Sex differences in the global burden of multidrug- resistant tuberculosis without extensive drug resistance in the general population and people living with HIV/AIDS, 1990-2019.

OBJECTIVE: Currently, human immunodeficiency virus (HIV) and multi-drug resistant tuberculosis (MDR-TB) without extensive drug resistance (XDR) are significant challenges in terms of the global burden of disease. This study aimed to evaluate the trends of the global burden of MDR-TB without XDR and HIV/AIDS-MDR-TB without XDR, focusing on differences in socioeconomic status and sex for 204 countries and territories across periods from 1990 to 2019. MATERIALS AND METHODS: Data from the Global Burden of Disease (GBD) 2019 study were obtained to construct a separate index measuring the burden of MDR-TB without XDR and HIV/AIDS-MDR-TB without XDR. Incidence, prevalence, mortality, and disability-adjusted life years (DALYs) were calculated for each case and group. A population-attributable fraction approach was used to assess mortality and incidence of HIV/AIDS and MDR-TB coinfection. 95% uncertainty intervals (UIs) were presented for all measures. RESULTS: Our global estimates suggest that there were approximately 450,000 (95% UI 247,000-785,000) incident cases of MDR-TB without XDR and 109,000 (43,000-210,000) deaths caused by MDR-TB without XDR among individuals who were HIV-negative in 2019. For HIV-positive individuals, the corresponding figures were approximately 47,000 (33,000-67,000) incident cases of MDR-TB and 19,000 (8,000-36,000) deaths due to MDR-TB in the same year. In 2019, higher numbers of incident cases and deaths were observed in males compared to females among individuals who were HIV-negative. Conversely, for HIV-positive individuals, females had higher numbers of incident cases and deaths compared to males. Specifically, the estimated numbers for incident cases were 23,000 (15,000-33,000) for females and 24,000 (17,000-35,000) for males, while the estimated numbers for deaths were 9,600 (4,000-17,900) for females and 9,800 (4,100-18,500) for males. Male-to-female ratios have remained above 1.0 from 1990 to 2019 in both incident cases and number of deaths for HIV-negative individuals. However, for HIV and MDR-TB coinfection, both ratios were below 1.0 in most of the time series. CONCLUSIONS: Males had more cases and deaths due to MDR-TB without XDR than females in HIV-negative patients, while females faced a higher incidence and mortality in HIV/AIDS-MDR-TB without XDR. Interventions are needed to deal with such factors, which increase the burden of coinfection among females across the world.

A Novel Dose Rate Optimization Method to Maximize Ultrahigh-Dose-Rate Coverage of Critical Organs at Risk Without Compromising Dosimetry Metrics in Proton Pencil Beam Scanning FLASH Radiation Therapy.

PURPOSE: This study aimed to investigate a dose rate optimization framework based on the spot-scanning patterns to improve ultrahigh-dose-rate coverage of critical organs at risk (OARs) for proton pencil beam scanning (PBS) FLASH radiation therapy (ultrahigh dose-rate (often referred to as >40 Gy per second) delivery) and present implementation of a genetic algorithm (GA) method for spot sequence optimization to achieve PBS FLASH dose rate optimization under relatively low nozzle beam currents. METHODS AND MATERIALS: First, a multifield FLASH plan was developed to meet all the dosimetric goals and optimal FLASH dose rate coverage by considering the deliverable minimum monitor unit constraint. Then, a GA method was implemented into the in-house treatment platform to maximize the dose rate by exploring the best spot delivery sequence. A phantom study was performed to evaluate the effectiveness of the dose rate optimization. Then, 10 consecutive plans for patients with lung cancer previously treated using PBS intensity-modulated proton therapy were optimized using 45 GyRBE in 3 fractions for both transmission and Bragg peak FLASH radiation therapy for further validation. The spot delivery sequence of each treatment field was optimized using this GA. The ultrahigh-dose-rate-volume histogram and dose rate coverage V40GyRBE/s were investigated to assess the efficacy of dose rate optimization quantitatively. RESULTS: Using a relatively low monitor unit/spot of 150, corresponding to a nozzle beam current of 65 nA, the FLASH dose rate ratio V40GyRBE/s of the OAR contour of the core was increased from 0% to ∼60% in the phantom study. In the patients with lung cancer, the ultrahigh-dose-rate coverage V40GyRBE/s was improved from 15.2%, 15.5%, 17.6%, and 16.0% before the delivery sequence optimization to 31.8%, 43.5%, 47.6%, and 30.5% after delivery sequence optimization in the lungs-GTV (gross tumor volume), spinal cord, esophagus, and heart (for all, P < .001). When the beam current increased to 130 nA, V40GyRBE/s was improved from 45.1%, 47.1%, 51.2%, and 51.4% to 65.3%, 83.5%, 88.1%, and 69.4% (P < .05). The averaged V40GyRBE/s for the target and OARs increased from 12.9% to 41.6% and 46.3% to 77.5% for 65 and 130 nA, respectively, showing significant improvements based on a clinical proton system. After optimizing the dose rate for the Bragg peak FLASH technique with a beam current of 340 nA, the V40GyRBE/s values for the lung GTV, spinal cord, esophagus, and heart were increased by 8.9%, 15.8%, 22%, and 20.8%, respectively. CONCLUSIONS: An optimal plan quality can be maintained as the spot delivery sequence optimization is a separate independent process after the plan optimization. Both the phantom and patient results demonstrated that novel spot delivery sequence optimization can effectively improve the ultrahigh-dose-rate coverage for critical OARs, which can potentially be applied in clinical practice for better OARs-sparing efficacy.

Validation and reproducibility of in vivo dosimetry for pencil beam scanned FLASH proton treatment in mice.

PURPOSE: To investigate quality assurance (QA) techniques for in vivo dosimetry and establish its routine uses for proton FLASH small animal experiments with a saturated monitor chamber. METHODS AND MATERIALS: 227 mice were irradiated at FLASH or conventional (CONV) dose rates with a 250 MeV FLASH-capable proton beamline using pencil beam scanning to characterize the proton FLASH effect on abdominal irradiation and examining various endpoints. A 2D strip ionization chamber array (SICA) detector was positioned upstream of collimation and used for in vivo dose monitoring during irradiation. Before each irradiation series, SICA signal was correlated with the isocenter dose at each delivered dose rate. Dose, dose rate, and 2D dose distribution for each mouse were monitored with the SICA detector. RESULTS: Calibration curves between the upstream SICA detector signal and the delivered dose at isocenter had good linearity with minimal R2 values of 0.991 (FLASH) and 0.985 (CONV), and slopes were consistent for each modality. After reassigning mice, standard deviations were less than 1.85 % (FLASH) and 0.83 % (CONV) for all dose levels, with no individual subject dose falling outside a ± 3.6 % range of the designated dose. FLASH fields had a field-averaged dose rate of 79.0 ± 0.8 Gy/s and mean local average dose rate of 160.6 ± 3.0 Gy/s. In vivo dosimetry allowed for the accurate detection of variation between the delivered and the planned dose. CONCLUSION: In vivo dosimetry benefits FLASH experiments through enabling real-time dose and dose rate monitoring allowing mouse cohort regrouping when beam fluctuation causes delivered dose to vary from planned dose.

Differences in Patterns of Care and Referral Between Proton and Photon Therapy.

Purpose: To report demographic and clinical characteristics of patients who were more likely to receive proton beam therapy (PBT) than photon therapy from facilities with access to proton centers. Materials and Methods: We utilized the national cancer database to identify the facilities with access to PBT between 2004 and 2015 and compared the relative usage of photons and PBT for demographic and clinical scenarios in breast, prostate, and nonsmall cell cancer. Results: In total, 231 facilities with access to proton centers accounted for 168 323 breast, 39 975 lung, and 77 297 prostate cancer patients treated definitively. Proton beam therapy was used in 0.5%, 1.5%, and 8.9% of breast, lung, and prostate cases. Proton beam therapy was correlated with a farther distance traveled and longer start time from diagnosis for each site (P < .05).For breast, demographic correlates of PBT were treatment in the west coast (odds ratio [OR] = 4.81), age <60 (OR = 1.25), white race (OR = 1.94), and metropolitan area (OR = 1.58). Left-sided cancers (OR = 1.28), N2 (OR = 1.71), non-ER+/PR+/Her2Neu- cancers (OR = 1.24), accelerated partial breast irradiation (OR = 1.98), and hypofractionation (OR = 2.35) were predictors of PBT.For nonsmall cell cancer, demographic correlates of PBT were treatment in the south (OR = 2.6), metropolitan area (OR = 1.72), and Medicare insurance (OR = 1.64). Higher comorbid score (OR = 1.36), later year treated (OR = 3.16), and hypofractionation (not SBRT) (OR = 3.7) were predictors of PBT.For prostate, correlates of PBT were treatment in the west coast (OR = 2.48), age <70 (OR = 1.19), white race (OR = 1.41), metropolitan area (OR = 1.25), higher income/education (OR = 1.25), and treatment at an academic center (OR = 33.94). Lower comorbidity score (OR = 1.42), later year treated (OR = 1.37), low-risk disease (OR = 1.45), definitive compared to postoperative (OR = 6.10), and conventional fractionation (OR = 1.64) were predictors of PBT. Conclusion: Even for facilities with established referrals to proton centers, PBT utilization was low; socioeconomic status was potentially a factor. Proton beam therapy was more often used with left-sided breast and low-risk prostate cancers, without a clear clinical pattern in lung cancer.

PTCOG Gastrointestinal Subcommittee Lower Gastrointestinal Tract Malignancies Consensus Statement.

Purpose: Radiotherapy delivery in the definitive management of lower gastrointestinal (LGI) tract malignancies is associated with substantial risk of acute and late gastrointestinal (GI), genitourinary, dermatologic, and hematologic toxicities. Advanced radiation therapy techniques such as proton beam therapy (PBT) offer optimal dosimetric sparing of critical organs at risk, achieving a more favorable therapeutic ratio compared with photon therapy. Materials and Methods: The international Particle Therapy Cooperative Group GI Subcommittee conducted a systematic literature review, from which consensus recommendations were developed on the application of PBT for LGI malignancies. Results: Eleven recommendations on clinical indications for which PBT should be considered are presented with supporting literature, and each recommendation was assessed for level of evidence and strength of recommendation. Detailed technical guidelines pertaining to simulation, treatment planning and delivery, and image guidance are also provided. Conclusion: PBT may be of significant value in select patients with LGI malignancies. Additional clinical data are needed to further elucidate the potential benefits of PBT for patients with anal cancer and rectal cancer.

Prospective evaluation of patient-reported outcomes of invisible ink tattoos for the delivery of external beam radiation therapy: the PREFER trial.

Introduction: Invisible ink tattoos (IITs) avoid cosmetic permanence of visible ink tattoos (VITs) while serving as more reliable landmarks for radiation setup than tattooless setups. This trial evaluated patient-reported preference and feasibility of IIT implementation. Methods and materials: In an IRB-approved, single institution, prospective trial, patients receiving proton therapy underwent IIT-based treatment setup. A survey tool assessed patient preference on tattoos using a Likert scale. Matched patients treated using our institutional standard tattooless setup were identified; treatment times and image guidance requirements were evaluated between tattooless and IIT-based alignment approaches. Distribution differences were estimated using Wilcoxon rank-sum tests or Chi-square tests. Results: Of 94 eligible patients enrolled, median age was 58 years, and 58.5% were female. Most common treatment sites were breast (18.1%), lung (17.0%) and pelvic (14.9%). Patients preferred to receive IITs versus VITs (79.8% pre-treatment and 75.5% post-treatment, respectively). Patients were willing to travel farther from home to avoid VITs versus IITs (p<0.01). Females were willing to travel (45.5% vs. 23.1%; p=0.04) and pay additional money to avoid VITs (34.5% vs. 5.1%; p<0.01). Per-fraction average +treatment time and time from on table/in room to first beam were shorter with IIT-based vs. tattooless setup (12.3min vs. 14.1min; p=0.04 and 24.1min vs. 26.2min; p=0.02, respectively). Discussion: In the largest prospective trial on IIT-based radiotherapy setup to date, we found that patients prefer IITs to VITs. Additionally, IIT-based alignment is an effective and efficient strategy in comparison with tattooless setup. Standard incorporation of IITs for patient setup should be strongly considered.

Reirradiation With Proton Therapy for Recurrent Malignancies of the Esophagus and Gastroesophageal Junction: Results of the Proton Collaborative Group Multi-Institutional Prospective Registry Trial.

Purpose: Treatment options for recurrent esophageal cancer (EC) previously treated with radiation therapy (RT) are limited. Reirradiation (reRT) with proton beam therapy (PBT) can offer lower toxicities by limiting doses to surrounding tissues. In this study, we present the first multi-institutional series reporting on toxicities and outcomes after reRT for locoregionally recurrent EC with PBT. Methods and Materials: Analysis of the prospective, multicenter, Proton Collaborative Group registry of patients with recurrent EC who had previously received photon-based RT and underwent PBT reRT was performed. Patient/tumor characteristics, treatment details, outcomes, and toxicities were collected. Local control (LC), distant metastasis-free survival (DMFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Event time was determined from reRT start. Results: Between 2012 and 2020, 31 patients received reRT via uniform scanning/passive scattering (61.3%) or pencil beam scanning (38.7%) PBT at 7 institutions. Median prior RT, PBT reRT, and cumulative doses were 50.4 Gy (range, 37.5-110.4), 48.6 Gy (relative biological effectiveness) (25.2-72.1), and 99.9 Gy (79.1-182.5), respectively. Of these patients, 12.9% had 2 prior RT courses, and 67.7% received PBT with concurrent chemotherapy. Median follow-up was 7.2 months (0.9-64.7). Post-PBT, there were 16.7% locoregional only, 11.1% distant only, and 16.7% locoregional and distant recurrences. Six-month LC, DMFS, and OS were 80.5%, 83.4%, and 69.1%, respectively. One-year LC, DMFS, and OS were 67.1%, 83.4%, and 27%, respectively. Acute grade ≥3 toxicities occurred in 23% of patients, with 1 acute grade 5 toxicity secondary to esophageal hemorrhage, unclear if related to reRT or disease progression. No grade ≥3 late toxicities were reported. Conclusions: In the largest report to date of PBT for reRT in patients with recurrent EC, we observed acceptable acute toxicities and encouraging rates of disease control. However, these findings are limited by the poor prognoses of these patients, who are at high risk of mortality. Further research is needed to better assess the long-term benefits and toxicities of PBT in this specific patient population.

Evaluation of force pain thresholds to ensure collision safety in worker-robot collaborative operations.

With the growing demand for robots in the industrial field, robot-related technologies with various functions have been introduced. One notable development is the implementation of robots that operate in collaboration with human workers to share tasks, without the need of any physical barriers such as safety fences. The realization of such collaborative operations in practice necessitates the assurance of safety if humans and robots collide. Thus, it is important to establish criteria for such collision scenarios to ensure robot safety and prevent injuries. Collision safety must be ensured in both pinching (quasi-static contact) and impact (transient contact) situations. To this end, we measured the force pain thresholds associated with impacts and evaluated the biomechanical limitations. This measurements were obtained through clinical trials involving physical collisions between human subjects and a device designed for generating impacts, and the force pain thresholds associated with transient collisions between humans and robots were analyzed. Specifically, the force pain threshold was measured at two different locations on the bodies of 37 adults aged 19-32 years, using two impactors with different shapes. The force pain threshold was compared with the results of other relevant studies. The results can help identify biomechanical limitations in a precise and reliable manner to ensure the safety of robots in collaborative applications.

Total Synthesis and Cytotoxicity Evaluation of Pareitropone and Analogues.

A concise synthesis of pareitropone by oxidative cyclization of a phenolic nitronate is delineated. The use of TMSOTf as an additive to promote the facile formation of a strained norcaradiene intermediate provides convenient access to highly condensed multicyclic tropones in high yields. This synthesis is modular, efficient, and scalable, highlighting the synthetic utility of radical anion coupling reactions in annulation reactions. This work is discussed in the context of total syntheses of the tropoloisoquinoline alkaloids. Also included are the preparation of several congeners and a brief description of their biological activities.

Diagnosis of osteochondral lesions of the talus on Dual-layer spectral detector CT arthrography: clinical feasibility of virtual noncontrast images.

AIM: To compare the image quality of virtual noncontrast (VNC) and true noncontrast (TNC) CT images and to evaluate the clinical feasibility of VNC CT images for assessing osteochondral lesions of the talus (OLTs). MATERIALS AND METHODS: Forty-five OLT patients who underwent ankle CT arthrography (CTA) using dual-layer spectral detector CT were enrolled. Reconstruction of VNC and three-dimensional volume rendering images was performed. Afterward, image noise, the signal-to-noise ratio (SNR), and the contrast-to-noise ratio (CNR) were measured. For the subjective evaluation, two board-certified musculoskeletal radiologists [R2-1] assessed spatial resolution, overall image quality, and lesion conspicuity. The accuracy rate for OLT grading was determined in 23 patients who underwent arthroscopic surgery. RESULTS: While VNC images showed significantly less noise than TNC images, TNC images showed better SNRs and CNRs (p<.01). In the subjective analysis, TNC images showed better overall image quality (p<.001). For the 3D volume rendering images, VNC images scored significantly higher for lesion conspicuity (p<.001). The accuracy rates of CTA and CTA with VNC images for OLT grading were 79.2% and 83.3%, respectively. Regarding confidence level, when CTA and VNC images were evaluated together, the confidence level was significantly higher than that when only CTA images were evaluated (p<.001). CONCLUSION: VNC imaging can provide better confidence level of OLT grading and evaluation of the integrity of the subchondral bone plate when combined with conventional CTA without additional radiation dose to the patient. In addition, VNC images-based 3D volume rendering reconstruction would be helpful for preoperative planning in OLT patients.

Comparative Evaluation of Proton Therapy and Volumetric Modulated Arc Therapy for Brachial Plexus Sparing in the Comprehensive Reirradiation of High-Risk Recurrent Breast Cancer.

Purpose: Recurrent or new primary breast cancer requiring comprehensive regional nodal irradiation after prior radiation therapy (RT) to the supraclavicular area and upper axilla is challenging due to cumulative brachial plexus (BP) dose tolerance. We assessed BP dose sparing achieved with pencil beam scanning proton therapy (PBS-PT) and photon volumetric modulated arc therapy (VMAT). Methods and Materials: In an institutional review board-approved planning study, all patients with ipsilateral recurrent breast cancer treated with PBS-PT re-RT (PBT1) with at least partial BP overlap from prior photon RT were identified. Comparative VMAT plans (XRT1) using matched BP dose constraints were developed. A second pair of proton (PBT2) and VMAT (XRT2) plans using standardized target volumes were created, applying uniform prescription dose of 50.4 per 1.8 Gy and a maximum BP constraint <25 Gy. Incidence of brachial plexopathy was also assessed. Results: Ten consecutive patients were identified. Median time between RT courses was 48 months (15-276). Median first, second, and cumulative RT doses were 50.4 Gy (range, 42.6-60.0), 50.4 Gy relative biologic effectiveness (RBE) (45.0-64.4), and 102.4 Gy (RBE) (95.0-120.0), respectively. Median follow-up was 15 months (5-33) and 18 months for living patients (11-33) Mean BP max was 37.5 Gy (RBE) for PBT1 and 36.9 Gy for XRT1. Target volume coverage of V85% (volume receiving 85% of prescription dose), V90%, and V95% were numerically lower for XRT1 versus PBT1. Similarly, axilla I-III and supraclavicular area coverage were significantly higher for PBT2 than XRT2 at dose levels of V55%, V65%, V75%, V85%, and V95%. Only axilla I V55% did not reach significance (P = .06) favoring PBS-PT. Two patients with high cumulative BPmax (95.2 Gy [RBE], 101.6 Gy [RBE]) developed brachial plexopathy symptoms with ulnar nerve distribution neuropathy without pain or weakness (1 of 2 had symptom resolution after 6 months without intervention). Conclusions: PBS-PT improved BP sparing and target volume coverage versus VMAT. For patients requiring comprehensive re-RT for high-risk, nonmetastatic breast cancer recurrence with BP overlap and reasonable expectation for prolonged life expectancy, PBT may be the preferred treatment modality.

Association between waist circumference change after smoking cessation and incidence of hypertension in Korean adults.

OBJECTIVES: This study investigates the association between smoking cessation and hypertension incidence, as well as the association between waist circumference change after smoking cessation and hypertension incidence. STUDY DESIGN: This was a nationwide population-based cohort study. METHODS: We used the Korean Health Screening Cohort data and included 158,505 participants who had undergone two or more health examinations between 2008 and 2011, with follow-ups throughout 2019. Smoking cessation and waist changes were captured based on difference between first and follow-up screening dates. Hazard ratio (HR) and 95% confidence interval (CI) for hypertension risk were estimated using multivariable Cox proportional hazard regression models. RESULTS: There were 31,270 cases of hypertension during a median follow-up of 8.50 years. After adjusting for potential confounding factors, HR for hypertension were 1.01 (95% CI: 0.97-1.05), 0.91 (95% CI: 0.87-0.95), and 0.88 (95% CI: 0.85-0.91) for recent quitters, long-term quitters, and non-smokers, respectively, compared with current smokers. HR for hypertension, compared with current smokers, were 0.89 (95% CI: 0.84-0.94), 0.91 (95% CI: 0.85-0.97), and 0.99 (95% CI: 0.91-1.08) for long-term quitters with no waist gain, long-term quitters with waist gain of 0.1-5.0 cm, and long-term quitters with waist gain of ≥5.0 cm, respectively. CONCLUSIONS: Long-term smoking cessation was significantly associated with decreased risk of hypertension, and long-term smoking cessation with no waist gain or less than 5.0 cm of waist gain was significantly associated with decreased risk of hypertension. However, more than 5.0 cm of waist gain can attenuate the effect of long-term smoking cessation on lowering the risk of hypertension.

Prognostic implications of HER2NEU-low in metastatic breast cancer.

INTRODUCTION: We explored characteristics and clinical outcomes of HER2-negative and HER2-low metastatic breast cancers using real-world data. METHODS: We queried the National Cancer Database to identify MBC patients that were HER2-low or HER2-negative per immunohistochemical staining. A binomial regression analysis identified demographic and clinical correlates of each subtype. A Cox multivariable regression analysis (MVA) and propensity-match analysis were performed to identify correlates of survival. RESULTS: Excluding missing data, 24,636 MBC patients diagnosed between 2008 and 2015 were identified; 27.9% were HER2-negative and 72.1% were HER2-low. There were no relevant demographic differences between the groups. HER2-low tumors were half as likely to have concomitant hormone receptor-positive status (p < 0.01). The 3-year survival rate among hormone receptor-negative patients was 33.8% for HER2-low and 32.2% for HER2-negative (p < 0.05), and 60.9% and 55.6% in HER2-low and HER2-negative cases among hormone receptor-positive patients (p < 0.05), respectively. HER2-low cases were associated with better survival on MVA (HR =0.95, 95% CI 0.91-0.99) and remained superior with propensity-matching (HR = 0.92, 95% CI 0.89-0.96). In a subset analysis isolated to hormone receptor-positive cases, HER2-low remained correlated with improved survival (HR = 0.93, 95% CI 0.89-0.98) with propensity-matched MVA. Correlates of worse survival include older age as a continuous variable (HR = 1.02, 95% CI 1.02-1.02) and Black race (HR = 1.26, 95% CI 1.20-1.32) [all p < 0.01]. CONCLUSIONS: In the largest such analysis performed to date, our study demonstrates a small but statistically significant association with improved survival for HER2-low tumors compared to HER2-negative tumors in MBC.

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.

Effects of hip joint kinematics on the effective pelvis stiffness and hip impact force during simulated sideways falls.

Improved understanding is required on how hip fracture risk is influenced by landing configuration. We examined how hip impact dynamics was affected by hip joint kinematics during simulated sideways falls. Twelve young adults (7 males, 5 females) of mean age 23.5 (SD = 1.5) years, participated in pelvis release experiments. Trials were acquired with the hip flexed 15° and 30° for each of three hip rotations: +15° ("external rotation"), 0°, and -15° ("internal rotation"). During falls, force-deformation data of the pelvis were recorded. Outcome variables included the peak hip impact force (Fexperimental) and effective stiffness of the pelvis (k1st, ksecant, and kms) determined with different methods suggested in literature, and predicted hip impact force during a fall from standing height (F1st, Fsecant and Fms). The two-way repeated-measures ANOVA was used to test whether these variables were associated with hip joint angles. The Fexperimental, ksecant and Fsecant were associated with hip rotation (F = 5.587, p = 0.005; F = 9.278, p < 0.0005; F = 5.778, p = 0.004, respectively), and 15 %, 31 % and 17 % smaller in 15° external than internal rotation (848 versus 998 N; 24.6 versus 35.6 kN/m; 2,637 versus 3,170 N, respectively). However, none of the outcome variables were associated with hip flexion (p > 0.05). Furthermore, there were no interactions between the hip rotation and flexion for all outcome variables (p > 0.05). Our results provide insights on hip impact dynamics, which may help improve a hip model to assess hip fracture risk during a fall.

Accelerated Partial Breast Irradiation for HER2-Positive Early-Stage Breast Cancer.

PURPOSE: HER2-positive (HER2+) breast cancer historically exhibited the most adverse local outcomes and, consequently, has had limited representation among trials of partial breast irradiation (PBI). We hypothesized that with contemporary HER2-targeted agents, patients may now exhibit excellent disease control outcomes after adjuvant PBI. METHODS AND MATERIALS: Using a prospectively maintained institutional database, we identified patients with HER2+ breast cancer treated with breast conserving surgery (BCS) and PBI from 2000 to 2022. Salient clinicopathologic and treatment parameters were collected. All patients received external beam PBI to 40 Gy in 10 daily fractions. Cumulative incidence functions were calculated to estimate the incidence of local recurrence (LR) with the competing risk of death. RESULTS: We identified 1248 patients who underwent PBI at our institution, of whom the study cohort comprised 52 (4%) with HER2+ breast cancer (median age, 64 years; range, 44-87). Nearly all had T1 tumors (98%; median size, 12 mm [range, 1-21 mm]). Most had estrogen receptor positive disease (88%), and all patients had negative surgical margins. Nearly all underwent sentinel node biopsy (94%), with the remainder undergoing no surgical axillary evaluation. Forty-two (81%) received chemotherapy; 40 (77%), hormone therapy; and 42 (81%), HER2-directed therapy, most commonly trastuzumab. At 143.8 person-years of follow-up (range, 7-226 months for each patient), we observed 2 LR events at 14 and 26 months, respectively, yielding a 2-year LR rate of 3.8%. No regional or distant recurrences were observed, nor were any breast-specific mortality events. Two deaths were observed, both without evidence of disease. CONCLUSIONS: Among a cohort of patients with HER2+ early-stage breast cancer managed with BCS and PBI, we observed a 2-year LR rate of 3.8%, with no regional or distant recurrences and excellent overall survival. These findings require confirmation with longer follow-up among larger cohorts but appear consistent with the excellent results of contemporary randomized trials of PBI unselected for HER2 status.

A Potent Kalihinol Analogue Disrupts Apicoplast Function and Vesicular Trafficking in P. falciparum Malaria.

Here we report the discovery of MED6-189, a new analogue of the kalihinol family of isocyanoterpene (ICT) natural products. MED6-189 is effective against drug-sensitive and -resistant P. falciparum strains blocking both intraerythrocytic asexual replication and sexual differentiation. This compound was also effective against P. knowlesi and P. cynomolgi. In vivo efficacy studies using a humanized mouse model of malaria confirms strong efficacy of the compound in animals with no apparent hemolytic activity or apparent toxicity. Complementary chemical biology, molecular biology, genomics and cell biological analyses revealed that MED6-189 primarily targets the parasite apicoplast and acts by inhibiting lipid biogenesis and cellular trafficking. Genetic analyses in P. falciparum revealed that a mutation in PfSec13, which encodes a component of the parasite secretory machinery, reduced susceptibility to the drug. The high potency of MED6-189 in vitro and in vivo, its broad range of efficacy, excellent therapeutic profile, and unique mode of action make it an excellent addition to the antimalarial drug pipeline.

Health and job-related factors associated with work ability in older working populations of Korea.

BACKGROUND: Knowledge about determinants of workability is crucial for designing interventions to increase the participation of older employees in the workforce and maintain or increase their productivity levels at work. AIMS: This study explored the impact of health conditions and job characteristics on poor work ability. METHODS: This study used data from the Korean Longitudinal Study of Aging (KLoSA) from 2014 to 2020, which is a nationally representative population-based panel study of Korean citizens aged ≥45 years. The KLoSA survey assessed subjective work ability using work ability score. The participants were asked if they had been diagnosed with any underlying diseases by a physician. The job characteristics were assessed in terms of working conditions and satisfaction. Generalized estimating equations were used to calculate the odds ratios (ORs) and 95% confidence intervals for workers' health-related variables and job characteristics associated with poor work ability. RESULTS: The results showed that workers' health-related factors were associated with poor work ability; poor vision (OR = 1.52) and bad hearing ability (OR = 2.37); low gripping strength (OR = 2.29); poor self-rated health (OR = 3.77) and various diseases such as hypertension, diabetes, cancer, chronic lung disease, liver disease, heart disease, cerebrovascular disease, mental illness, arthritis, prostate disease, gastrointestinal disease and disc disease. Additionally, high physical work demands (OR = 1.51) and low job satisfaction (OR = 4.23) were highly correlated with poor work ability. CONCLUSIONS: The findings addressing poor work abilities caused by individuals' health- and job-related factors can help prioritize worker health management and the development of more effective human capital investment strategies at the workplace.