix.

Recent developments in chemoradiotherapy for locally advanced cancer of the cervix.

Patients with locally advanced cervical cancer comprise a significant proportion of the total population with cervical cancer, particularly in developing countries. The inability to control pelvic tumors is still a significant concern. Although neoadjuvant chemotherapy is associated with a high response rate, data from randomized trials clearly do not support the use of neoadjuvant chemotherapy prior to definitive irradiation. However, the results of concurrent cisplatin (Platinol)-based chemotherapy and radiotherapy are highly promising for locally advanced cancer of the cervix and should be considered as a treatment option. To decrease the risk of distant metastasis and improve survival, more effective drugs or drug combinations need to be developed.

A prospective evaluation of the timing of postoperative radiotherapy for preventing heterotopic ossification following traumatic acetabular fractures.

PURPOSE: Preoperative and immediate postoperative irradiation of traumatic acetabular fractures (TAF), although known to reduce heterotopic ossification (HO), can cause significant organizational and logistic difficulties. We sought to determine an acceptable time interval between surgery and radiation without compromising control, as well as to update our large experience and to further validate our treatment philosophy. METHODS AND MATERIALS: Beginning in June 1995, we began a prospective study, irradiating 152 patients on postoperative days 1, 2, or 3. There were also 17 patients delayed further secondary to medical difficulties. RESULTS: All patients treated since June 1995 received 700 cGy/1 fx. Fifty-eight patients received radiation within 24 hours of surgery, 41 within 2 days, 53 within 3 days, 13 within 4 days, and 4 were delayed further. Delaying irradiation for up to 4 days postoperatively caused no statistical increase in HO (p = 0.625). Of 263 patients in our retrospective cohort, HO occurred in 5.3% of patients who received irradiation versus 60% of patients who did not. CONCLUSION: In our prospective study, we noted no perceptible increase in HO with up to a 3-day interval between surgery and radiotherapy. This allows a more structured treatment schedule and allows the patient more time to heal and recover. Updated results from our overall series continue to demonstrate that adjuvant radiation decreases the incidence and severity of HO after TAF.