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The phase I/II AU-003 study in patients with treatment-naïve (TN) or relapsed/refractory (R/R) chronic lymphocytic leukaemia/small lymphocytic lymphoma demonstrated that zanubrutinib therapy results in clinically meaningful and durable responses with acceptable safety and tolerability. We report updated safety and efficacy data for 123 patients with a median follow-up of 47·2 months. Patients received zanubrutinib 160 mg twice daily (81 patients), 320 mg once daily (40), or 160 mg once daily (two). Discontinuations due to adverse events or disease progression were uncommon. The overall response rate (ORR) was 95·9% (TN, 100%; R/R, 95%) with 18·7% achieving complete response (CR). Ongoing response at 3 years was reported in 85·7%. The ORR in patients with del(17p)/tumour protein p53 mutation was 87·5% (CR 16·7%). The 2- and 3-year progression-free survival estimates were 90% (TN, 90%; R/R, 91%) and 83% (TN, 81%; R/R, 83%) respectively. The most reported Grade ≥3 adverse events were neutropenia (15·4%), pneumonia (9·8%), hypertension (8·9%) and anaemia (6·5%). The annual incidence of atrial fibrillation, major haemorrhage, Grade ≥3 neutropenia and Grade ≥3 infection decreased over time. With a median follow-up of ~4 years, responses remain clinically meaningful and durable and long-term tolerability to zanubrutinib therapy continues.

Cardiac hypertrophy is necessary for the heart to accommodate an increase in workload. Physiological, compensated hypertrophy (e.g. with exercise) is reversible and largely due to cardiomyocyte hypertrophy. Pathological hypertrophy (e.g. with hypertension) is associated with additional features including increased fibrosis and can lead to heart failure. RAF kinases (ARAF/BRAF/RAF1) integrate signals into the extracellular signal-regulated kinase 1/2 cascade, a pathway implicated in cardiac hypertrophy, and activation of BRAF in cardiomyocytes promotes compensated hypertrophy. Here, we used mice with tamoxifen-inducible cardiomyocyte-specific BRAF knockout (CM-BRAFKO) to assess the role of BRAF in hypertension-associated cardiac hypertrophy induced by angiotensin II (AngII; 0.8 mg/kg/d, 7 d) and physiological hypertrophy induced by phenylephrine (40 mg/kg/d, 7 d). Cardiac dimensions/functions were measured by echocardiography with histological assessment of cellular changes. AngII promoted cardiomyocyte hypertrophy and increased fibrosis within the myocardium (interstitial) and around the arterioles (perivascular) in male mice; cardiomyocyte hypertrophy and interstitial (but not perivascular) fibrosis were inhibited in mice with CM-BRAFKO. Phenylephrine had a limited effect on fibrosis but promoted cardiomyocyte hypertrophy and increased contractility in male mice; cardiomyocyte hypertrophy was unaffected in mice with CM-BRAFKO, but the increase in contractility was suppressed and fibrosis increased. Phenylephrine induced a modest hypertrophic response in female mice and, in contrast with the males, tamoxifen-induced loss of cardiomyocyte BRAF reduced cardiomyocyte size, had no effect on fibrosis and increased contractility. The data identify BRAF as a key signalling intermediate in both physiological and pathological hypertrophy in male mice, and highlight the need for independent assessment of gene function in females.

Alcohol use increases the risk for some cancers and can cause complications during treatment. The prevalence of alcohol use during chemotherapy has not been well documented in current literature. This pilot study aimed to examine self-reported alcohol use during chemotherapy among cancer survivors as a basis for future research and interventions.We surveyed Wisconsin cancer survivors (N=69) who participated in the ongoing population-based research study, Survey of the Health of Wisconsin (SHOW), on alcohol use during chemotherapy.Of the cancer survivors who reported receiving chemotherapy, 30.4% (N=21) reported consuming alcohol while receiving chemotherapy, and 38.1% (N=8) of those who drank reported complications. Alcohol use during chemotherapy was higher among older adults (age 65+, rate ratio [RR], 1.9; 95% CI, 0.7-4.9), men (RR, 2.7; 95% CI, 1.3-5.4), former and current smokers (former: RR, 1.6; 95% CI, 0.7-3.8, current: RR, 2.5; 95% CI, 1.1-5.8), and those with non-alcohol-related cancers (RR, 2.0; 95% CI, 0.9-4.2.).Alcohol use during chemotherapy is common and may increase the risk of complications. More research is needed to better understand this problem and to design effective interventions.

Background Taxation on sugar-sweetened beverages (SSBs) has been adopted in more than 40 countries but remained under discussion in Vietnam. This study aimed to estimate the health impacts of different SSBs tax plans currently under discussion to provide an evidence base to inform decision-making about a SSBs tax policy in Vietnam. Method & findings Five tax scenarios were modelled, representing three levels of price increase: 5%, 11% and 19–20%. Scenarios of the highest price increase were assessed across three different tax designs: ad valorem, volume-based specific tax & sugar-based specific tax. We modelled SSBs consumption in each tax scenario; how this reduction in consumption translates to a reduction in total energy intake and how this relationship in turn translates to an average change in body weight and obesity status among adults by applying the calorie-to weight conversion factor. Changes in type 2 diabetes burden were then calculated based on the change in average BMI of the modelled cohort. A Monte Carlo simulation approach was applied on the conversion factor of weight change and diabetes risk reduction for the sensitivity analysis. We found that the taxation that involved a 5% price increase gave relatively small impacts while increasing SSBs’ price up to 20% appeared to impact substantially on overweight and obesity rates (reduction of 12.7% and 12.4% respectively) saving 27 million USD for direct medical cost. The greatest reduction was observed for overweight and obesity class I. The decline in overweight and obesity rates was slightly higher for women than men. Conclusion This study supports the SSB tax policy in pursuit of public health benefits, especially where the tax increase involves around a 20% price increase. The health benefit and revenue gains were evident across all three tax designs with the specific tax based on sugar density achieving greatest effects.

Objectives Helicopter transport of trauma patients remains controversial. We examined the survival rates of patients undergoing helicopter versus ground transport to a Level 1 trauma center. Methods Retrospective analysis was performed on trauma patients treated between 2014 and 2017. Student’s t-test was used to compare air versus ground transport times. A logistic regression was then used to examine the association of transportation type on survival controlling for demographics, mechanism of injury, transport time, field intubation, and injury severity. Results Of 3967 patients identified, 69.6% (2762) were male, and the average age was 40 years. Most patients suffered blunt injuries (86.8%, 3445), while the remaining had penetrating injuries (11.6%, 459) or burns (1.6%, 63). The majority of patients were transferred by ground (3449) with only 13% (518) transferred by air. Patients transported by air had increased Injury Severity Score (ISS) with a median of 17 (IQR 9-24) versus 9 (IQR 5-14), increased length of stay (LOS) at 6 days versus 3 ( P < .001), and increased mortality at 12.6% vs 6.5% ( P < .001). Patients transported by air arrived 16.6 ± 6.7 minutes faster compared with ground for the zip codes examined. When adjusting for the mechanism of injury, ISS, age, gender, intubation status, and transport time, air transport was associated with an increased likelihood of survival (odds ratio [OR] = 1.57, 95% CI = 1.06-2.40). Conclusion In our analysis of 3967 patients, those transported by air had a significant improvement in the likelihood of survival compared with those transported by ground even when adjusting for both ISS and time.

The objective of this study was to determine the effects of flunixin meglumine or meloxicam on behavioral response and performance characteristics associated with surgical castration in crossbred bulls. Intact male Bos taurus calves (n = 252; averaging 176 kg) were randomly allocated into one of three treatment groups within pen: control (CON), flunixin meglumine (FLU; 2.2 mg/kg intravenous injection), or meloxicam (MEL; 2.0 mg/kg per os). The individual animal was the experimental unit. Calves were individually weighed on days 0 and 14 of the trial to evaluate performance outcomes. On study day 0, treatments were administered, according to their random allocation, immediately prior to surgical castration using the Henderson tool method. Visual analog scale (VAS) assessment and categorical attitude score (CAS) were collected on days −1, 0 (6 h post-castration), 1, 2, 3, and 4 in the study. The VAS was assigned using a 100 mm horizontal line with “normal” labeled at one end of the line and “moribund” at the other end of the horizontal line. The masked observer assigned a mark on the horizontal line based upon the observed severity of pain exhibited by that individual animal. The CAS was assigned by the same observer using five different categories with a score of 0 being “normal”. Average daily gain tended (P = 0.09) to be associated with the treatment group, and MEL had a greater (P = 0.04) average daily gain through day 14 compared with CON. A significant (P < 0.01) treatment by day interaction was indicated for VAS score, and MEL had lower VAS scores on days 0, 1, 2, and 3 post-castration compared with CON; FLU had lower VAS scores on days 0 and 1 compared with CON. A significant treatment by day interaction was not present (P = 0.25) for CAS. The FLU had lesser percent CAS ≥1 (17.5%; P = 0.05) compared with CON (29.4%); MEL has lesser percent CAS ≥1 observations (14.9%; P = 0.01) compared with CON. The median VAS increased as CAS was more severe. Results indicated MEL and FLU calves temporally improved behavioral responses following surgical castration with positive numerical trends for a 14 d average daily gain (ADG). The VAS system appeared to be an effective method of subjective evaluation of pain in beef calves in this study. Route of administration, duration of therapy, and low relative cost make oral meloxicam a reasonable analgesic treatment in calves when administered at the time of surgical castration.

Background The COVID-19 pandemic had a severe impact on women’s birth experiences. To date, there are no studies that use both quantitative and qualitative data to compare women’s birth experiences before and during the pandemic, across more than one country. Aim To examine women’s birth experiences during the COVID-19 pandemic and to compare the experiences of women who gave birth in the United Kingdom (UK) or the Netherlands (NL) either before or during the pandemic. Method This study is based on analyses of quantitative and qualitative data from the online Babies Born Better survey. Responses recorded by women giving birth in the UK and the NL between June and December 2020 have been used, encompassing women who gave birth between 2017 and 2020. Quantitative data were analysed descriptively, and chi-squared tests were performed to compare women who gave birth pre- versus during pandemic and separately by country. Qualitative data was analysed by inductive thematic analysis. Findings Respondents in both the UK and the NL who gave birth during the pandemic were as likely, or, if they had a self-reported above average standard of life, more likely to rate their labour and birth experience positively when compared to women who gave birth pre-pandemic. This was despite the fact that those labouring in the pandemic reported a lack of support and limits placed on freedom of choice. Two potential explanatory themes were identified in the qualitative data: respondents had lower expectations of care during the pandemic, and they appreciated the efforts of staff to give individualised care, despite the rules. Conclusion Our study implies that many women labouring during the COVID-19 pandemic experienced restrictions, but their experience was mitigated by staff actions. However, personalised care should not be maintained by the good will of care providers, but should be a priority in maternity care policy to benefit all service users equitably.

The extracellular signal-regulated kinase 1/2 (ERK1/2) cascade promotes cardiomyocyte hypertrophy and is cardioprotective, with the three RAF kinases forming a node for signal integration. Our aims were to determine if BRAF is relevant for human heart failure, whether BRAF promotes cardiomyocyte hypertrophy, and if Type 1 RAF inhibitors developed for cancer (that paradoxically activate ERK1/2 at low concentrations: the ‘RAF paradox') may have the same effect. BRAF was up-regulated in heart samples from patients with heart failure compared with normal controls. We assessed the effects of activated BRAF in the heart using mice with tamoxifen-activated Cre for cardiomyocyte-specific knock-in of the activating V600E mutation into the endogenous gene. We used echocardiography to measure cardiac dimensions/function. Cardiomyocyte BRAFV600E induced cardiac hypertrophy within 10 d, resulting in increased ejection fraction and fractional shortening over 6 weeks. This was associated with increased cardiomyocyte size without significant fibrosis, consistent with compensated hypertrophy. The experimental Type 1 RAF inhibitor, SB590885, and/or encorafenib (a RAF inhibitor used clinically) increased ERK1/2 phosphorylation in cardiomyocytes, and promoted hypertrophy, consistent with a ‘RAF paradox' effect. Both promoted cardiac hypertrophy in mouse hearts in vivo, with increased cardiomyocyte size and no overt fibrosis. In conclusion, BRAF potentially plays an important role in human failing hearts, activation of BRAF is sufficient to induce hypertrophy, and Type 1 RAF inhibitors promote hypertrophy via the ‘RAF paradox'. Cardiac hypertrophy resulting from these interventions was not associated with pathological features, suggesting that Type 1 RAF inhibitors may be useful to boost cardiomyocyte function.

SIGNIFICANCE: Retinal vascular tone is set to a level that facilitates the vasodilation and vasoconstriction. Hypercapnia reduces their “vasodilatory reserve” and impairs their reactivity to changes in intraocular or blood pressure. Therefore, eyes with systemic or local hypercapnia may have greater risk of developing ischemia in face of perfusion pressure perturbation. PURPOSE: Retinal vessels are regulated by both myogenic and metabolic mechanisms. We considered whether alteration of metabolic status would modify the vascular response to ocular perfusion pressure (OPP) lowering in rat retina. METHODS: In pentobarbital anesthetized adult Brown Norway rats, normocapnia or hypercapnia was achieved by artificially ventilating animals with air or 5% carbon dioxide in ~30% oxygen, respectively. OPP was gradually reduced to ~20 mmHg by either lowering blood pressure (slowly drawing blood from a femoral artery/vein) or manometrically increasing intraocular pressure (IOP) under normocapnic or hypercapnic conditions. In all four groups (n = 7 eyes for each), a confocal scanning laser ophthalmoscope was used to acquire image sequences centered on the optic nerve throughout pressure modification. The diameter of arterioles and venules at various OPP levels was measured and expressed as percentage relative to their own baseline. The response of arterioles and venules to OPP lowering was compared between normocapnic and hypercapnic groups. RESULTS: Average arterial carbon dioxide partial pressure was 36.9 ± 2.6 mmHg in normocapnic and 64.1 ± 5.9 mmHg in hypercapnic (P < 0.001) animals. In the normocapnic groups, blood pressure lowering and IOP elevation resulted in significant vasodilatation of both arterioles and venules (P < 0.0001). In the hypercapnic groups, OPP lowering induced vasodilation was significantly attenuated compared to the corresponding normocapnic groups (P < 0.0001 for both, 2-way ANOVA). CONCLUSIONS: Hypercapnia significantly modified myogenic vascular autoregulation in response to OPP reduction.

Patients' trauma burdens are a combination of anatomic damage, physiologic derangement, and the resultant depletion of reserve. Typically, Injury Severity Score (ISS)15 defines major anatomic injury and Revised Trauma Score (RTS)7.84 defines major physiologic derangement, but there is no standard definition for reserve. The Need For Trauma Intervention (NFTI) identifies severely depleted reserves (NFTI+) with emergent interventions and/or early mortality. We hypothesized NFTI would have stronger associations with outcomes and better model fit than ISS and RTS.Thirty-eight adult and pediatric U.S. trauma centers submitted data for 88,488 encounters. Mixed models tested ISS greater than 15, RTS less than 7.84, and NFTI's associations with complications, survivors' discharge to continuing care, and survivors' length of stay (LOS).The NFTI had stronger associations with complications and LOS than ISS and RTS (odds ratios [99.5% confidence interval]: NFTI = 9.44 [8.46-10.53]; ISS = 5.94 [5.36-6.60], RTS = 4.79 [4.29-5.34]; LOS incidence rate ratios (99.5% confidence interval): NFTI = 3.15 [3.08-3.22], ISS = 2.87 [2.80-2.94], RTS = 2.37 [2.30-2.45]). NFTI was more strongly associated with continuing care discharge but not significantly more than ISS (relative risk [99.5% confidence interval]: NFTI = 2.59 [2.52-2.66], ISS = 2.51 [2.44-2.59], RTS = 2.37 [2.28-2.46]). Cross-validation revealed that in all cases NFTI's model provided a much better fit than ISS greater than 15 or RTS less than 7.84.In this multicenter study, NFTI had better model fit and stronger associations with the outcomes than ISS and RTS. By determining depletion of reserve via resource consumption, NFTI+ may be a better definition of major trauma than the standard definitions of ISS greater than 15 and RTS less than 7.84. Using NFTI may improve retrospective triage monitoring and statistical risk adjustments.Prognostic, level IV.

During September 2018, a tick was submitted to Public Health England's Tick Surveillance Scheme for identification. The tick was sent from a veterinarian who removed it from a horse in Dorset, England, with no history of overseas travel. The tick was identified as a male Hyalomma rufipes using morphological and molecular methods and then tested for a range of tick-borne pathogens including; Alkhurma virus, Anaplasma, Babesia, Bhanja virus, Crimean-Congo Haemorrhagic fever virus, Rickettsia and Theileria. The tick tested positive for Rickettsia aeschlimannii, a spotted fever group rickettsia linked to a number of human cases in Africa and Europe. This is the first time H. rufipes has been reported in the United Kingdom (UK), and the lack of travel by the horse (or any in-contact horses) suggests that this could also be the first evidence of successful moulting of a Hyalomma nymph in the UK. It is postulated that the tick was imported into the UK on a migratory bird as an engorged nymph which was able to complete its moult to the adult stage and find a host. This highlights that passive tick surveillance remains an important method for the detection of unusual species that may present a threat to public health in the UK. Horses are important hosts of Hyalomma sp. adults in their native range, therefore, further surveillance studies should be conducted to check horses for ticks in the months following spring bird migration; when imported nymphs may have had time to drop off their avian host and moult to adults. The potential human and animal health risks of such events occurring more regularly are discussed.

Insulin and insulin-like growth factor stimulate protein synthesis and cardioprotection in the heart, acting through their receptors (INSRs, IGF1Rs) and signalling via protein kinase B (PKB, also known as Akt). Protein synthesis is increased in hearts perfused at alkaline pHo to the same extent as with insulin. Moreover, α1-adrenergic receptor (α1-AR) agonists (e.g. phenylephrine) increase protein synthesis in cardiomyocytes, activating PKB/Akt. In both cases, the mechanisms are not understood. Our aim was to determine if insulin receptor-related receptors (INSRRs, activated in kidney by alkaline pH) may account for the effects of alkaline pHo on cardiac protein synthesis, and establish if α1-ARs signal through the insulin receptor family. Alkaline pHo activated PKB/Akt signalling to the same degree as insulin in perfused adult male rat hearts. INSRRs were expressed in rat hearts and, by immunoblotting for phosphorylation (activation) of INSRRs/INSRs/IGF1Rs, we established that INSRRs, together with INSRs/IGF1Rs, are activated by alkaline pHo. The INSRR/INSR/IGF1R kinase inhibitor, linsitinib, prevented PKB/Akt activation by alkaline pHo, indicating that INSRRs/INSRs/IGF1Rs are required. Activation of PKB/Akt in cardiomyocytes by α1-AR agonists was also inhibited by linsitinib. Furthermore, linsitinib inhibited cardiomyocyte hypertrophy induced by α1-ARs in cultured cells, reduced the initial cardiac adaptation (24 h) to phenylephrine in vivo (assessed by echocardiography) and increased cardiac fibrosis over 4 days. We conclude that INSRRs are expressed in the heart and, together with INSRs/IGF1Rs, the insulin receptor family provide a potent system for promoting protein synthesis and cardioprotection. Moreover, this system is required for adaptive hypertrophy induced by α1-ARs.

Human papillomavirus (HPV) is a recognized cause of cancer in both males and females. HPV vaccination prevents development of HPV-associated diseases.Wisconsin HPV vaccination rates (2016-2019) were obtained from the Wisconsin Immunization Registry. Data was stratified by age, sex, Medicaid status, race/ethnicity, and ZIP code. Wisconsin vaccination rates were compared with national trends using data from the 2016, 2018, and 2019 National Immunization Survey-Teen.Wisconsin HPV vaccination rates remain consistently below national averages. HPV vaccination rates are improving-especially among males; however, vaccine coverage at the recommended age of 11-12 remains low. Rates of vaccine uptake differ by race/ethnicity, rurality/urbanicity, and Medicaid status.Further initiatives are needed to increase awareness and acceptance of HPV vaccination for cancer prevention throughout Wisconsin.

The novel coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2, has created a global pandemic, with many cases affecting the elderly. However, children have been affected as well, with ∼2.4% to 3.7% of cases reported. This case is the first published case of an adolescent presenting with rhabdomyolysis as the first sign of novel coronavirus disease 2019, with extremely elevated creatinine kinase levels, approaching almost 400 000 U/L. This case adds to the growing body of literature of a variety of life-threatening manifestations associated with severe acute respiratory syndrome coronavirus 2 infection and highlights the importance of how prompt recognition of these unique presentations of the disease is important to mitigate complications.

Purpose: Glia and their communication via connexin 43 (Cx43) gap junctions are known to mediate neurovascular coupling, a process driven by metabolic demand. However, it is unclear whether Cx43 mediated glial communication intermediates classical autoregulation. Here we used viral transfection and a glial fibrillary acidic protein (GFAP) promoter to downregulate glial Cx43 to evaluate its role in retinal vascular autoregulation to ocular perfusion pressure (OPP) reduction. Methods: Adult rats were intravitreally injected with the viral active construct or a control. Three weeks after the injection, eyes were imaged using confocal scanning laser ophthalmoscopy before and during a period of OPP decrease induced by blood draw to lower blood pressure or by manometric IOP elevation. Vessel diameter responses to the OPP decrease were compared between Cx43-downregulated and control-injected eyes. The extent of Cx43 downregulation was evaluated by Western blot and immunohistochemistry. Results: In control eyes, the OPP decrease induced dilatation of arterioles, but not venules. In Cx43-downregulated eyes, Cx43 expression in whole retina was decreased by approximately 40%. In these eyes, the resting diameter of the venules increased significantly, but there was no effect on arterioles. In Cx43-downregulated eyes, vasoreactivity evoked by blood pressure lowering was significantly compromised in both arterioles (P = 0.005) and venules (P = 0.001). Cx43 downregulation did not affect the arteriole responses to IOP elevation, whereas the responses of the venules showed a significantly greater decrease in diameter (P < 0.001). Conclusions: The downregulation of retinal Cx43 in GFAP-expressing cells compromises vasoreactivity of both arterioles and venules in response to an OPP decrease achieved via blood pressure lowering or IOP elevation. The results also suggest that Cx43-mediated glial communication actively regulates resting venular diameter.

CO2 surgical lasers are widely used for procedures in veterinary and human medicine. There is evidence to suggest surgery using a CO2 laser reduces pain and swelling and improves healing time compared with surgery with a scalpel. Millions of piglets in North America are surgically castrated each year using a scalpel. Therefore, piglet welfare may be improved by making refinements to the surgical procedure. The objectives of this preliminary study were to determine the ability of a CO2 surgical laser to (1) reduce pain and (2) improve wound healing of piglets undergoing surgical castration. Two-day-old male Yorkshire × Landrace piglets were used and randomly assigned to 1 of 3 treatments (n = 10 piglets/treatment group): surgical castration with the CO2 laser, surgical castration with a scalpel, or sham (uncastrated control). Piglets were video recorded in their pens for 1 hr preprocedure and from 0 to 2, 6 to 8, and at 24 hr postprocedure for behavior scoring. Surgical site images were collected at baseline, 0, 8, 24, 48, 72, 96, 120, 144, and 168 hr postcastration for wound healing assessment. Infrared thermography images of the surgical site were also taken at baseline, 0, 0.5, 8, and 24 hr postprocedure to assess inflammation. Finally, blood was collected from each piglet at baseline and 0.5 hr postcastration to assess cortisol levels, prostaglandin E metabolite and pig-major acute phase protein concentration. Laser-castrated piglets displayed more pain behaviors across the observation period than scalpel-castrated piglets (P = 0.05). Laser-castrated piglets also displayed significantly more agonistic behavior than both scalpel-castrated piglets (P = 0.005) and sham piglets (P = 0.036); yet, laser-castrated piglets had significantly lower temperatures at the site of incision compared with scalpel-castrated piglets (P = 0.0211). There was no significant difference in wound healing or any of the blood parameters assessed between laser-castrated and scalpel-castrated piglets. There was evidence of thermal tissue damage on the scrotum of piglets that were castrated using the CO2 laser. This may have resulted in the unremarkable healing time and the increased pain behavior observed in this study. The surgical laser technique should be refined before conclusions can be made regarding the utility of a CO2 laser for piglet castration.

The purpose of this study was to examine whether vehicle type based on size (car vs. other = truck/van/SUV) had an impact on the speeding, acceleration, and braking patterns of older male and female drivers (70 years and older) from a Canadian longitudinal study. The primary hypothesis was that older adults driving larger vehicles (e.g., trucks, SUVs, or vans) would be more likely to speed than those driving cars. Participants (n = 493) had a device installed in their vehicles that recorded their everyday driving. The findings suggest that the type of vehicle driven had little or no impact on per cent of time speeding or on the braking and accelerating patterns of older drivers. Given that the propensity for exceeding the speed limit was high among these older drivers, regardless of vehicle type, future research should examine what effect this behaviour has on older-driver road safety.

Child maltreatment is a global public health issue that has been linked with multiple negative health and life outcomes.This study evaluates the association between children placed in out-of-home care and neighborhood-level factors using eight years of administrative data.Between 2011-2018, 33,890 unique instances of child welfare involvement were captured in a department of child and family services database in a southern state in the United States.Removal addresses were geocoded and linked to the U.S. Census Bureau's American Community Survey to obtain census tract socioeconomic factors. Incidence overall and stratified by individual and neighborhood-level factors was computed. Rate ratios, relative indexes of inequality, and concentration curves quantified disparities in incidence of child welfare involvement by neighborhood-level factors.Incidence of children less than 19 years old placed into out-of-home care was 255 per 100,000 person-years (95 % CI: 252, 258). At the individual level, incidence was highest among children5 and 15-17 years old, comparable between male and female children, and higher among Black children. At the neighborhood level, incidence was highest in census tracts with lower median household incomes, higher percentages of households below poverty or of female-headed or single-parent households, higher unemployment rates, and fewer residents with some college education or health insurance.Incidence of children placed into out-of-home care is disproportionally higher for those who live in disadvantaged communities. Understanding neighborhood-level risk factors that may be linked to child welfare involvement can help inform policy and target prevention efforts.

Few individuals hospitalized with Substance Use Disorder (SUD) complications participate in recovery support services after discharge. Peer recovery coaching represents one potential new method for promoting recovery.A six-month prospective randomized controlled trial compared outcomes between the standard of care and a physician-initiated recovery coaching intervention. The primary outcome measure was engagement in recovery support services, and the secondary outcome measures were substance use frequency and self-reported physical and mental health using the SF-12 survey. Participants (N = 98) were eligible if they were identified by a healthcare provider as having a SUD and were hospitalized due to SUD complications.Engagement rate over the six-month post-discharge time period was higher for participants in the recovery coaching intervention (84 %, 95 % CI: 78%-91%) compared to the standard of care control condition (34 %, 95 % CI: 25 %-44 %), log OR = 28.59, p.001. No overall group differences in substance use frequency (p = .80), self-reported physical (p = .69) or mental (p = .89) health were observed.An inpatient linkage to recovery coaching services improves engagement rates and can feasibly be implemented in a single-center inpatient service. This intervention is promising for promoting both short-term and long-term engagement in recovery support services.

Bruton tyrosine kinase (BTK) inhibition is an effective treatment approach for patients with Waldenström macroglobulinemia (WM). The phase 3 ASPEN study compared the efficacy and safety of ibrutinib, a first-generation BTK inhibitor, with zanubrutinib, a novel highly selective BTK inhibitor, in patients with WM. Patients with MYD88L265P disease were randomly assigned 1:1 to treatment with ibrutinib or zanubrutinib. The primary end point was the proportion of patients achieving a complete response (CR) or a very good partial response (VGPR) by independent review. Key secondary end points included major response rate (MRR), progression-free survival (PFS), duration of response (DOR), disease burden, and safety. A total of 201 patients were randomized, and 199 received ≥1 dose of study treatment. No patient achieved a CR. Twenty-nine (28%) zanubrutinib patients and 19 (19%) ibrutinib patients achieved a VGPR, a nonstatistically significant difference (P = .09). MRRs were 77% and 78%, respectively. Median DOR and PFS were not reached; 84% and 85% of ibrutinib and zanubrutinib patients were progression free at 18 months. Atrial fibrillation, contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms, and pneumonia, as well as adverse events leading to treatment discontinuation, were less common among zanubrutinib recipients. Incidence of neutropenia was higher with zanubrutinib, although grade ≥3 infection rates were similar in both arms (1.2 and 1.1 events per 100 person-months). These results demonstrate that zanubrutinib and ibrutinib are highly effective in the treatment of WM, but zanubrutinib treatment was associated with a trend toward better response quality and less toxicity, particularly cardiovascular toxicity.

Inhibitors of Bruton’s tyrosine kinase (BTK) have established therapeutic activity in patients with Waldenström macroglobulinemia (WM). Zanubrutinib, a potent and selective BTK inhibitor, was evaluated in a phase 1/2 study in patients with WM who were either treatment-naïve (TN) or had relapsed/refractory (R/R) disease. Patients had disease requiring treatment per International Workshop on Waldenström Macroglobulinemia (IWWM) criteria. Treatment was 160 mg of oral zanubrutinib twice daily (n = 50) or 320 mg once daily (n = 23). Efficacy endpoints included overall response rate (ORR) and very good partial response/complete response (VGPR/CR) rates per IWWM-6 criteria (with modification of VGPR definition published previously). Between September 2014 and March 2018, 77 patients (24 TN and 53 R/R) began treatment. At a median follow-up of 36.0 months for patients with R/R disease and 23.5 months for TN, 72.7% remained on treatment. Reasons for treatment discontinuation included any adverse events in 13.0% of patients (1 treatment related), disease progression (10.4%), and other (3.9%). The ORR was 95.9%, and the VGPR/CR rate was 45.2%, which increased over time: 20.5% at 6 months, 32.9% at 12 months, and 43.8% at 24 months. Estimated 3-year progression-free survival rate was 80.5%, and overall survival rate was 84.8%. Adverse events of interest included contusion (32.5%, all grade 1), neutropenia (18.2%), major hemorrhage (3.9%), atrial fibrillation/flutter (5.2%), and grade 3 diarrhea (2.6%). Long-term treatment with single-agent zanubrutinib resulted in deep and durable responses in some patients with WM. The safety profile of long-term zanubrutinib therapy in these patients was acceptable. This trial was registered at www.clinicaltrials.gov as #NCT02343120.

Hyalomma marginatum is widely distributed across the Mediterranean, Northern Africa and the Middle East. Current climate conditions in Northern Europe are thought to limit the species’ ability to moult to the adult stage. It is a vector of several pathogens of human and veterinary concern, including Crimean-Congo haemorrhagic fever virus, for which it is the primary vector in Europe. Here, we report the first human exposure to a locally acquired adult H. marginatum in England, and the second detection in England of Rickettsia aeschlimannii associated with imported Hyalomma.

Marginal zone lymphoma of the central nervous system (CNS MZL) is rare. The clinical features, treatment, and prognosis are not well characterized. We performed a multicenter retrospective study of CNS MZL. Twenty‐six patients were identified: half with primary and half with secondary CNS involvement. The median age was 59 years (range 26‐78), 62% female and 79% with ECOG performance status ≤ 1. The most common disease site was the dura (50%). Treatment was determined by the treating physician and varied substantially. After a median follow up of 1.9 years, the estimated 2‐year progression‐free (PFS) and overall survival (OS) rates were 59% and 80%, respectively. Secondary CNS MZL was associated with 2‐year OS of 58%. CNS MZL is rare, but relative to other forms of CNS lymphoma, outcomes appear favorable, particularly among the subset of patients with dural presentation and primary CNS presentation., Marginal zone lymphoma of the central nervous system (CNS MZL) is rare. In this multicenter retrospective study of 26 patients, the estimated 2‐year overall survival rate was 80%. Outcomes appear favorable, particularly among the subset of patients with primary dural presentation.

Immune dysregulation is a common feature of myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), particularly in early stages. However, the genetic basis remains poorly understood. We recently reported that macrophages from mice deficient in tet methylcytosine dioxygenase 2 (Tet2), a model of MDS/CMML, are hyperinflammatory and have increased expression of arginase 1 (Arg1). In macrophages and myeloid derived suppressor cells (MDSCs) expression of Arg1 contributes to T-cell suppression and immune evasion by L-arginine depletion, in the setting of chronic inflammation and cancer. Since human MDS and CMML are driven by TET2 mutations and associated with chronic inflammation, we hypothesized that arginase enzymatic activity and ARG1 expression would be increased in human MDS/CMML bone marrow. Elevated arginase activity was observed in bone marrow mononuclear cells of MDS and CMML patients with lower-grade features. Immunohistochemical studies confirmed that myelomonocytic cells overexpress ARG1. Additionally, mutations in the epigenetic regulators TET2 and DNMT3A corresponded to high ARG1 expression and activity. These findings suggest ARG1 is a biomarker of immune dysregulation in early MDS and CMML. Recent murine findings have implicated Tet2 and Dnmt3a in regulation of innate immunity. Our study suggests similar changes may be driven by human TET2 and DNMT3A mutations.

The American Association for the Surgery of Trauma (AAST) anatomic severity grading system for adhesive small bowel obstruction (ASBO) was validated at a single institution. We aimed to externally validate the AAST ASBO grading system using the Eastern Association for the Surgery of Trauma multi-institutional small bowel obstruction prospective observational study.Adults (age ≥ 18) with (ASBO) were included. Baseline demographics, physiologic parameters (heart rate, blood pressure, respiratory rate), laboratory tests (lactate, hemoglobin, creatinine, leukocytosis), imaging findings, operative details, length of stay, and Clavien-Dindo complications were collected. The AAST ASBO grades were assigned by two independent reviewers based on imaging findings. Kappa statistic, univariate, and multivariable analyses were performed.There were 635 patients with a mean (±SD) age of 61 ± 17.8 years, 51% female, and mean body mass index was 27.5 ± 8.1. The AAST ASBO grades were: grade I (n = 386, 60.5%), grade II (n = 135, 21.2%), grade III (n = 59, 9.2%), grade IV (n = 55, 8.6%). Initial management included: nonoperative (n = 385; 61%), laparotomy (n = 200, 31.3%), laparoscopy (n = 13, 2.0%), and laparoscopy converted to laparotomy (n = 37, 5.8%). An increased median [IQR] AAST ASBO grade was associated with need for conversion to an open procedure (2 [1-3] vs. 3 [2-4], p = 0.008), small bowel resection (2 [2-2] vs. 3 [2-4], p0.0001), postoperative temporary abdominal closure (2 [2-3] vs. 3 [3-4], p0.0001), and stoma creation (2 [2-3] vs. 3 [2-4], p0.0001). Increasing AAST grade was associated with increased anatomic severity noted on imaging findings, longer duration of stay, need for intensive care, increased rate of complication, and higher Clavien-Dindo complication grade.The AAST ASBO severity grading system has predictive validity for important clinical outcomes and allows for standardization across institutions, providers, and future research focused on optimizing preoperative diagnosis and management algorithms.Prognostic, level III.

Purpose Higher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy. Patients and Methods Patients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m2 daily for 5 days, etoposide 75 mg/m2 daily for 5 days, and idarubicin 9 mg/m2 daily for either 2 or 3 days (standard and intensive arms, respectively). The primary end point was leukemia-free survival (LFS). Results Two hundred ninety-three patients 16 to 60 years of age, excluding those with core binding factor AML and acute promyelocytic leukemia, were randomly assigned to treatment groups (146 to the standard arm and 147 to the intensive arm). Both groups were balanced for age, karyotypic risk, and FLT3–internal tandem duplication and NPM1 gene mutations. One hundred twenty patients in the standard arm (82%) and 95 patients in the intensive arm (65%) completed planned consolidation ( P < .001). Durations of severe neutropenia and thrombocytopenia were prolonged in the intensive arm, but there were no differences in serious nonhematological toxicities. With a median follow-up of 5.3 years (range, 0.6 to 9.9 years), there was a statistically significant improvement in LFS in the intensive arm compared with the standard arm (3-year LFS, 47% [95% CI, 40% to 56%] v 35% [95% CI, 28% to 44%]; P = .045). At 5 years, the overall survival rate was 57% in the intensive arm and 47% in the standard arm ( P = .092). There was no evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3–internal tandem duplication and NPM1 gene mutation subgroups. Conclusion An increased cumulative dose of idarubicin during consolidation therapy for adult AML resulted in improved LFS, without increased nonhematologic toxicity.

In the brain, transmembrane AMPAR regulatory proteins (TARPs) critically influence the distribution, gating, and pharmacology of AMPARs, but the contribution of these auxiliary subunits to AMPAR-mediated signaling in the spinal cord remains unclear. We found that the Type I TARP γ-2 (stargazin) is present in lamina II of the superficial dorsal horn, an area involved in nociception. Consistent with the notion that γ-2 is associated with surface AMPARs, CNQX, a partial agonist at AMPARs associated with Type I TARPs, evoked whole-cell currents in lamina II neurons, but such currents were severely attenuated in γ-2-lacking stargazer (stg/stg) mice. Examination of EPSCs revealed the targeting of γ-2 to be synapse-specific; the amplitude of spontaneously occurring miniature EPSCs (mEPSCs) was reduced in neurons from stg/stg mice, but the amplitude of capsaicin-induced mEPSCs from C-fiber synapses was unaltered. This suggests that γ-2 is associated with AMPARs at synapses in lamina II but excluded from those at C-fiber inputs, a view supported by our immunohistochemical colabeling data. Following induction of peripheral inflammation, a model of hyperalgesia, there was a switch in the current-voltage relationships of capsaicin-induced mEPSCs, from linear to inwardly rectifying, indicating an increased prevalence of calcium-permeable (CP) AMPARs. This effect was abolished in stg/stg mice. Our results establish that, although γ-2 is not typically associated with calcium-impermeable AMPARs at C-fiber synapses, it is required for the translocation of CP-AMPARs to these synapses following peripheral inflammation. SIGNIFICANCE STATEMENT In the brain, transmembrane AMPAR regulatory proteins (TARPs) critically determine the functional properties of AMPARs, but the contribution of these auxiliary subunits to AMPAR-mediated signaling in the spinal cord remains unclear. An increase in the excitability of neurons within the superficial dorsal horn (SDH) of the spinal cord is thought to underlie heighted pain sensitivity. One mechanism considered to contribute to such long-lived changes is the remodeling of the ionotropic AMPA-type glutamate receptors that underlie fast excitatory synaptic transmission in the SDH. Here we show that the TARP γ-2 (stargazin) is present in SDH neurons and is necessary in a form of inflammatory pain-induced plasticity, which involves an increase in the prevalence of synaptic calcium-permeable AMPARs.

Purpose The purpose of this study was to test the hypothesis that retinal glial cells modify basal vessel diameter and pressure-initiated vascular regulation in rat retina. Methods In rats, L-2-aminoadipic acid (LAA, 10 nM) was intravitreally injected to inhibit glial cell activity. Twenty-four hours following injection, retinal glial intracellular calcium (Ca2+) was labeled with the fluorescent calcium indicator Fluo-4/AM (F4, 1 mM). At 110 minutes after injection, intraocular pressure (IOP) was elevated from 20 to 50 mm Hg. Prior to and during IOP elevation, Ca2+ and retinal vessel diameter were assessed using a spectral-domain optical coherence tomography/confocal scanning laser ophthalmoscope. Dynamic changes in Ca2+ and diameter from IOP elevation were quantified. The response in LAA-treated eyes was compared with vehicle treated control eyes. Results L-2-Aminoadipic acid treatment significantly reduced F4-positive cells in the retina (LAA, 16 ± 20 vs. control, 55 ± 37 cells/mm2; P = 0.02). Twenty-four hours following LAA treatment, basal venous diameter was increased from 38.9 ± 3.9 to 51.8 ± 6.4 μm (P < 0.0001, n = 20), whereas arterial diameter was unchanged (from 30.3 ± 3.5 to 30.7 ± 2.8 μm; P = 0.64). In response to IOP elevation, LAA-treated eyes showed a smaller increase in glial cell Ca2+ around both arteries and veins in comparison with control (P < 0.001 for both). There was also significantly greater IOP-induced vasoconstriction in both vessel types (P = 0.05 and P = 0.02, respectively; n = 6 each). Conclusions The results suggest that glial cells can modulate basal retinal venous diameter and contribute to pressure-initiated vascular responses.

Social identities play an important role in many aspects of life, not least in those pertaining to health and well-being. Decades of research shows that these relationships are driven by a range of social identity processes, including identification with groups, social support received from groups, and multiple group memberships. However, to date, researchers have not had access to methods that simultaneously capture these social identity processes. To fill this void, this article introduces an online Social Identity Mapping (oSIM) tool designed to assess the multidimensional and connected nature of social identities. Four studies (total N = 721) featuring community, student, new parent, and retiree samples, test the reliability and validity of oSIM. Results indicate that the tool is easy to use, engaging, has good internal consistency as well as convergent and discriminant validity, and predicts relevant outcomes across a range of contexts. Furthermore, using meta-analytic findings, the tool is able to index a higher-order social identity construct, here introduced as a supergroup. This new concept provides holistic information about groups (reflecting an integrated index of several social identity processes) that are predictive of well-being outcomes, as well as outcomes related to successful adjustment to challenging life events. We discuss how the tool can be used to tackle key debates in the literature and contribute to theory by affording researchers the opportunity to capture the nuanced and contextual nature of social identity in action. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

In this work, we develop a robust, extensible tool to automatically and accurately count retinal ganglion cell axons in optic nerve (ON) tissue images from various animal models of glaucoma. We adapted deep learning to regress pixelwise axon count density estimates, which were then integrated over the image area to determine axon counts. The tool, termed AxoNet, was trained and evaluated using a dataset containing images of ON regions randomly selected from whole cross sections of both control and damaged rat ONs and manually annotated for axon count and location. This rat-trained network was then applied to a separate dataset of non-human primate (NHP) ON images. AxoNet was compared to two existing automated axon counting tools, AxonMaster and AxonJ, using both datasets. AxoNet outperformed the existing tools on both the rat and NHP ON datasets as judged by mean absolute error, R2 values when regressing automated vs. manual counts, and Bland-Altman analysis. AxoNet does not rely on hand-crafted image features for axon recognition and is robust to variations in the extent of ON tissue damage, image quality, and species of mammal. Therefore, AxoNet is not species-specific and can be extended to quantify additional ON characteristics in glaucoma and potentially other neurodegenerative diseases.

Objective: We sought to identify factors that influence Human Papillomavirus (HPV) vaccination rates in individuals at two higher education institutions in South Carolina (SC).Participants: We surv...

We present an analysis of 98 consecutive patients with peripheral T-cell lymphoma (PTCL) treated over a 10-year period within Western Australia. The most common frontline therapies were CHO(E)P (47%), HyperCVAD (21%), and reduced intensity therapy or supportive care alone (19%). Median and 4-year overall survival (OS) for the whole cohort were 1.59 years and 34%. Amongst CHO(E)P and HyperCVAD-treated patients, elevated LDH, advanced stage, IPI1, and non-ALK + ALCL histology predicted inferior progression-free survival (PFS). Inferior OS was predicted by elevated LDH, age60, IPI1, and non-ALK + ALCL histology. Response rates and PFS were not significantly different between patients treated with CHO(E)P or HyperCVAD. OS was longer in the HyperCVAD group, however this was not significant on multivariable analysis and appears to relate to the younger age and more aggressive therapy at relapse in this group. Our data confirmed the prognostic utility of the IPI in patients with PTCL and do not demonstrate a clear benefit of HyperCVAD.

Case Presentation A 59-year-old man presented to the ED with a chief complaint of shortness of breath. His past medical history was significant for end-stage renal disease secondary to lithium toxicity, immunosuppression subsequent to cadaveric renal transplantation, bipolar disorder, and hypertension. His shortness of breath had begun 6 months previously and was initially intermittent; it then progressed to constant shortness of breath over the few weeks before presentation. He had no fever, hemoptysis, or chest pain. The patient was admitted to hospital for further evaluation.

Both the opioid and gun violence epidemics are recurrent public health issues in the United States. We sought to determine the effect of opioid dependence on gunshot injury treatment outcomes.Using the 2016 National Readmission Database, patients were included if they had a principal diagnosis of firearm injury. Opioid dependence was identified using appropriate International Classification of Diseases, 10th Revision, Clinical Modification codes. The primary outcome was 30-day all-cause readmission. Secondary outcomes were in-hospital and 1-year mortality, resource utilization, and most common reasons for admission and readmission. Confounders were adjusted for using multivariate regression analysis.A total of 31,303 patients were included, 695 of whom were opioid dependent. Opioid-dependent patients were more likely to be young (35.1 y, range: 33.4-36.7 y) and male (89.9%) compared with patients without opioid dependence. Opioid dependence was associated with higher 30-day readmission rates (adjusted odds ratio [aOR]: 1.67, 95% confidence interval [CI]: 1.12-2.50, P = 0.01). However, opioid dependence was associated with lower in-hospital (aOR: 0.16, CI: 0.07-0.38, P 0.01) and 1-year (aOR: 0.15, CI: 0.06-0.38, P 0.01) mortality, longer mean length of stay (adjusted mean difference [aMD]: 2.09 d, CI: 0.43-3.76, P = 0.03), and total hospitalization costs (aMD: $6,318, CI: $ 257-$12,380, P = 0.04). Both groups had similar total hospitalization charges (aMD: $$10,491, CI: -$12,618-$33,600, P-value = 0.37).Opioid dependence leads to higher rates of 30-day readmission and resource utilization among patients with firearm injuries. However, the in-hospital and 1-year mortality rates are lower among patients with opioid dependence secondary to lower injury acuity.

Determining triage activation levels in geriatric patients who fall (GF), and patients with penetrating wounds can be difficult and inaccurate, resulting in excessive overtriage (OT) and undertriage (UT) rates. We developed trauma activation prediction models using field data to predict with greater accuracy trauma activation level and triage rates consistent with the ACS recommendations. Using data from the 2014 National Trauma Data Bank, we created binary regression equations for each type of injury (GF and penetrating wounds). The 2014 data were randomized and divided into two halves. The first half for each injury type was used to generate prediction models, whereas the second half of the 2014 data were combined with 2013 and 2015 National Trauma Data Bank data for model verification. Binary regression equations were generated from vital signs collected by EMS. A Cribari grid with ISS ≥ 15 was used to determine the appropriateness of activation level. Chi-square analysis was used to determine significant differences between OT, UT, and accuracy predictions. Using our triage models, we were able to obtain UT rates of less than 4 per cent for GF with OT rates of less than 40 per cent, UT rates less than 4.1 per cent and OT of less than 50 per cent for patients with gunshot wounds, and UT rates less than 4 per cent and OT rates less than 25 per cent for patients who had stab wounds. Our developed trauma level prediction models enable health providers to predict trauma activation levels that can result in OT and UT rates in the recommended ranges by the ACS.

Ticks on horses may transmit several diseases of clinical significance in the UK including equine granulocytic anaplasmosis ( Anaplasma phagocytophilum ),1 louping ill virus infection2 and Lyme disease ( Borrelia species).3 The geographical range of Dermacentor reticulatus (the ornate cow tick or marsh tick), a known vector of equine piroplasmosis ( Babesia caballi and Theileria equi ), seems to be expanding within the UK.4 > Veterinary professionals … may be the first to spot ticks feeding on horses Veterinary professionals play a key role in diagnosing such cases and …

Objective To measure the frequency US pediatricians report screening and referring for social needs and identify pediatrician and practice-level predictors for screening and referral. Methods Data were from the American Academy of Pediatrics Periodic Survey for October 2014 to March 2015 with a response rate of 46.6% (732/1570). Respondents reported on: 1) routine screening of low-income families for social needs, 2) attitudes toward screening, and 3) referral of low-income families for community resources. Results were analyzed by pediatrician and practice characteristics. Results Although most pediatricians (61.6%) thought that screening is important, fewer (39.9%) reported that screening is feasible or felt prepared addressing families' social needs (20.2%). The topics that pediatricians reported routinely asking low-income families about at visits (defined as ≥50% visits) were need for childcare (41.5%) and transportation barriers (28.4%). Pediatricians were less likely to report asking about housing (18.7%), food (18.6%), and utilities/heating (14.0%) insecurity. In multivariable analyses, pediatricians were more likely to report both that they screen and refer when they reported having more patients in financial hardship and having someone in the practice with the responsibility to connect low-income families to community services. Pediatricians who endorsed the importance of screening and who reported being prepared were also more likely to screen/refer. Conclusions A minority of pediatricians report routinely screening for social needs. Pediatricians were more likely to report that they screen and refer if they had positive attitudes toward the importance of screening, felt prepared, and had support staff to assist families in need.

BACKGROUND: The prognosis for primary CNS lymphoma has improved with the use of high-dose methotrexate-based chemotherapy, but patient outcomes remain poor. Rituximab, a chimeric monoclonal antibody that targets the CD20 cell surface protein, has substantial activity in systemic CD20-positive diffuse large B-cell lymphoma, but its efficacy in primary CNS lymphoma is unknown and low penetration of the large rituximab molecule through the blood-brain barrier could limit its effect. We aimed to investigate the addition of rituximab to a high-dose methotrexate-based chemotherapy regimen in patients with newly diagnosed primary CNS lymphoma.METHODS: This intergroup, multicentre, open-label, randomised phase 3 study was done at 23 hospitals in the Netherlands, Australia, and New Zealand. Non-immunocompromised patients aged 18-70 years with newly diagnosed primary CNS lymphoma were randomly assigned (1:1) to receive methotrexate-based chemotherapy with or without intravenous rituximab. We used a web-based randomisation system with stratification by centre, age, and Eastern Cooperative Oncology Group-WHO performance status, and a minimisation procedure. All group assignment was open label and neither investigators nor patients were masked to allocation. All patients were treated with two 28-day cycles of induction chemotherapy, consisting of intravenous methotrexate 3 g per m2 on days 1 and 15, intravenous carmustine 100 mg per m2 on day 4, intravenous teniposide 100 mg per m2 on days 2 and 3, and oral prednisone 60 mg per m2 on days 1-5, with (R-MBVP) or without (MBVP) intravenous rituximab 375 mg per m2 on days 0, 7, 14, and 21 in cycle one and days 0 and 14 in cycle two. Patients with response at the end of induction subsequently received high-dose cytarabine and, in patients aged 60 years or younger, low-dose whole-brain radiotherapy. The primary endpoint was event-free survival, with events defined as not reaching complete response or complete response unconfirmed at the end of treatment, or progression or death after response; analysis was adjusted for age and performance score. Patients were analysed on a modified intention-to-treat basis. This trial is registered with the Nederlands Trial Register, number NTR2427, and the Australian New Zealand Clinical Trials Registry, number ACTRN12610000908033. The trial was closed on May 27, 2016, after achieving complete accrual, and follow-up is ongoing.FINDINGS: Between Aug 3, 2010, and May 27, 2016, we recruited 200 patients (109 men and 91 women; median age was 61 years [IQR 55-67]). We randomly assigned 100 patients to MBVP and 99 patients to R-MBVP. One patient was randomly assigned to the R-MBVP group but found to be ineligible because of an incorrect diagnosis and was excluded from all analyses. After a median follow-up of 32·9 months (IQR 23·9-51·5), 98 patients had had an event (51 in the MBVP group and 47 in the R-MBVP group), of whom 79 had died (41 in the MBVP group and 38 in the R-MBVP group). Event-free survival at 1 year was 49% (95% CI 39-58) in the MBVP group (no rituximab) and 52% (42-61) in the R-MBVP group (with rituximab; hazard ratio 1·00, 95% CI 0·70-1·43, p=0·99). Grade 3 or 4 adverse events occurred in 58 (58%) patients in the MBVP group and 63 (64%) patients in the R-MBVP group, with infections (24 [24%] patients receiving MBVP vs 21 [21%] patients receiving R-MBVP), haematological toxicity (15 [15%] vs 12 [12%]), and nervous system disorders (ten [10%] vs 15 [15%]) being the most common. Life-threatening or fatal serious adverse events occurred in 12 (12%) patients in the MBVP group and ten (10%) patients in the R-MBVP group, and five (5%) patients in the MBVP group and three (3%) in the R-MBVP group died from treatment-related causes.INTERPRETATION: We found no clear benefit of addition of rituximab to methotrexate, carmustine, teniposide, and prednisone chemotherapy in primary CNS lymphoma. Therefore, the results of this study do not support the use of rituximab as a component of standard treatment in primary CNS lymphoma.FUNDING: Roche, the Dutch Cancer Society, and Stichting STOPhersentumoren.

In the treatment of diffuse large B-cell lymphoma, a persistently positive [18F]fluorodeoxyglucose positron emission tomography (PET) scan typically carries a poor prognosis. In this prospective multi-center phase II study, we sought to establish whether treatment intensification with R-ICE (rituximab, ifosfamide, carboplatin, and etoposide) chemotherapy followed by 90Y-ibritumomab tiuxetan–BEAM (BCNU, etoposide, cytarabine, and melphalan) for high-risk diffuse large B-cell lymphoma patients who are positive on interim PET scan after 4 cycles of R-CHOP-14 (rituximab, cyclophosphamide, doxorubicin, and prednisone) can improve 2-year progression-free survival from a historically unfavorable rate of 40% to a rate of 65%. Patients received 4 cycles of R-CHOP-14, followed by a centrally-reviewed PET performed at day 17–20 of cycle 4 and assessed according to International Harmonisation Project criteria. Median age of the 151 evaluable patients was 57 years, with 79% stages 3–4, 54% bulk, and 54% International Prognostic Index 3–5. Among the 143 patients undergoing interim PET, 101 (71%) were PET-negative (96 of whom completed R-CHOP), 42 (29%) were PET-positive (32 of whom completed R-ICE and 90Y-ibritumomab tiuxetan-BEAM). At a median follow up of 35 months, the 2-year progression-free survival for PET-positive patients was 67%, a rate similar to that for PET-negative patients treated with R-CHOP-14 (74%, P=0.11); overall survival was 78% and 88% (P=0.11), respectively. In an exploratory analysis, progression-free and overall survival were markedly superior for PET-positive Deauville score 4 versus score 5 (P=0.0002 and P=0.001, respectively). Therefore, diffuse large B-cell lymphoma patients who are PET-positive after 4 cycles of R-CHOP-14 and who switched to R-ICE and 90Y-ibritumomab tiuxetan-BEAM achieved favorable survival outcomes similar to those for PET-negative R-CHOP-14-treated patients. Further studies are warranted to confirm these promising results. (Registered at: ACTRN12609001077257).

Purpose We compare spectral-domain optical coherence tomography (SDOCT) measurements of minimum rim width (MRW), minimum rim area (MRA), and peripapillary retinal nerve fiber layer thickness (RNFLT) to complete orbital optic nerve axon counts in nonhuman primates (NHP) with unilateral experimental glaucoma (EG). Methods Biweekly SDOCT measurements of MRW, MRA, and RNFLT were acquired under manometric IOP control (10 mm Hg) in 51 NHP during baseline (mean ± SD, 5.0 ± 1.6 sessions) and after laser photocoagulation was applied to the trabecular meshwork of one eye to induce chronic IOP elevation. At the study endpoint (predefined for each NHP), 100% axon counts were obtained from each optic nerve. Results For SDOCT parameters at baseline, the correlation between the two eyes of each animal was strongest for RNFLT (R = 0.97) and MRW (R = 0.97), but lower for MRA (R = 0.85). At the final time point, average values in EG eyes relative to control eyes were: -22% for RNFLT, -38% for MRW, -36% for MRA, and -36% for optic nerve axons. The correlation with axon counts was strongest for RNFLT (R = 0.81), compared to MRW (R = 0.72, P = 0.001) or MRA (R = 0.70, P = 0.001). Diagnostic sensitivity was 75% for RNFLT, 90% for MRW, and 88% for MRA; all had 100% specificity. Conclusions Peripapillary RNFLT was correlated more closely with total orbital optic nerve axon count than were the ONH parameters MRW or MRA. This is likely because glaucomatous deformation (beyond axon loss alone) has a greater influence on the ONH parameters MRW and MRA than on RNFLT.

Objective To examine whether resident characteristics and experiences are related to practice in underserved areas. Methods Cross-sectional survey of a national random sample of pediatric residents (n = 1000) and additional sample of minority residents (n = 223) who were graduating in 2009 was conducted. Using weighted logistic regression, we examined relationships between resident characteristics (background, values, residency experiences, and practice goals) and reported 1) expectation to practice in underserved area and 2) postresidency position in underserved area. Results Response rate was 57%. Forty-one percent of the residents reported that they had an expectation of practicing in an underserved area. Of those who had already accepted postresidency positions, 38% reported positions in underserved areas. Service obligation in exchange for loans/scholarships and primary care/academic pediatrics practice goals were the strongest predictors of expectation of practicing in underserved areas (respectively, adjusted odds ratio 4.74, 95% confidence interval 1.87–12.01; adjusted odds ratio 3.48, 95% confidence interval 1.99–6.10). Other significant predictors include hospitalist practice goals, primary care practice goals, importance of racial/ethnic diversity of patient population in residency selection, early plan (before medical school) to care for underserved families, mother with a graduate or medical degree, and higher score on the Universalism value scale. Service obligation and primary care/academic pediatrics practice goal were also the strongest predictors for taking a postresidency job in underserved area. Conclusions Trainee characteristics such as service obligations, values of humanism, and desire to serve underserved populations offer the hope that policies and public funding can be directed to support physicians with these characteristics to redress the maldistribution of physicians caring for children.

Objective To examine trends in pediatricians working part-time and residents seeking part-time work and to examine associated characteristics. Study design The American Academy of Pediatrics (AAP) Periodic Survey of Fellows and the AAP Annual Survey of Graduating Residents were used to examine part-time employment. Fourteen periodic surveys were combined with an overall response rate of 57%. Part-time percentages were compared for surveys conducted from 2006-2009 and 2010-2013. The AAP Annual Surveys of Graduating Residents (combined response rate = 60%) from 2006-2009 were compared with 2010-2013 surveys for residents seeking and obtaining part-time positions following training. Multivariable logistic regression models identified characteristics associated with part-time work. Results Comparable percentages of pediatricians worked part-time in 2006-2009 (23%) and 2010-2013 (23%). There was similarly no statistically significant difference in residents seeking part-time work (30%-28%), and there was a slight decline in residents accepting part-time work (16%-13%, aOR .75, 95% CI .56-.96). Increases in working part-time were not found for any subgroups examined. Women consistently were more likely than men to work part-time (35% vs 9%), but they showed different patterns of part-time work across age. Women in their 40s (40%) were more likely than other women (33%) and men in their 60s (20%) were more likely than other men (5%) to work part-time. Conclusions There has been a levelling off in the number of pediatricians working part-time and residents seeking part-time work. Overall, women remain more likely to work part-time, although 1 in 5 men over 60 work part-time.

Overseas travel to regions where ticks are found can increase travellers&rsquo, exposure to ticks and pathogens that may be unfamiliar to medical professionals in their home countries. Previous studies have detailed non-native tick species removed from recently returned travellers, occasionally leading to travel-associated human cases of exotic tick-borne disease. There are 20 species of tick endemic to the UK, yet UK travellers can be exposed to many other non-native species whilst overseas. Here, we report ticks received by Public Health England&rsquo, s Tick Surveillance Scheme from humans with recent travel history between January 2006 and December 2018. Altogether, 16 tick species were received from people who had recently travelled overseas. Confirmed imports (acquired outside of the UK) were received from people who recently travelled to 22 countries. Possible imports (acquired abroad or within the UK) were received from people who had recently travelled to eight European countries. Species-specific literature reviews highlighted nine of the sixteen tick species are known to vector at least one tick-borne pathogen to humans in the country of acquisition, suggesting travellers exposed to ticks may be at risk of being bitten by a species that is a known vector, with implications for novel tick-borne disease transmission to travellers.

The Channel Islands are British Crown dependencies located in the English Channel to the west of the Normandy coast in northern France. Whilst there have been studies investigating tick occurrence and distribution in different habitats on the mainland of the UK and in France, the Channel Islands have been relatively understudied. As such, little is known about whether the sheep tick, Ixodes ricinus, is present, and whether there is a potential risk of Lyme borreliosis on the Channel Islands. To ascertain the presence of I. ricinus on the three largest islands in the archipelago: Jersey, Guernsey and Alderney, surveys of ticks questing in the vegetation and ticks feeding on hosts were undertaken during April and May 2016. Across all three islands, the highest numbers of ticks were found in woodland habitats. Ixodes ricinus was the predominant questing tick species found on Jersey, and Ixodes ventalloi the most common questing tick species on Alderney and Guernsey, with little or no evidence of questing I. ricinus on either island. During field studies on small mammals, I. ricinus was the predominant tick species feeding on Jersey bank voles (Myodes glareolus caesarius), with Ixodes hexagonus the most common species infesting hedgehogs on Guernsey. We propose that the greater diversity of small mammals on Jersey may be important in supporting immature stages of I. ricinus, in contrast to Guernsey and Alderney. Morphological identification of tick species was confirmed by PCR sequencing based on amplification of the cytochrome c oxidase subunit one (cox1) gene (COI DNA barcoding). To date, there have been few records of human tick bites in the Channel Islands, suggesting that the current risk from tick-borne disease may be low, but continued reporting of any human tick bites, along with reporting of cases of Lyme borreliosis will be important for continued assessment of the impact of tick-borne diseases in the Channel Islands.