Factors Associated With and Characteristics of Patients Receiving Proton Therapy at the End of Life.

Purpose: To identify the characteristics, indications, and toxicities among patients receiving proton beam therapy (PBT) in the final year of life at an academic medical center. Materials and Methods: A retrospective review of patients who received PBT within the final 12 months of life was performed. Electronic medical records were reviewed for patient and treatment details from 2010 to 2019. Patients were followed from the start of PBT until death or last follow-up. Acute (3 months) toxicities were graded using the Common Terminology Criteria for Adverse Events v5.0. Imaging response was assessed using the Response Evaluation Criteria in Solid Tumors v1.1. The χ2 test was used to evaluate factors associated with palliative treatment. Simple logistic regression was used to evaluate factors associated with toxicity. Results: Bet299 patients were treated at the end of life (EOL) out of 5802 total patients treated with PBT (5.2%). Median age was 68 years (19-94 years), 58% male. The most common cancer was nonsmall cell lung cancer (27%). Patients were treated for symptom palliation alone (11%), durable control (57%), curative intent (16%), local recurrence (14%), or oligometastatic disease (2%). Forty-five percent received reirradiation. Median treatment time was 32 days (1-189 days). Acute toxicity was noted in 85% of the patients (31% G1, 53% G2, 15% G3). Thirteen patients (4%) experienced chronic toxicity. Breast and hematologic malignancy were associated with palliative intent χ2 (1, N = 14) = 17, P = .013; (χ2 (1, N = 14) = 18, P = .009). Conclusion: The number of patients treated with PBT at the EOL was low compared to all comers. Many of these patients received treatment with definitive doses and concurrent systemic therapy. Some patients spent a large portion of their remaining days on treatment. A prognostic indicator may better optimize patient selection for PBT at the EOL.

Proton FLASH Radiotherapy Ameliorates Radiation-induced Salivary Gland Dysfunction and Oral Mucositis and Increases Survival in a Mouse Model of Head and Neck Cancer.

Head and neck cancer radiotherapy often damages salivary glands and oral mucosa, severely negatively impacting patients' quality of life. The ability of FLASH proton radiotherapy (F-PRT) to decrease normal tissue toxicity while maintaining tumor control compared with standard proton radiotherapy (S-PRT) has been previously demonstrated for several tissues. However, its potential in ameliorating radiation-induced salivary gland dysfunction and oral mucositis and controlling orthotopic head and neck tumor growth has not been reported. The head and neck area of C57BL/6 mice was irradiated with a single dose of radiotherapy (ranging from 14-18 Gy) or a fractionated dose of 8 Gy × 3 of F-PRT (128 Gy/second) or S-PRT (0.95 Gy/second). Following irradiation, the mice were studied for radiation-induced xerostomia by measuring their salivary flow. Oral mucositis was analyzed by histopathologic examination. To determine the ability of F-PRT to control orthotopic head and neck tumors, tongue tumors were generated in the mice and then irradiated with either F-PRT or S-PRT. Mice treated with either a single dose or fractionated dose of F-PRT showed significantly improved survival than those irradiated with S-PRT. F-PRT-treated mice showed improvement in their salivary flow. S-PRT-irradiated mice demonstrated increased fibrosis in their tongue epithelium. F-PRT significantly increased the overall survival of the mice with orthotopic tumors compared with the S-PRT-treated mice. The demonstration that F-PRT decreases radiation-induced normal tissue toxicity without compromising tumor control, suggests that this modality could be useful for the clinical management of patients with head and neck cancer.

FLASH Proton Radiation Therapy Mitigates Inflammatory and Fibrotic Pathways and Preserves Cardiac Function in a Preclinical Mouse Model of Radiation-Induced Heart Disease.

PURPOSE: Studies during the past 9 years suggest that delivering radiation at dose rates exceeding 40 Gy/s, known as "FLASH" radiation therapy, enhances the therapeutic index of radiation therapy (RT) by decreasing normal tissue damage while maintaining tumor response compared with conventional (or standard) RT. This study demonstrates the cardioprotective benefits of FLASH proton RT (F-PRT) compared with standard (conventional) proton RT (S-PRT), as evidenced by reduced acute and chronic cardiac toxicities. METHODS AND MATERIALS: Mice were imaged using cone beam computed tomography to precisely determine the heart's apex as the beam isocenter. Irradiation was conducted using a shoot-through technique with a 5-mm diameter circular collimator. Bulk RNA-sequencing was performed on nonirradiated samples, as well as apexes treated with F-PRT or S-PRT, at 2 weeks after a single 40 Gy dose. Inflammatory responses were assessed through multiplex cytokine/chemokine microbead assay and immunofluorescence analyses. Levels of perivascular fibrosis were quantified using Masson's Trichrome and Picrosirius red staining. Additionally, cardiac tissue functionality was evaluated by 2-dimensional echocardiograms at 8- and 30-weeks post-PRT. RESULTS: Radiation damage was specifically localized to the heart's apex. RNA profiling of cardiac tissues treated with PRT revealed that S-PRT uniquely upregulated pathways associated with DNA damage response, induction of tumor necrosis factor superfamily, and inflammatory response, and F-PRT primarily affected cytoplasmic translation, mitochondrion organization, and adenosine triphosphate synthesis. Notably, F-PRT led to a milder inflammatory response, accompanied by significantly attenuated changes in transforming growth factor ß1 and α smooth muscle actin levels. Critically, F-PRT decreased collagen deposition and better preserved cardiac functionality compared with S-PRT. CONCLUSIONS: This study demonstrated that F-PRT reduces the induction of an inflammatory environment with lower expression of inflammatory cytokines and profibrotic factors. Importantly, the results indicate that F-PRT better preserves cardiac functionality, as confirmed by echocardiography analysis, while also mitigating the development of long-term fibrosis.

Temporal Evolution and Diagnostic Diversification of Patients Receiving Proton Therapy in the United States: A Ten-Year Trend Analysis (2012 to 2021) From the National Association for Proton Therapy.

PURPOSE: The National Association for Proton Therapy conducted 8 surveys of all operational United States proton centers (2012-2021) and analyzed the patients treated, diagnoses, and treatment complexity to evaluate trends and diversification of patients receiving proton therapy. METHODS AND MATERIALS: Detailed surveys were sent in 2015, which requested data from 2012 to 2014, and then annually thereafter to active proton centers in the United States. The numbers of patient treated at each center for the preceding calendar year(s) were collated for tumors in the following categories: central nervous system, intraocular, pituitary, skull base/skeleton, head/neck, lung, retroperitoneal/soft tissue sarcoma, pediatric (solid tumors in children of age ≤18), gastrointestinal tract, urinary tract, female pelvic, prostate, breast, and "other." Complexity levels were assessed using Current Procedural Terminology codes 77520-77525. RESULTS: Survey response rates were excellent (100% in 2015 to 94.9% in 2021); additional publicly available information provided near-complete information on all centers. Trend comparisons between 2012 and 2021 showed that the total annual number of patients treated with protons gradually increased from 5377 to 15,829. The largest numeric increases were for head/neck (316 to 2303; 7.3-fold), breast (93 to 1452; 15.6-fold), and gastrointestinal tumors (170 to 1259; 7.4-fold). Patient numbers also increased significantly for central nervous system (598 to 1743; 2.9-fold), pediatric (685 to 1870; 2.7-fold), and skull base tumors (179 to 514; 2.9-fold). For prostate cancer, the percentage of proton-treated patients decreased from 43.4% to 25.0% of the total. Simple compensated treatments decreased from 43% in 2012 to 7% in 2021, whereas intermediate complexity treatments increased from 45% to 73%. CONCLUSIONS: The number of patients treated with protons is gradually increasing, with a substantial proportionate decline in patients with prostate cancer receiving proton therapy. The number of patients treated for "commonly accepted" indications for protons (eg, pediatric, central nervous system, and skull base tumors) is gradually increasing. Greater proportional increases were observed for breast, lung, head/neck, and gastrointestinal tumors. Treatment complexity is gradually increasing over time.

SMAD4 loss predicts worse overall and distant metastasis-free survival in patients with resected pancreatic adenocarcinoma.

BACKGROUND: In select patients, pancreatic adenocarcinoma remains a local disease, yet there are no validated biomarkers to predict this behavior and who may benefit from aggressive local treatments. This study sought to determine if SMAD4 (mothers against decapentaplegic homolog 4) messenger RNA-sequencing (RNA-seq) expression is a robust method for predicting overall survival (OS) and distant metastasis-free survival (DMFS) in patients with resected pancreatic adenocarcinoma. METHODS: Utilizing The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), 322 patients with resected stage I-III pancreatic adenocarcinoma were identified. In TCGA, multivariable proportional hazards models were used to determine the association of SMAD4 genomic aberrations and RNA-seq expression with OS and DMFS. In the ICGC, analysis sought to confirm the predictive performance of RNA-seq via multivariable models and receiver operator characteristic curves. RESULTS: In TCGA, the presence of SMAD4 genomic aberrations was associated with worse OS (hazard ratio [HR], 1.55; 95% CI, 1.00-2.40; p = .048) but not DMFS (HR, 1.33; 95% CI, .87-2.03; p = .19). Low SMAD4 RNA-seq expression was associated with worse OS (HR, 1.83; 95% CI, 1.17-2.86; p = .008) and DMFS (HR, 1.70; 95% CI, 1.14-2.54; p = .009). In the ICGC, increased SMAD4 RNA-seq expression correlated with improved OS (area under the curve [AUC], .92; 95% CI, .86-.94) and DMFS (AUC, .84; 95% CI, .82-.87). CONCLUSIONS: In patients with resected pancreatic adenocarcinoma, SMAD4 genomic aberrations are associated with worse OS but do not predict for DMFS. Increased SMAD4 RNA-seq expression is associated with improved OS and DMFS in patients with resected pancreatic adenocarcinoma. This reproducible finding suggests SMAD4 RNA-seq expression may be a useful marker to predict metastatic spread.

Radiation dose is associated with improved local control for large, but not small, hepatocellular carcinomas.

BACKGROUND: With advances in understanding liver tolerance, conformal techniques, image guidance, and motion management, dose-escalated radiotherapy has become a potential treatment for inoperable hepatocellular carcinoma (HCC). We aimed to evaluate the possible impact of biologically effective dose (BED) on local control and toxicity among patients with HCC. METHODS AND MATERIALS: Patients treated at our institution from 2009 to 2018 were included in this retrospective analysis if they received definitive-intent radiotherapy with a nominal BED of at least 60 Gy. Patients were stratified into small and large tumors using a cutoff of 5 cm, based on our clinical practice. Toxicity was assessed using ALBI scores and rates of clinical liver function deterioration. RESULTS: One hundred and twenty-eight patients were included, with a mean follow-up of 16 months. The majority of patients (90.5%) had a good performance status (ECOG 0-1), with Child-Pugh A (66.4%) and ALBI Grade 2 liver function at baseline (55.4%). Twenty (15.6%) patients had a local recurrence in the irradiated field during the follow-up period. Univariate and multivariate Cox proportional hazard analyses showed that only BED significantly predicted local tumor recurrence. Higher BED was associated with improved local control in tumors with equivalent diameters over 5 cm but not in smaller tumors. There was no difference in liver toxicity between the low and high-dose groups. CONCLUSIONS: Higher radiotherapy dose is associated with improved local control in large tumors but not in tumors smaller than 5 cm in diameter. High-dose radiotherapy was not associated with increased liver toxicity.

Annual review of selected scientific literature: A report of the Committee on Scientific Investigation of the American Academy of Restorative Dentistry.

The Scientific Investigation Committee of the American Academy of Restorative Dentistry offers this review of the 2022 dental literature to briefly touch on several topics of interest to modern restorative dentistry. Each committee member brings discipline-specific expertise in their subject areas that include (in order of the appearance in this report): prosthodontics; periodontics, alveolar bone, and peri-implant tissues; dental materials and therapeutics; occlusion and temporomandibular disorders; sleep-related breathing disorders; oral medicine and oral and maxillofacial surgery; and dental caries and cariology. The authors focused their efforts on reporting information likely to influence the daily dental treatment decisions of the reader with an emphasis on innovations, new materials and processes, and future trends in dentistry. With the tremendous volume of literature published daily in dentistry and related disciplines, this review cannot be comprehensive. Instead, its purpose is to update interested readers and provide valuable resource material for those willing to subsequently pursue greater detail on their own. Our intent remains to assist colleagues in navigating the tremendous volume of newly minted information produced annually. Finally, we hope that readers find this work helpful in managing patients.

Assessment of Differences in Academic Rank and Compensation by Gender and Race/Ethnicity Among Academic Radiation Oncologists in the United States.

Purpose: Advancing equity, diversity, and inclusion in the physician workforce is essential to providing high-quality and culturally responsive patient care and has been shown to improve patient outcomes. To better characterize equity in the field of radiation oncology, we sought to describe the current academic radiation oncology workforce, including any contemporary differences in compensation and rank by gender and race/ethnicity. Methods and Materials: We conducted a retrospective cohort study using data from the Society of Chairs of Academic Radiation Oncology Programs (SCAROP) 2018 Financial Survey. Multivariable logistic regression models were used to identify factors associated with associate or full professor rank. Compensation was compared by gender and race/ethnicity overall and stratified by rank and was further analyzed using multivariable linear regression models. Results: Of the 858 academic radiation oncologists from 63 departments in the United States in the sample, 33.2% were female, 65.2% were White, 27.2% were Asian, and 7.6% were underrepresented in medicine (URiM). There were 44.0% assistant professors, 32.0% associate professors, and 22.8% full professors. Multivariable logistic regression analysis for factors associated with associate or full professor rank did not reveal statistically significant associations between gender or race/ethnicity with academic rank (odds ratio [OR], 0.86; 95% confidence interval [CI], 0.56-1.32; P = .48 for gender; OR, 0.81; 95% CI, 0.5-1.30; P = .37 for Asian vs White; and OR, 0.69; 95% CI, 0.31-1.55; P = .37 for URiM vs White), but CIs were wide due to sample size, and point estimates were <1. Similarly, multivariable linear regression analysis modeling the log relative total compensation did not detect statistically significant differences between radiation oncologists by gender (-1.7%; 95% CI, -6.8% to 3.4%; P = .51 for female vs male) or race/ethnicity (-1.6%; 95% CI, -7.3% to 4.0%; P = .57 for Asian vs White and -3.0%; 95% CI, -12.1% to 6.0%; P = .51 for URiM vs White). Conclusions: The low numbers of women and faculty with URiM race/ethnicity in this radiation oncology faculty sample limits the ability to compare career trajectory and compensation by those characteristics. Given that point estimates were <1, our findings do not contradict larger multispecialty studies that suggest an ongoing need to monitor equity.

Pediatric abusive head trauma: visual outcomes, evoked potentials, diffusion tensor imaging, and relationships to retinal hemorrhages.

PURPOSE: Function and anatomy of the visual system were evaluated in children with abusive head trauma (AHT). The relationships between retinal hemorrhages at presentation were examined with outcome measures. METHODS: Retrospective review of data in children with AHT for 1) visual acuity at last follow-up, 2) visual evoked potentials (VEP) after recovery, 3) diffusion metrics of white matter tracts and grey matter within the occipital lobe on diffusion tensor imaging (DTI), and 4) patterns of retinal hemorrhages at presentation. Visual acuity was converted into logarithm of minimum angle of resolution (logMAR) after correction for age. VEPs were also scored by objective signal-to-noise ratio (SNR). RESULTS: Of 202 AHT victims reviewed, 45 met inclusion criteria. Median logMAR was reduced to 0.8 (approximately 20/125 Snellen equivalent), with 27% having no measurable vision. Thirty-two percent of subjects had no detectable VEP signal. VEPs were significantly reduced in subjects initially presenting with traumatic retinoschisis or hemorrhages involving the macula (p < 0.01). DTI tract volumes were decreased in AHT subjects compared to controls (p < 0.001). DTI metrics were most affected in AHT victims showing macular abnormalities on follow-up ocular examination. However, DTI metrics were not correlated with visual acuity or VEPS. There was large inter-subject variability within each grouping. DISCUSSION: Mechanisms causing traumatic retinoschisis, or traumatic abnormalities of the macula, are associated with significant long-term visual pathway dysfunction. AHT associated abnormalities of the macula, and visual cortical pathways were more fully captured by VEPs than visual acuity or DTI metrics.

Using Holistic Residency Applicant Review and Selection in Radiation Oncology to Enhance Diversity and Inclusion-An ASTRO SCAROP-ADROP-ARRO Collaboration.

Disproportionate sex, racial, and ethnic diversity remains in the radiation oncology physician workforce despite widespread awareness and longitudinal efforts to improve representation. In this collaborative review, we define the rationale and components of holistic review and how it can be best used to provide a comprehensive evaluation of applicants to residency programs in radiation oncology. We initially discuss the current state of diversity in the field of radiation oncology and highlight the components of the residency selection process that may serve to perpetuate existing biases. Subsequently, the Accreditation Council for Graduate Medical Education and Association of American Medical Colleges holistic review framework is reviewed in detail to demonstrate the balanced assessment of potential applicants. The implementation of holistic review in medical school and residency selection to date is examined to underscore the potential value of holistic review in the radiation oncology residency selection process. Finally, recommendations for the practical implementation of holistic review in radiation oncology trainee selection are outlined.

Understanding Bilateral Skull Fractures in Infancy: A Retrospective Multicenter Case Review.

BACKGROUND: Bilateral skull fractures in infancy often raise suspicion for abuse. Nevertheless, literature suggests that they may occur accidentally. However, empiric data are lacking. OBJECTIVE: This multicenter retrospective review aimed to characterize bilateral skull fractures in a large sample. PARTICIPANTS AND SETTING: Medical records for infants younger than 24 months with bilateral skull fractures involving hospital consultation with a child abuse pediatrician (CAP) were reviewed from 2005 to 2020 at 13 nationally represented institutions. METHODS: Standardized data collection across institutions included historical features, fracture characteristics, and additional injuries, as well as the CAP's determination of accident versus abuse. Pooled data were analyzed for descriptive and bivariate analyses. RESULTS: For 235 cases, 141 were accidental, and 94 abuse. The majority occurred in young infants, and a history of a fall was common in 70% of cases. More than 80% involved both parietal bones. Bilateral simple linear fractures were more common in accidental cases, 79% versus 35%, whereas a complex fracture was more frequent in abuse cases, 55% versus 21% ( P < 0.001). Almost two thirds of accidental cases showed approximation of the fractures at the sagittal suture, compared with one third of abuse cases ( P < 0.001). Whereas focal intracranial hemorrhage was seen in 43% of all cases, diffuse intracranial hemorrhage was seen more in abuse cases (45%) than accidents (11%). Skin trauma was more common in abusive than accidental injury (67% vs 17%, P < 0.001), as were additional fractures on skeletal survey (49% vs 3%, P < 0.001). CONCLUSIONS: A fall history was common in bilateral skull fractures deemed accidental by a CAP. Most accidental cases involved young infants with biparietal simple linear fractures, without skin trauma or additional fractures. A skeletal survey may aid in the determination of accidental or abusive injury for unwitnessed events resulting in bilateral skull fractures in infants.

Design and implementation of an Internet-Based cancer risk assessment tool: Use over 10 years.

BACKGROUND: Prevention and early intervention can improve survival and quality of life across all cancers. Patient understanding of risk factors and associated actionable lifestyle changes and screening programs is not well understood by clinicians METHODS: An Internet-based tool, Reduce My Risk, was created in 2009 and made available on oncolink.org. Users voluntarily completed a survey regarding demographics and cancer risk factors, and received information about their cancer risk RESULTS: Twenty eight thousand and one surveys were completed from 2009 to 2019. Median age was 26 years (18-101); 60% were females, 87% lived in North America, and 37% had at least a bachelor's degree. Users reported on behavioral/ modifiable risk factors: 13% were current smokers, 52% were current consumers of alcohol, and 8% of those had ≥14 drinks/week. Body mass index (BMI) was ≥30 in 19%; 74% of all surveys reported dietary risks and 36% reported infrequent exercise. Excess UV exposure was reported by 19%. Among women, 36% reported performing breast self-examinations monthly, and 50% reported receiving clinician breast examinations at least once every 3 years. Sixty seven percent of men 55-75 years reported screening prostate specific antigen testing, with 50% receiving annual digital rectal examinations. Nonmodifiable risk factors included family cancer history (64%), genetic syndrome (3%), and cancer-predisposing health conditions (26%) CONCLUSIONS: Ninety-seven percent of users reported modifiable risk factors, and 60% reported ≥4 of these risk factors. Understanding detailed characteristics of a large number of respondents has the potential to improve educational interventions to reduce cancer risk through behavioral modification and cancer screening across the general public.

Association between obstructive sleep apnea and periodontitis in Chinese male adults: A cross-sectional study.

STATEMENT OF PROBLEM: An association between obstructive sleep apnea and periodontitis has been suggested, but supporting data are lacking. PURPOSE: The purpose of this cross-sectional study was to investigate any association between obstructive sleep apnea and periodontitis in Chinese male adults. MATERIAL AND METHODS: Ninety-three male adults (aged between 24 and 35 years) were recruited and examined between June and September 2019. Obstructive sleep apnea was diagnosed by using portable, overnight polysomnography, and all participants were classified into study and control groups based on the apnea-hypopnea index. Periodontal examinations were conducted before polysomnography measuring probing depth, clinical attachment level, and bleeding on probing. An objective nasal airway resistance assessment was also performed before polysomnography to quantify mouth breathing during sleep. RESULTS: Overall, 40 (43.0%) participants had periodontitis, and 19 (20.4%) had obstructive sleep apnea; in those diagnosed with periodontitis, 13 of 40 (32.5%) also had obstructive sleep apnea. Obstructive sleep apnea was positively associated with periodontitis (odds ratio =3.719, 95% CI=1.234 to 11.209, P=.020). The obstructive sleep apnea group showed significantly higher bleeding on probing (P=.034) and clinical attachment level (P=.046). Correlation analysis showed a weak but positive correlation between the severity of obstructive sleep apnea and that of periodontitis. The regression analysis identified the lowest oxygen saturation (odds ratio=0.894, 95% CI=0.842 to 0.949, P=.002) to be significantly associated with the prevalence of periodontitis. CONCLUSIONS: A significant association was observed between obstructive sleep apnea and periodontitis. Low oxygen saturation might be a predictive index for periodontitis, suggesting that hypoxia caused by obstructive sleep apnea might be related to the symptoms of periodontitis.

Delusions of parasitosis and delusions of parasitosis by proxy in a mother and her children.

Delusions of parasitosis by proxy is an uncommon entity wherein an individual projects a delusional belief onto another person who lacks capacity to hold the same belief. We report a case of delusions of parasitosis by proxy in a mother who believed that she was infested with scabies and projected her fixed, delusional belief of scabies infestation onto her children. She subjected her children to numerous home remedies and medical treatments as well as removing them from school in an effort to cure them of the supposed infestation. Child maltreatment can be a concern in such cases with a low threshold for involving child protective services if harm to the children is suspected.

A phenomenological model of proton FLASH oxygen depletion effects depending on tissue vasculature and oxygen supply.

Introduction: Radiation-induced oxygen depletion in tissue is assumed as a contributor to the FLASH sparing effects. In this study, we simulated the heterogeneous oxygen depletion in the tissue surrounding the vessels and calculated the proton FLASH effective-dose-modifying factor (FEDMF), which could be used for biology-based treatment planning. Methods: The dose and dose-weighted linear energy transfer (LET) of a small animal proton irradiator was simulated with Monte Carlo simulation. We deployed a parabolic partial differential equation to account for the generalized radiation oxygen depletion, tissue oxygen diffusion, and metabolic processes to investigate oxygen distribution in 1D, 2D, and 3D solution space. Dose and dose rates, particle LET, vasculature spacing, and blood oxygen supplies were considered. Using a similar framework for the hypoxic reduction factor (HRF) developed previously, the FEDMF was derived as the ratio of the cumulative normoxic-equivalent dose (CNED) between CONV and UHDR deliveries. Results: Dynamic equilibrium between oxygen diffusion and tissue metabolism can result in tissue hypoxia. The hypoxic region displayed enhanced radio-resistance and resulted in lower CNED under UHDR deliveries. In 1D solution, comparing 15 Gy proton dose delivered at CONV 0.5 and UHDR 125 Gy/s, 61.5% of the tissue exhibited ≥20% FEDMF at 175 µm vasculature spacing and 18.9 µM boundary condition. This percentage reduced to 34.5% and 0% for 8 and 2 Gy deliveries, respectively. Similar trends were observed in the 3D solution space. The FLASH versus CONV differential effect remained at larger vasculature spacings. A higher FLASH dose rate showed an increased region with ≥20% FEDMF. A higher LET near the proton Bragg peak region did not appear to alter the FLASH effect. Conclusion: We developed 1D, 2D, and 3D oxygen depletion simulation process to obtain the dynamic HRF and derive the proton FEDMF related to the dose delivery parameters and the local tissue vasculature information. The phenomenological model can be used to simulate or predict FLASH effects based on tissue vasculature and oxygen concentration data obtained from other experiments.

Novel chemical entities inhibiting Mycobacterium tuberculosis growth identified by phenotypic high-throughput screening.

We performed a high-throughput phenotypic whole cell screen of Mycobacterium tuberculosis against a diverse chemical library of approximately 100,000 compounds from the AbbVie corporate collection and identified 24 chemotypes with anti-tubercular activity. We selected two series for further exploration and conducted structure-activity relationship studies with new analogs for the 4-phenyl piperidines (4PP) and phenylcyclobutane carboxamides (PCB). Strains with mutations in MmpL3 demonstrated resistance to both compound series. We isolated resistant mutants for the two series and found mutations in MmpL3. These data suggest that MmpL3 is the target, or mechanism of resistance for both series.

Annual review of selected scientific literature: A report of the Committee on Scientific Investigation of the American Academy of Restorative Dentistry.

The Scientific Investigation Committee of the American Academy of Restorative Dentistry offers this review of the 2021 dental literature in restorative dentistry to inform busy dentists regarding noteworthy scientific and clinical progress over the past year. Each member of the committee brings discipline-specific expertise to coverage of this broad topical area. Specific subject areas addressed, in order of the appearance in this report, include COVID-19 and the dental profession (new); prosthodontics; periodontics, alveolar bone, and peri-implant tissues; implant dentistry; dental materials and therapeutics; occlusion and temporomandibular disorders; sleep-related breathing disorders; oral medicine and oral and maxillofacial surgery; and dental caries and cariology. The authors focused their efforts on reporting information likely to influence daily dental treatment decisions with an emphasis on future trends in dentistry. With the tremendous volume of dentistry and related literature being published daily, this review cannot possibly be comprehensive. Rather, its purpose is to update interested readers and provide important resource material for those interested in pursuing greater details on their own. It remains our intent to assist colleagues in negotiating the extensive volume of important information being published annually. It is our hope that readers find this work useful in successfully managing the patients and dental problems they encounter.

Acute toxicity in patients treated with concurrent chemoradiotherapy with proton versus intensity-modulated radiation therapy for nonmetastatic head and neck cancers.

BACKGROUND: We evaluated if proton therapy is associated with decreased acute toxicities compared to intensity-modulated radiation therapy (IMRT) in patients receiving concurrent chemoradiotherapy for head and neck cancers. METHODS: We analyzed 580 patients with nonmetastatic head and neck cancers. Primary endpoint was any 90-day grade ≥3 toxicity, prospectively collected and graded per CTCAEv4. Modified Poisson regression models were used. RESULTS: Ninety-five patients received proton and 485 IMRT. The proton group had more HPV-positive tumors (65.6 vs. 58.0%, p = 0.049), postoperative treatment (76.8 vs. 62.1%, p = 0.008), unilateral neck treatment (18.9 vs. 6.6%, p < 0.001) and significantly lower doses to organs-at-risk compared to IMRT group. Adjusted for patient and treatment characteristics, the proton group had decreased grade 2 dysgeusia (RR0.67, 95%CI 0.53-0.84, p = 0.004) and a trend toward lower grade ≥3 toxicities (RR0.60, 95%CI 0.41-0.88, p = 0.06). CONCLUSIONS: Proton therapy was associated with significantly reduced grade 2 dysgeusia and nonstatistically significant decrease in acute grade ≥3 toxicities compared to IMRT.

Extra-axial haemorrhages in young children with skull fractures: abuse or accident?

OBJECTIVE: Infant and toddler subdural haemorrhages (SDH) are often considered indicative of abuse or major trauma. However, accidental impact events, such as falls, cause contact extra-axial haemorrhages (EAHs). The current study sought to determine frequency and clinical behaviour of EAHs with infant and toddler accidental and abusive skull fractures. PATIENTS AND METHODS: Children aged <4 years with accidental skull fractures and abusive fractures identified by CT at two paediatric tertiary care centres. Clinical data were abstracted by child abuse paediatricians and images were reviewed by paediatric radiologists. Data were analysed using univariate and multivariate logistic regression as well as descriptive statistics. RESULTS: Among 227 subjects, 86 (37.9%) had EAHs. EAH was present in 73 (34.8%) accidental and 13 (76.5%) of the abusive injuries. Intracranial haemorrhage rates were not different for children with major or minor accidents but were fewer than abused. EAH was equally common with falls <4 and >4 ft. EAH depths did not differ by mechanism, but 69% of accidental EAHs were localised solely at fracture sites vs 38% abuse. Widespread and multifocal EAHs were more common with abuse. Children with abuse or major accidental injuries presented with lower initial Glasgow Coma Scales than those with minor accidents. Abused children had initial loss of consciousness more often than those with either minor or major accidents. CONCLUSIONS: Simple contact EAHs were common among children with minor and major accidental skull fractures. Accidental EAHs were more localised with less neurological dysfunction than abusive.

Activity Monitoring for Toxicity Detection and Management in Patients Undergoing Chemoradiation for Gastrointestinal Malignancies.

PURPOSE: Physical activity is associated with decreased hospitalization during cancer treatment. We hypothesize that activity data can help identify and triage high-risk patients with GI cancer undergoing concurrent chemoradiation. MATERIALS AND METHODS: This prospective study randomly assigned patients to activity monitoring versus observation. In the intervention arm, a 20% decrease in daily steps or 20% increase in heart rate triggered triage visits to provide supportive care, medication changes, and escalation of care. In the observation group, activity data were recorded but not monitored. The primary objective was to show a 20% increase in triage visits in the intervention group. Secondary objectives were estimating the rates of emergency department (ED) visits and hospitalizations. Crude and adjusted odds ratios were computed using logistic regression modeling. RESULTS: There were 22 patients in the intervention and 18 in the observation group. Baseline patient and treatment characteristics were similar. The primary objective was met, with 3.4 more triage visits in the intervention group than in the observation group (95% CI, 2.10 to 5.50; P < .0001). Twenty-six (65.0%) patients required at least one triage visit, with a higher rate in the intervention arm compared with that in the observation arm (86.4% v 38.9%; odds ratio, 9.95; 95% CI, 2.13 to 46.56; P = .004). There was no statistically significant difference in ED visit (9.1% v 22.2%; P = .38) or hospitalization (4.5% v 16.7%; P = .31). CONCLUSION: It is feasible to use activity data to trigger triage visits for symptom management. Further studies are investigating whether automated activity monitoring can assist with early outpatient management to decrease ED visits and hospitalizations.