Nivolumab With or Without Ipilimumab Combined with Stereotactic Body Radiotherapy in patients with Metastatic Biliary Tract Cancer: A Randomized Phase 2 Study.

PURPOSE: Evaluate the clinical benefits of nivolumab with/without ipilimumab combined with stereotactic body radiotherapy (SBRT) in patients with pretreated metastatic biliary tract cancer (mBTC). EXPERIMENTAL DESIGN: The study was a phase 2 randomized trial with Simon's optimal 2-stage design requiring 36 evaluable patients per group after second stage. Sixty-one patients were included from September 2018 to January 2022 and randomized (1:1) to receive SBRT (15 Gy × 1 on day one to a primary or metastatic lesion) and nivolumab (3 mg/kg intravenously on day one and every 2 weeks) with/without ipilimumab (1 mg/kg intravenously on day one and every 6 weeks). Primary endpoint was clinical benefit rate (CBR), defined as the percentage of patients with complete response, partial response or stable disease. Decision to continue accrual into the second stage depended on CBR from first stage. RESULTS: Forty-two patients received SBRT/nivolumab/ipilimumab with a CBR of 31.0% (95% CI, 17.6-47.1). Five patients (11.9%) achieved partial response with median duration of 4.4 months (range, 1.1-21.5). Nineteen patients received SBRT/nivolumab. This group was closed after the initial stage based on a CBR of 10.5% (95% CI, 1.3-33.1). Adverse events were graded with National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Grade ≥3 treatment-related adverse events occurred in 13 (31%) and 3 (16%) patients in the SBRT/nivolumab/ipilimumab and SBRT/nivolumab groups, respectively. One patient died from immune-related hepatitis in the SBRT/nivolumab/ipilimumab group. CONCLUSION: Combining SBRT, nivolumab and ipilimumab is well tolerated, feasible, and shows response in a subgroup of patients with mBTC.

Diseases Involving the Lung Peribronchovascular Region: a CT-Pathologic Classification.

TOPIC IMPORTANCE: Chest computed tomography (CT) holds a major role in the diagnosis of lung disease, many of which affect the peri-bronchovascular (PBV) region. Identification and categorization of PBV abnormalities on CT can assist in formulating a differential diagnosis and directing further diagnostic evaluation. REVIEW FINDINGS: The PBV region of the lung encompasses the pulmonary arteries, airways, and lung interstitium. Understanding disease processes associated with structures of the PBV region and their appearances on CT aids in prompt diagnosis. This manuscript reviews current knowledge in anatomy and pathology of the lung interstitium composed of intercommunicating pre-lymphatic spaces, lymphatics, collagen bundles, lymph nodes, bronchial arteries; diffuse lung diseases that present in a PBV distribution; and an approach to classifying diseases according to patterns of imaging presentations. Lung PBV diseases can appear on CT as diffuse thickening, fibrosis, masses/mass-like consolidation, ground glass or air-space consolidation, and cysts, acknowledging some disease may have multiple presentations.

Metformin for endometrial hyperplasia.

BACKGROUND: Endometrial cancer is one of the most common gynaecological cancers in the world. Rates of endometrial cancer are rising, in part because of rising obesity rates. Endometrial hyperplasia is a precancerous condition in women that can lead to endometrial cancer if left untreated. Endometrial hyperplasia occurs more commonly than endometrial cancer. Progesterone tablets that are currently used to treat women with endometrial hyperplasia are associated with adverse effects in up to 84% of women. A levonorgestrel intrauterine device may improve compliance, but it is invasive, is not acceptable to all women, and is associated with irregular vaginal bleeding in 82% of cases. Therefore, an alternative treatment for women with endometrial hyperplasia is needed. Metformin, a drug that is often used to treat people with diabetes, has been shown, in some human studies, to reverse endometrial hyperplasia. However, the effectiveness and safety of metformin for treatment of endometrial hyperplasia remain uncertain. This is an update of a review first published in 2017. OBJECTIVES: To determine the effectiveness and safety of metformin in treating women with endometrial hyperplasia. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Specialised Register, CENTRAL, MEDLINE, PubMed, Embase, Google Scholar, OpenGrey, LILACS, and two trials registers from inception to 5 September 2022. We searched the bibliographies of all relevant studies, and contacted experts in the field for any additional trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and cross-over trials comparing metformin (used alone or in combination with other medical therapies) versus placebo, no treatment, any conventional medical treatment, or any other active intervention for women with histologically confirmed endometrial hyperplasia of any type. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility, extracted data from included studies, assessed the risk of bias in the included studies, and assessed the certainty of the evidence for each outcome. We resolved disagreements by discussion or by deferring to a third review author. When study details were missing, review authors contacted the study authors. The primary outcome of this review was regression of endometrial hyperplasia histology (with or without atypia) towards normal histology. MAIN RESULTS: We included seven RCTs, in which a total of 387 women took part. In the comparison, Metformin plus megestrol versus megestrol alone, we rated the certainty of the evidence as low for the outcome, regression of endometrial hyperplasia. We rated the quality of the evidence as very low for the rest of the outcomes, in all three comparisons. Although there was a low risk of selection bias, there was a high risk of bias in the blinding of personnel and outcome assessment (performance bias and detection bias) in many studies. This update identified four new RCTs and six ongoing RCTs. Metformin versus megestrol We are uncertain whether metformin increases the regression of endometrial hyperplasia towards normal histology over megestrol (odds ratio (OR) 4.89, 95% confidence interval (CI) 1.56 to 15.32; P = 0.006; 2 RCTs, 83 participants; I² = 7%; very low-certainty evidence). This evidence suggests that if the rate of regression with megestrol is 61%, the rate of regression with metformin would be between 71% and 96%. It is unresolved whether metformin results in different rates of abnormal uterine bleeding or hysterectomy compared to megestrol. No study in this comparison reported progression of hyperplasia to endometrial cancer, recurrence of endometrial hyperplasia, health-related quality of life, or adverse effects during treatment. Metformin plus megestrol versus megestrol monotherapy The combination of metformin and megestrol may enhance the regression of endometrial hyperplasia towards normal histology more than megestrol alone (OR 3.27, 95% CI 1.65 to 6.51; P = 0.0007; 4 RCTs, 258 participants; I² = 0%, low-certainty evidence). This suggests that if the rate of regression with megestrol monotherapy is 54%, the rate of regression with the addition of metformin would be between 66% and 84%. In one study, 3/8 (37.5%) of participants who took metformin had nausea that settled without further treatment. It is unresolved whether the combination of metformin and megestrol results in different rates of recurrence of endometrial hyperplasia, progression of endometrial hyperplasia to endometrial cancer, or hysterectomy compared to megestrol monotherapy. No study in this comparison reported abnormal uterine bleeding, or health-related quality of life. Metformin plus levonorgestrel (intrauterine system) versus levonorgestrel (intrauterine system) monotherapy We are uncertain whether there is a difference between groups in the regression of endometrial hyperplasia towards normal histology (OR 0.29, 95% CI 0.01 to 7.56; 1 RCT, 46 participants; very low-certainty evidence). This evidence suggests that if the rate of regression with levonorgestrel monotherapy is 96%, the rate of regression with the addition of metformin would be between 73% and 100%. It is unresolved whether the combination of metformin and levonorgestrel results in different rates of abnormal uterine bleeding, hysterectomy, or the development of adverse effects during treatment compared to levonorgestrel monotherapy. No study in this comparison reported recurrence of endometrial hyperplasia, progression of hyperplasia to endometrial cancer, or health-related quality of life. AUTHORS' CONCLUSIONS: Review authors found insufficient evidence to either support or refute the use of metformin, specifically megestrol acetate, given alone or in combination with standard therapy, for the treatment of women with endometrial hyperplasia. Robustly designed and adequately powered randomised controlled trials, yielding long-term outcome data are still needed to address this clinical question.

A mixed-methods study to investigate feasibility and acceptability of an early warning score for preterm infants in neonatal units in Kenya: results of the NEWS-K study : Neonatal early warning scores in Kenya.

Preterm birth (< 37 weeks gestation) complications are the leading cause of neonatal mortality. Early-warning scores (EWS) are charts where vital signs (e.g., temperature, heart rate, respiratory rate) are recorded, triggering action. To evaluate whether a neonatal EWS improves clinical outcomes in low-middle income countries, a randomised trial is needed. Determining whether the use of a neonatal EWS is feasible and acceptable in newborn units, is a prerequisite to conducting a trial. We implemented a neonatal EWS in three newborn units in Kenya. Staff were asked to record infants' vital signs on the EWS during the study, triggering additional interventions as per existing local guidelines. No other aspects of care were altered. Feasibility criteria were pre-specified. We also interviewed health professionals (n = 28) and parents/family members (n = 42) to hear their opinions of the EWS. Data were collected on 465 preterm and/or low birthweight (< 2.5 kg) infants. In addition to qualitative study participants, 45 health professionals in participating hospitals also completed an online survey to share their views on the EWS. 94% of infants had the EWS completed at least once during their newborn unit admission. EWS completion was highest on the day of admission (93%). Completion rates were similar across shifts. 15% of vital signs triggered escalation to a more senior member of staff. Health professionals reported liking the EWS, though recognised the biggest barrier to implementation was poor staffing. Newborn unit infant to staff ratios varied between 10 and 53 staff per 1 infant, depending upon time of shift and staff type. A randomised trial of neonatal EWS in Kenya is possible and acceptable, though adaptations are required to the form before implementation.

Chest Intensive Care Unit Imaging: Pearls and Pitfalls.

Imaging plays a major role in the care of the intensive care unit (ICU) patients. An understanding of the monitoring devices is essential for the interpretation of imaging studies. An awareness of their expected locations aids in identifying complications in a timely manner. This review describes the imaging of ICU monitoring and support catheters, tubes, and pulmonary and cardiac devices, some more commonly encountered and others that have been introduced into clinical patient care more recently. Special focus will be placed on chest radiography and potential pitfalls encountered.

Radiation Therapy for Lung Cancer: Imaging Appearances and Pitfalls.

Radiation therapy is part of a multimodality treatment approach to lung cancer. The radiologist must be aware of both the expected and the unexpected imaging findings of the post-radiation therapy patient, including the time course for development of post- radiation therapy pneumonitis and fibrosis. In this review, a brief discussion of radiation therapy techniques and indications is presented, followed by an image-heavy differential diagnostic approach. The review focuses on computed tomography imaging examples to help distinguish normal postradiation pneumonitis and fibrosis from alternative complications, such as infection, local recurrence, or radiation-induced malignancy.

Long acting progestogens versus combined oral contraceptive pill for preventing recurrence of endometriosis related pain: the PRE-EMPT pragmatic, parallel group, open label, randomised controlled trial.

OBJECTIVES: To evaluate the clinical effectiveness of long acting progestogens compared with the combined oral contraceptive pill in preventing recurrence of endometriosis related pain. DESIGN: The PRE-EMPT (preventing recurrence of endometriosis) pragmatic, parallel group, open label, randomised controlled trial. SETTING: 34 UK hospitals. PARTICIPANTS: 405 women of reproductive age undergoing conservative surgery for endometriosis. INTERVENTIONS: Participants were randomised in a 1:1 ratio using a secure internet facility to a long acting progestogen (depot medroxyprogesterone acetate or levonorgestrel releasing intrauterine system) or the combined oral contraceptive pill. MAIN OUTCOME MEASURES: The primary outcome was pain measured three years after randomisation using the pain domain of the Endometriosis Health Profile 30 (EHP-30) questionnaire. Secondary outcomes (evaluated at six months, one, two, and three years) included the four core and six modular domains of the EHP-30, and treatment failure (further therapeutic surgery or second line medical treatment). RESULTS: 405 women were randomised to receive a long acting progestogen (n=205) or combined oral contraceptive pill (n=200). At three years, there was no difference in pain scores between the groups (adjusted mean difference -0.8, 95% confidence interval -5.7 to 4.2, P=0.76), which had improved by around 40% in both groups compared with preoperative values (an average of 24 and 23 points for long acting progestogen and combined oral contraceptive pill groups, respectively). Most of the other domains of the EHP-30 also showed improvement at all time points compared with preoperative scores, without evidence of any differences between groups. Women randomised to a long acting progestogen underwent fewer surgical procedures or second line treatments compared with those randomised to the combined oral contraceptive pill group (73 v 97; hazard ratio 0.67, 95% confidence interval 0.44 to 1.00). CONCLUSIONS: Postoperative prescription of a long acting progestogen or the combined oral contraceptive pill results in similar levels of improvement in endometriosis related pain at three years, with both groups showing around a 40% improvement compared with preoperative levels. While women can be reassured that both options are effective, the reduced risk of repeat surgery for endometriosis and hysterectomy might make long acting reversible progestogens preferable for some. TRIAL REGISTRATION: ISRCTN registry ISRCTN97865475.

Incidental Apical Pleuroparenchymal Scarring on Computed Tomography: Diagnostic Yield, Progression, Morphologic Features and Clinical Significance.

PURPOSE: Apical pleuroparenchymal scarring (APPS) is commonly seen on chest computed tomography (CT), though the imaging and clinical features, to the best of our knowledge, have never been studied. The purpose was to understand APPS's typical morphologic appearance and associated clinical features. PATIENTS AND METHODS: A random generator selected 1000 adult patients from all 21516 chest CTs performed at urban outpatient centers from January 1, 2016 to December 31, 2016. Patients with obscuring apical diseases were excluded to eliminate confounding factors. After exclusions, 780 patients (median age: 64 y; interquartile range: 56 to 72 y; 55% males) were included for analysis. Two radiologists evaluated the lung apices of each CT for the extent of abnormality in the axial plane (mild: <5 mm, moderate: 5 to 10 mm, severe: >10 mm), craniocaudal plane (extension halfway to the aortic arch, more than halfway, vs below the arch), the predominant pattern (nodular vs reticular and symmetry), and progression. Cohen kappa coefficient was used to assess radiologists' agreement in scoring. Ordinal logistic regression was used to determine associations of clinical and imaging variables with APPS. RESULTS: APPS was present on 65% (507/780) of chest CTs (54% mild axial; 80% mild craniocaudal). The predominant pattern was nodular and symmetric. Greater age, female sex, lower body mass index, greater height, and white race were associated with more extensive APPS. APPS was not found to be associated with lung cancer in this cohort. CONCLUSION: Classifying APPS by the extent of disease in the axial or craniocaudal planes, in addition to the predominant pattern, enabled statistically significant associations to be determined, which may aid in understanding the pathophysiology of apical scarring and potential associated risks.

Photon-counting CT in Thoracic Imaging: Early Clinical Evidence and Incorporation Into Clinical Practice.

Photon-counting CT (PCCT) is an emerging advanced CT technology that differs from conventional CT in its ability to directly convert incident x-ray photon energies into electrical signals. The detector design also permits substantial improvements in spatial resolution and radiation dose efficiency and allows for concurrent high-pitch and high-temporal-resolution multienergy imaging. This review summarizes (a) key differences in PCCT image acquisition and image reconstruction compared with conventional CT; (b) early evidence for the clinical benefit of PCCT for high-spatial-resolution diagnostic tasks in thoracic imaging, such as assessment of airway and parenchymal diseases, as well as benefits of high-pitch and multienergy scanning; (c) anticipated radiation dose reduction, depending on the diagnostic task, and increased utility for routine low-dose thoracic CT imaging; (d) adaptations for thoracic imaging in children; (e) potential for further quantitation of thoracic diseases; and (f) limitations and trade-offs. Moreover, important points for conducting and interpreting clinical studies examining the benefit of PCCT relative to conventional CT and integration of PCCT systems into multivendor, multispecialty radiology practices are discussed.

Racial and Ethnic Disparities in Patient Restraint in Emergency Departments by Police Transport Status.

Importance: Black patients are more likely than White patients to be restrained during behavioral crises in emergency departments (EDs). Although the perils of policing mental health for Black individuals are recognized, it is unclear whether or to what extent police transport mediates the association between Black race and use of physical restraint in EDs. Objective: To evaluate the degree to which police transport mediates the association between Black race and use of physical restraint in EDs. Design, Setting, and Participants: This retrospective, cross-sectional study used electronic health record data from ED visits by adults (aged ≥18 years) to 3 hospitals in the southeastern US and 10 in the northeastern US between January 1, 2015, and December 31, 2022. Data were analyzed from September 1, 2022, to May 30, 2023. Exposures: Race, ethnicity, and police transport to the hospital. Main Outcomes and Measures: The primary outcome variable was the presence of an order for restraints during an ED visit. Results: A total of 4 263 437 ED visits by 1 257 339 patients (55.5% of visits by female and 44.5% by male patients; 26.1% by patients 65 years or older) were included in the study. Black patients accounted for 27.5% of visits; Hispanic patients, 17.6%; White patients, 50.3%; and other or unknown race or ethnicity, 4.6%. In models adjusted for age, sex, site, previous behavioral or psychiatric history, and visit diagnoses, Black patients were at increased odds of experiencing restraint compared with White patients (adjusted odds ratio [AOR], 1.33 [95% CI, 1.28-1.37]). Within the mediation analysis, Black patients had higher odds of being brought to the hospital by police compared with all other patients (AOR, 1.38 [95% CI, 1.34-1.42]). Patients brought to the ED under police transport had increased odds of experiencing restraint compared with all other modes of transport (AOR, 5.51 [95% CI, 5.21-5.82]). The estimated proportion of use of restraints for Black patients mediated by police transport was 10.70% (95% CI, 9.26%-12.53%). Conclusions and Relevance: In this cross-sectional study of ED visits across 13 hospitals, police transport may have mediated the association between Black race and use of physical restraint. These findings suggest a need to further explore the mechanisms by which transport to emergency care may influence disparate restrictive interventions for patients experiencing behavioral emergencies.

Prognostic value of margin clearance in total and distal pancreatectomy specimens with pancreatic ductal adenocarcinoma in a Danish population-based nationwide study.

BACKGROUND: The prognostic role of resection margin status following total (TP) and distal (DP) pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) is insufficiently evaluated. In Denmark, pancreatic surgery, including the postoperative pathological examination of the resection specimens, is confined to four centres, all reporting to the Danish Pancreatic Cancer Database (DPCD). In this Danish population-based nationwide study on TP and DP for PDAC from 2015-2019, based on data from DPCD, we evaluated whether there is a prognostically relevant minimum margin clearance definition and whether certain margins hold independent prognostic information. METHODS: Clinical and pathological data were retrieved from DPCD and supplemented by review of pathology reports and re-microscopy, if needed. One of the study pathologists performed all re-microscopy. The prognostic significance of margin status was evaluated by dichotomisation of the TP cohort (n = 101) and the DP cohort (n = 90) into involved and uninvolved groups, using different clearance definitions (0.5 - ≥3.0 mm). RESULTS: Following TP, direct involvement of the superior mesenteric artery (SMA) margin had independent prognostic value. When using a clearance definition of ≥ 0.5 or ≥ 1.5 mm for SMA, median survival for R0 versus R1 was 19 (95% CI 14-26) versus 10 (95% CI 5-20) months (p = 0.010), and 21 (95% CI 15-30) versus 10 (95% CI 8-19) months (p = 0.011), respectively. Overall margin status was not of significant prognostic importance following neither DP nor TP. CONCLUSION: In this Danish population-based nationwide study, SMA margin involvement was a significant isolated prognostic factor following TP, whereas combined assessment of all circumferential margins did not hold statistically significant prognostic information. Following DP, resection margin status did not affect survival.

The Brazilian COVID-19 vaccination campaign: a modelling analysis of sociodemographic factors on uptake.

OBJECTIVE: Dose shortages delayed access to COVID-19 vaccination. We aim to characterise inequality in two-dose vaccination by sociodemographic group across Brazil. DESIGN: This is a cross-sectional study. SETTING: We used data retrieved from the Brazilian Ministry of Health databases published between 17 January 2021 and 6 September 2021. METHODS: We assessed geographical inequalities in full vaccination coverage and dose by age, sex, race and socioeconomic status. We developed a Campaign Optimality Index to characterise inequality in vaccination access due to premature vaccination towards younger populations before older and vulnerable populations were fully vaccinated. Generalised linear regression was used to investigate the risk of death and hospitalisation by age group, socioeconomic status and vaccination coverage. RESULTS: Vaccination coverage is higher in the wealthier South and Southeast. Men, people of colour and low-income groups were more likely to be only partially vaccinated due to missing or delaying a second dose. Vaccination started prematurely for age groups under 50 years which may have hindered uptake in older age groups. Vaccination coverage was associated with a lower risk of death, especially in older age groups (ORs 9.7 to 29.0, 95% CI 9. 4 to 29.9). Risk of hospitalisation was greater in areas with higher vaccination rates due to higher access to care and reporting. CONCLUSIONS: Vaccination inequality persists between states, age and demographic groups despite increasing uptake. The association between hospitalisation rates and vaccination is attributed to preferential delivery to areas of greater transmission and access to healthcare.

A preliminary randomized controlled trial of repetitive transcranial magnetic stimulation applied to the left dorsolateral prefrontal cortex in treatment seeking participants with cannabis use disorder.

BACKGROUND: Cannabis use disorder (CUD) is a common and consequential disorder. When applied to the dorsolateral prefrontal cortex (DLPFC), repetitive transcranial magnetic stimulation (rTMS) reduces craving across substance use disorders and may have therapeutic clinical effects when applied in serial-sessions. The present study sought to preliminarily determine whether serial-sessions of rTMS applied to the DLPFC had a therapeutic effect in CUD. METHODS: This study was a two-site, phase-2, double-blind, randomized-controlled-trial. Seventy-two treatment-seeking participants (37.5% Women, mean age 30.2±9.9SD) with ≥moderate-CUD were randomized to active or sham rTMS (Beam-F3, 10Hz, 20-total-sessions, two-sessions-per-visit, two-visits-per-week, with cannabis cues) while undergoing a three-session motivational enhancement therapy intervention. The primary outcome was the change in craving between pre- and post- treatment (Marijuana Craving Questionnaire Short-Form-MCQ-SF). Secondary outcomes included the number of weeks of abstinence and the number of days-per-week of cannabis use during 4-weeks of follow-up. RESULTS: There were no significant differences in craving between conditions. Participants who received active-rTMS reported numerically, but not significantly, more weeks of abstinence in the follow-up period than those who received sham-rTMS (15.5%-Active; 9.3%-Sham; rate ratio = 1.66 [95% CI: 0.84, 3.28]; p=0.14). Participants who received active-rTMS reported fewer days-per-week of cannabis use over the final two-weeks of the follow-up period than those receiving sham-rTMS (Active vs. Sham: -0.72; Z=-2.33, p=0.02). CONCLUSIONS: This trial suggests rTMS is safe and feasible in individuals with CUD and may have a therapeutic effect on frequency of cannabis use, though further study is needed with additional rTMS-sessions and a longer follow-up period.

Association between maternal growth in the pre-conception and early gestational period of nulliparous dairy heifers with anti-Müllerian hormone in their female offspring.

Anti-Müllerian hormone (AMH) is secreted by granulosa cells of healthy, growing follicles and is positively correlated with the ovarian reserve. Maternal and environmental factors, such as nutrition, disease, parity and endocrine disruptors, are thought to have a profound impact on ovarian reserve development during early foetal life. For genetic progress, it can be advantageous to breed dairy replacements from heifers to expedite the generation interval; however, there is some evidence that nulliparous animals produce female offspring with smaller ovarian reserves compared with multiparous animals. The objective of this prospective, observational study was to determine whether maternal growth in the pre-conception and early gestational period of nulliparous dairy heifers is associated with pre-weaning AMH concentrations in their female offspring. Our hypothesis was that excessive growth in this period would negatively impact AMH concentrations. Seasonal, pasture-based dairy heifer calves (n = 156) born from nulliparous dams, from six Irish farms, were blood sampled at an average of 60 days of age in spring 2022 and tested for AMH. Mixed-effects linear regression models were constructed with Box-Cox transformed AMH concentration as the dependent variable. The independent variables tested included maternal average daily gain (ADG) from pre-breeding examination (PBE) to pregnancy diagnosis (PD) between 30 and 60 days in calf (DIC), ADG from PBE to PD over 60 DIC and ADG between the two PDs. Calf breed and age at sampling were forced into the models, and the farm was treated as a random effect in all models. We found that as ADG increased from the pre-breeding period to their first PD visit, the AMH concentration in their offspring reduced. However, ADG explained only a small amount of the variation in AMH concentrations (marginal R2 = 0.041). In conclusion, the results of our study suggest that excessive growth prior to conception and in early gestation of nulliparous heifers could impact the ovarian reserve of their female offspring, and may imply that farmers should avoid excessive growth in the immediate pre-breeding and early gestational periods.

Creating a Roadmap to Quantitative Systems Pharmacology-Informed Rare Disease Drug Development: A Workshop Report.

One of the goals of the Accelerating Rare Disease Cures (ARC) program in the Center for Drug Evaluation and Research (CDER) at the US Food and Drug Administration (FDA) is the development and use of regulatory and scientific tools, including drug/disease modeling, dose selection, and translational medicine tools. To facilitate achieving this goal, the FDA in collaboration with the University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI) hosted a virtual public workshop on May 11, 2023, entitled "Creating a Roadmap to Quantitative Systems Pharmacology-Informed Rare Disease Drug Development." This workshop engaged scientists from pharmaceutical companies, academic institutes, and the FDA to discuss the potential utility of quantitative systems pharmacology (QSP) in rare disease drug development and identify potential challenges and solutions to facilitate its use. Here, we report the main findings from this workshop, highlight the key takeaways, and propose a roadmap to facilitate the use of QSP in rare disease drug development.

Prognostic importance of margin clearance in ampullary adenocarcinoma following pancreaticoduodenectomy in a Danish population-based nationwide study.

BACKGROUND: In this Danish nationwide population-based study, we evaluated the prognostically relevant minimum tumour-free margin width following pancreaticoduodenectomy (PD) for ampullary adenocarcinoma (AAC) and evaluated whether certain margins hold independent prognostic information. METHODS: We included 128 patients who underwent PD for AAC from 2015 to 2019. Clinical and pathological data including well-known prognostic factors were retrieved from the Danish Pancreatic Cancer Database. Missing data were obtained by review of pathology reports and re-microscopy of resection specimens. All PD specimens were examined using a standardised pathological protocol including multicolour inking, axial slicing and exact reporting of margin widths. The cohort was dichotomised into involved and uninvolved groups, using different margin clearance definitions (0.5-≥3.0 mm). RESULTS: Following PD for AAC, margin clearance of ≥1 mm was independently associated with improved chance of survival compared with <1 mm (HR: 0.30, 95 % CI: 0.14-0.64 (p = 0.002)). Posterior and anterior margin widths were narrower compared with superior mesenteric artery and vein margins. Posterior margin and anterior surface had isolated prognostic significance in multivariable analysis. CONCLUSION: Following PD for AAC, margin clearance of at least 1 mm is independently associated with improved survival. Our data further indicate that anterior surface and posterior margin hold particular prognostic value.

Racial Inequities in Police Transport for Patients to the Emergency Department: A Multicenter Analysis.

INTRODUCTION: Police involvement in patient transport to emergency medical care has increased over time, yet studies assessing racial inequities in transport are limited. This study evaluated the relationship between race and police transport to the emergency department for adult patients. METHODS: This cross-sectional study evaluated adult (aged ≥18 years) visits at 13 different emergency departments across two regional hospital systems in the Southeastern and Northeastern U.S. from 2015 to 2022. Data were extracted from electronic health records. This analysis evaluated the association between race and transport by police transport using generalized linear multivariable mixed model with a binary logistic link for presence of police transport. Data were nested by patient and adjusted for site, demographics, and diagnostic visit characteristics. RESULTS: Of 4,291,809 adult emergency department visits, 25,901 (0.6%) involved transport by police. Of the 25,901 visits in police-involved encounters, 10,513 (40.6%) patients were Black, and 9,827 (37.9%) were White. The adjusted model showed that Black patients were at higher odds of transport by police than White patients (AOR=1.64; 95% CI=1.57-1.72). Male sex, younger age (18-35 years), history of behavioral health diagnosis, and emergency department psychiatric or substance use disorders were independently associated with increased odds of police transport. CONCLUSIONS: This analysis revealed racial inequities in police-involved transport to emergency medical care, highlighting an urgent need to evaluate drivers of inequities and the ways in which police transport influences clinical outcomes.

ACR Appropriateness Criteria® Incidentally Detected Indeterminate Pulmonary Nodule.

Incidental pulmonary nodules are common. Although the majority are benign, most are indeterminate for malignancy when first encountered making their management challenging. CT remains the primary imaging modality to first characterize and follow-up incidental lung nodules. This document reviews available literature on various imaging modalities and summarizes management of indeterminate pulmonary nodules detected incidentally. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.