Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

The development of deep-ocean anoxia in a comprehensive ocean phosphorus model.

We analyse a model of the phosphorus cycle in the ocean given by Slomp and Van Cappellen (Biogeosciences 4:155-171, 2007. 10.5194/bg-4-155-2007). This model contains four distinct oceanic boxes and includes relevant parts of the water, carbon and oxygen cycles. We show that the model can essentially be solved analytically, and its behaviour completely understood without recourse to numerical methods. In particular, we show that, in the model, the carbon and phosphorus concentrations in the different ocean reservoirs are all slaved to the concentration of soluble reactive phosphorus in the deep ocean, which relaxes to an equilibrium on a time scale of 180,000 y, and we show that the deep ocean is either oxic or anoxic, depending on a critical parameter which we can determine explicitly. Finally, we examine how the value of this critical parameter depends on the physical parameters contained in the model. The presented methodology is based on tools from applied mathematics and can be used to reduce the complexity of other large, biogeochemical models. Supplementary Information: The online version contains supplementary material available at 10.1007/s13137-023-00221-0.

Quasi-steady uptake and bacterial community assembly in a mathematical model of soil-phosphorus mobility.

We mathematically model the uptake of phosphorus by a soil community consisting of a plant and two bacterial groups: copiotrophs and oligotrophs. Four equilibrium states emerge, one for each of the species monopolising the resource and dominating the community and one with coexistence of all species. We show that the dynamics are controlled by the ratio of chemical adsorption to bacterial death permitting either oscillatory states or quasi-steady uptake. We show how a steady state can emerge which has soil and plant nutrient content unresponsive to increased fertilization. However, the additional fertilization supports the copiotrophs leading to community reassembly. Our results demonstrate the importance of time-series measurements in nutrient uptake experiments.

The St. George's Respiratory Questionnaire in Pulmonary Sarcoidosis.

RATIONALE: The Saint George's Respiratory Questionnaire (SGRQ) is a frequently used tool to assess health status in pulmonary disease patients. However, its performance characteristics in sarcoidosis patients are not well characterized. METHODS: Data from a clinical trial of 138 symptomatic adults with sarcoidosis were used to examine the performance characteristics of SGRQ. Data were available at both baseline and week 24. Other assessments included FVC, FEV1, ATS dyspnea score, Borg's CR 10 dyspnea score, 6-min walk distance (6MWD), and Short Form-36 Physical Component Summary (SF-36 PCS) score. RESULTS: Baseline SGRQ was 46.8, indicating impaired health status. At baseline, SGRQ total score correlated significantly with % predicted FVC, FEV1, ATS dyspnea score, Borg's CR 10 dyspnea score, 6MWD, and SF-36 PCS (r = - 0.37, - 0.32, 0.57, 0.40, - 0.55, and - 0.80, respectively, p < 0.001). Change from baseline in SGRQ score also statistically significantly correlated with change from baseline in these parameters at week 24: r = - 0.25, - 0.20, 0.30, 0.22, - 0.20, - 0.45, respectively (p < 0.05). CONCLUSIONS: The SGRQ correlated with other outcome measures in sarcoidosis initially and with treatment. Improvement in FVC % predicted correlated with improvement in SGRQ. These data suggest the SGRQ may function as a reliable endpoint in clinical sarcoidosis trials.

Geographic access to buprenorphine prescribers for patients who use public transit.

OBJECTIVE: Urban Medicaid enrollees with opioid use disorder often rely on public transit to reach buprenorphine prescribers. Research has not shown whether public transit provides this population with adequate geographic access to buprenorphine prescribers. We examined travel times to buprenorphine prescribers by car and public transit in urban areas, and determined whether car-based Medicaid regulatory standards produce their intended geographic coverage. METHODS: We obtained data for this study from the Substance Abuse and Mental Health Services Administration's Buprenorphine Practitioner Locator, Microsoft Bing Maps, and the American Community Survey. We examined four urban counties at the centers of the metropolitan statistical areas with the highest 2017 accidental drug poisoning death rates: Kanawha, WV; Montgomery, OH; Philadelphia, PA; and St. Louis City, MO. These counties comprised 696 census tracts representing 1,038,564 households. We calculated travel times from each census tract center to the nearest buprenorphine prescribers by car and public transit, and compared that to 30-min regulatory standards and by whether census tracts had below median levels of car access. We calculated Global Moran's I statistics to determine whether spatial clustering was present among census tracts with limited access to buprenorphine prescribers. RESULTS: Households in all but two census tracts could access a buprenorphine prescriber within 30 min by car. However, households in 12.1% (84) of census tracts could not do so by public transit. The correlation between car- and public transit-based travel times to the nearest buprenorphine prescriber was 0.11 (95% CI = 0.07-0.22). More than 15% (47,918) of households in the two less densely populated counties could not travel to the nearest prescriber in 30 min and resided in census tracts where access to cars was relatively low. There was no evidence of spatial clustering among census tracts with public transit travel times exceeding 30 min, or among census tracts with public transit travel times exceeding 30 min and below median values of access to cars. CONCLUSIONS: Geographic access to buprenorphine prescribers is overestimated by regulatory standards that apply car-based travel time estimates, which are a weak proxy for public transit-based travel times. Since geographic areas with limited access to buprenorphine prescribers do not tend to cluster near one another, individually targeted interventions may be necessary to improve buprenorphine access and utilization.

Quantum-Limited Time-Frequency Estimation through Mode-Selective Photon Measurement.

By projecting onto complex optical mode profiles, it is possible to estimate arbitrarily small separations between objects with quantum-limited precision, free of uncertainty arising from overlapping intensity profiles. Here we extend these techniques to the time-frequency domain using mode-selective sum-frequency generation with shaped ultrafast pulses. We experimentally resolve temporal and spectral separations between incoherent mixtures of single-photon level signals ten times smaller than their optical bandwidths with a tenfold improvement in precision over the intensity-only Cramér-Rao bound.

Heralded generation of high-purity ultrashort single photons in programmable temporal shapes.

We experimentally demonstrate a source of nearly pure single photons in arbitrary temporal shapes heralded from a parametric down-conversion (PDC) source at telecom wavelengths. The technology is enabled by the tailored dispersion of in-house fabricated waveguides with shaped pump pulses to directly generate the PDC photons in on-demand temporal shapes. We generate PDC photons in Hermite-Gauss and frequency-binned modes and confirm a minimum purity of 0.81, even for complex temporal shapes.

Potential drug-drug and drug-disease interactions in well-functioning community-dwelling older adults.

WHAT IS KNOWN AND OBJECTIVE: There are few studies examining both drug-drug and drug-disease interactions in older adults. Therefore, the objective of this study was to describe the prevalence of potential drug-drug and drug-disease interactions and associated factors in community-dwelling older adults. METHODS: This cross-sectional study included 3055 adults aged 70-79 without mobility limitations at their baseline visit in the Health Aging and Body Composition Study conducted in the communities of Pittsburgh PA and Memphis TN, USA. The outcome factors were potential drug-drug and drug-disease interactions as per the application of explicit criteria drawn from a number of sources to self-reported prescription and non-prescription medication use. RESULTS: Over one-third of participants had at least one type of interaction. Approximately one quarter (25·1%) had evidence of had one or more drug-drug interactions. Nearly 10·7% of the participants had a drug-drug interaction that involved a non-prescription medication. % The most common drug-drug interaction was non-steroidal anti-inflammatory drugs (NSAIDs) affecting antihypertensives. Additionally, 16·0% had a potential drug-disease interaction with 3·7% participants having one involving non-prescription medications. The most common drug-disease interaction was aspirin/NSAID use in those with history of peptic ulcer disease without gastroprotection. Over one-third (34·0%) had at least one type of drug interaction. Each prescription medication increased the odds of having at least one type of drug interaction by 35-40% [drug-drug interaction adjusted odds ratio (AOR) = 1·35, 95% confidence interval (CI) = 1·27-1·42; drug-disease interaction AOR = 1·30; CI = 1·21-1·40; and both AOR = 1·45; CI = 1·34-1·57]. A prior hospitalization increased the odds of having at least one type of drug interaction by 49-84% compared with those not hospitalized (drug-drug interaction AOR = 1·49, 95% CI = 1·11-2·01; drug-disease interaction AOR = 1·69, CI = 1·15-2·49; and both AOR = 1·84, CI = 1·20-2·84). WHAT IS NEW AND CONCLUSION: Drug interactions are common among community-dwelling older adults and are associated with the number of medications and hospitalization in the previous year. Longitudinal studies are needed to evaluate the impact of drug interactions on health-related outcomes.

Spectrally Engineering Photonic Entanglement with a Time Lens.

A time lens, which can be used to reshape the spectral and temporal properties of light, requires the ultrafast manipulation of optical signals and presents a significant challenge for single-photon application. In this work, we construct a time lens based on dispersion and sum-frequency generation to spectrally engineer single photons from an entangled pair. The strong frequency anticorrelations between photons produced from spontaneous parametric down-conversion are converted to positive correlations after the time lens, consistent with a negative-magnification system. The temporal imaging of single photons enables new techniques for time-frequency quantum state engineering.

Tadalafil therapy for sarcoidosis-associated pulmonary hypertension.

Sarcoidosis-associated pulmonary hypertension (SAPH) is estimated to occur in at least 5% or more of sarcoidosis patients, and it contributes to significant morbidity and mortality. Optimal therapy for SAPH is not well established. We performed a 24-week open-label trial of tadalafil for SAPH at 2 academic medical centers. Subjects were required to have confirmed sarcoidosis plus a right heart catheterization within 12 months of enrollment showing a mean pulmonary artery pressure ≥ 25 mmHg, a pulmonary artery wedge pressure ≤ 15 mmHg, and a calculated pulmonary vascular resistance ≥ 3 Wood units. Subjects received 20 mg/day of tadalafil for the first 4 weeks and then 40 mg/day for the subsequent 20 weeks. Sixteen patients were screened, 12 of whom met criteria for enrollment. At 24 weeks, there was no overall improvement in 6-minute walk distance (6MWD). Five of the 12 subjects dropped out of the study early (2 for social reasons, 3 for medical reasons). There was no significant change in short form 36, St. George's respiratory questionnaire, or maximum Borg dyspnea scores over the 24 weeks. There were no significant adverse events or laboratory abnormalities clearly related to tadalafil in the cohort. The study did not meet the primary end point of change in 6MWD because of the small sample size. Tadalafil was generally safely administered in this cohort of SAPH patients. There was a relatively high dropout rate but no major adverse events and no clinical worsening. Larger studies are needed to explore this question further. (Trial registration: ClinicalTrials.gov identifier: NCT01324999).

Leishmania mexicana amastigotes inhibit p38 and JNK and activate PI3K/AKT: role in the inhibition of apoptosis of dendritic cells.

Leishmania mexicana is the causal agent of cutaneous leishmaniasis in Mexico. Dendritic cells (DC) are one of the host cells of Leishmania parasites. Intracellular microorganisms inhibit host cell apoptosis as a strategy to ensure their survival in infected cells. We have previously shown that Leishmania mexicana promastigotes and amastigotes inhibit camptothecin-induced apoptosis of monocyte-derived dendritic cells (moDC), but the mechanisms underlying the inhibition of apoptosis of DC by Leishmania have not been established. MAP kinases and PI3K participate in the process of apoptosis and are modulated by different species of Leishmania. As shown in this study, the infection of moDC with L. mexicana amastigotes diminished significantly the phosphorylation of the MAP kinases p38 and JNK. The inhibition of both kinases diminished significantly DNA fragmentation in moDC stimulated with camptothecin. On the other hand, L. mexicana amastigotes were able to activate the anti-apoptotic pathways PI3K and AKT. Our results indicate that L. mexicana amastigotes have the capacity to diminish MAP kinases activation and activate PI3K and AKT, which is probably one of the strategies employed by L. mexicana amastigotes to inhibit apoptosis in the infected moDC.

Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD.

STUDY OBJECTIVE: To examine the efficacy and safety of the once-daily, inhaled, long-acting muscarinic antagonist/ß2-agonist combination umeclidinium/vilanterol (UMEC/VI) compared with UMEC and VI monotherapies in patients with chronic obstructive pulmonary disease (COPD). METHODS: In this 24-week, double-blind, placebo-controlled, parallel-group study (ClinicalTrials.gov: NCT01313650) eligible patients were randomised 3:3:3:2 to treatment with UMEC/VI 62.5/25 mcg, UMEC 62.5 mcg, VI 25 mcg or placebo administered once daily via dry powder inhaler (N = 1532; intent-to-treat population). Primary endpoint was trough forced expiratory volume in one second (FEV1) on Day 169 (23-24 h post-dose). Additional lung-function, symptomatic, and health-related quality-of-life endpoints were assessed, including 0-6 h weighted-mean FEV1, rescue salbutamol use, Transition Dyspnoea Index (TDI), Shortness Of Breath With Daily Activity (SOBDA) and St. George's Respiratory Questionnaire (SGRQ) scores. Safety evaluations included adverse events (AEs), vital signs, 12-lead/24-h Holter electrocardiography parameters and clinical laboratory/haematology measurements. RESULTS: All active treatments produced statistically significant improvements in trough FEV1 compared with placebo on Day 169 (0.072-0.167 L, all p < 0.001); increases with UMEC/VI 62.5/25 mcg were significantly greater than monotherapies (0.052-0.095 L, p ≤ 0.004). Improvements were observed for UMEC/VI 62.5/25 mcg vs placebo for weighted-mean FEV1 on Day 168 (0.242 L, p < 0.001), rescue salbutamol use during Weeks 1-24 (-0.8 puffs/day, p = 0.001), TDI (1.2 units, p < 0.001), SOBDA (-0.17 units, p < 0.001) and SGRQ (-5.51 units, p < 0.001) scores. No clinically-significant changes in vital signs, electrocardiography, or laboratory parameters were observed. CONCLUSION: Once-daily UMEC/VI 62.5/25 mcg was well tolerated and provided clinically-significant improvements in lung function and symptoms in patients with COPD.

Bowel perforation in intestinal lymphoma: incidence and clinical features.

BACKGROUND: Perforation is a serious life-threatening complication of lymphomas involving the gastrointestinal (GI) tract. Although some perforations occur as the initial presentation of GI lymphoma, others occur after initiation of chemotherapy. To define the location and timing of perforation, a single-center study was carried out of all patients with GI lymphoma. PATIENTS AND METHODS: Between 1975 and 2012, 1062 patients were identified with biopsy-proven GI involvement with lymphoma. A retrospective chart review was undertaken to identify patients with gut perforation and to determine their clinicopathologic features. RESULTS: Nine percent (92 of 1062) of patients developed a perforation, of which 55% (51 of 92) occurred after chemotherapy. The median day of perforation after initiation of chemotherapy was 46 days (mean, 83 days; range, 2-298) and 44% of perforations occurred within the first 4 weeks of treatment. Diffuse large B-cell lymphoma (DLBCL) was the most common lymphoma associated with perforation (59%, 55 of 92). Compared with indolent B-cell lymphomas, the risk of perforation was higher with aggressive B-cell lymphomas (hazard ratio, HR = 6.31, P < 0.0001) or T-cell/other types (HR = 12.40, P < 0.0001). The small intestine was the most common site of perforation (59%). CONCLUSION: Perforation remains a significant complication of GI lymphomas and is more frequently associated with aggressive than indolent lymphomas. Supported in part by University of Iowa/Mayo Clinic SPORE CA97274 and the Predolin Foundation.

Video capsule retention in inflammatory bowel disease: an unusual presentation and discussion of retrieval methods.

Inflammatory Bowel Disease (IBD) is characterized by chronic inflammation in the gastrointestinal (GI) tract. Video capsule endoscopy (VCE) is widely used to investigate the small bowel, and capsule retention is the most serious potential complication. Endoscopic and surgical management has been reported, but in the absence of bowel obstruction, there is little consensus as to which should be employed. In this case report, we describe a patient who was investigated with VCE for weight loss and anaemia. He had previously undergone colectomy with ileoanal pouch formation for ulcerative colitis (UC). Capsule retention occurred at an ileal stricture and he was subsequently diagnosed with Crohn's disease (CD). We describe his medical management and successful capsule retrieval using endoscopic methods. This case also highlights the importance of screening for intestinal strictures in an atypical presentation of UC following colectomy.

Comment on "Refractive index of silicon at γ ray energies".

A Comment on the Letter by Habs et al., Phys. Rev. Lett. 108, 184802 (2012).

Ambrisentan for sarcoidosis associated pulmonary hypertension.

BACKGROUND: Sarcoidosis associated pulmonary hypertension (SAPH) is associated with significant morbidity and mortality. There is a paucity of information concerning therapy for this condition. METHODS: We performed a prospective, open-label, proof of concept trial of ambrisentan for SAPH. 21 subjects with SAPH received 5 mg/day of ambrisentan for 4 weeks and then 10/mg day for 20 subsequent weeks. RESULTS: No significant change was noted in the 6-minute walk distance over the course of the study (mean change between week 0 and 24: 9.8 +/- 54.6 meters, p: NS). There were also no significant differences between weeks 0 and 24 in terms of dyspnea as measured by the modified Borg scale, serum brain naturetic peptide, diffusing capacity, and quality of life as measured by the Short Form-36. There was a high dropout rate: overall: 11/21, 52%; social reasons: 3/21, 14%; medical reasons: 8/21, 38% because of dyspnea: 6/21, 29% and/or edema: 4/21, 19%. Of those who completed the 24 week study (10/21, 48%), there was an improvement in their WHO functional class and a marked improvement in their health related quality of life as measured by the St. George Respiratory questionnaire (-15.3 +/- 25.0). However both these improvments did not reach statistical significance possibly because of the small sample size. CONCLUSION: Although ambrisentan was not well tolerated by many of these subjects with SAPH, in those who remained in this 24-week trial, improvements in WHO functional class and in health related quality of life suggested a possible benefit of this drug in selected patients.

Start current and gain measurements for a Smith-Purcell free-electron laser.

Coherent Smith-Purcell radiation is a promising source of coherent emission in the THz domain. Although it has been observed in several experiments, some physical quantities related to the bunching of an initially continuous beam had not yet been studied experimentally. Among them, the gain as function of beam current, together with the value of the start current, needed to be addressed. We report here their measurements in a microwave experiment using a sheet beam. A start current of about 20 A/m was found. Two-dimensional simulations with a very thin beam agree well with our results.

Low-dose azathioprine or mercaptopurine in combination with allopurinol can bypass many adverse drug reactions in patients with inflammatory bowel disease.

BACKGROUND: The thiopurine drugs, azathioprine and mercaptopurine (MP), are established treatments for IBD. However, therapeutic failure caused by adverse drug reactions occurs frequently. AIM: To study combination of allopurinol with reduced-dose thiopurine in an attempt to avoid adverse drug reactions in the treatment of IBD. METHODS: Patients with drug reactions to full-dose thiopurines were recruited for combination therapy in two IBD centres in this retrospective study. Dosing was guided by measuring thiopurine methyltransferase (for UK patients) or thioguanine nucleotides and methyl-6MP (Australian patients). Response was monitored by clinical activity indices. RESULTS: Of 41 patients, 25 had non-hepatic and 16 had hepatitic reactions. Clinical remission was achieved in 32 patients (78%) with a median follow-up of 41 weeks (range 0.5-400). Patients who did not respond to combination therapy tended to fail early with the same adverse reaction. The relative risk of having an adverse reaction with methyl-6MP in the top interquartile range was 2.7 (1.3-28) times that with methyl-6MP in the lower three quartiles (95% confidence interval). CONCLUSION: The combined experience from our centres is the largest reported experience of this combination therapy strategy in IBD, and the first to provide evidence for benefit in thiopurine and allopurinol co-therapy to avoid non-hepatitic adverse drug reactions.

Prescribing statins to patients with nonalcoholic fatty liver disease: real cardiovascular benefits outweigh theoretical hepatotoxic risk.

Statins are among the most widely prescribed drugs in the western world and play a significant role in reducing cardiovascular risk. However, concern regarding their hepatic safety profile has meant that patients with concurrent liver pathology are often denied such benefits. In this review we consider the evidence for and against the prescription of statins to patients with nonalcoholic fatty liver disease, a group typically associated with high cardiovascular risk. Contrary to current opinion, we find that there is considerable evidence for and little evidence against the prescription of statins to this population and suggest that the guidelines advising against their use in these patients should be reviewed.