Hybrid organic–inorganic perovskites have emerged as promising gain media for tunable, solution-processed semiconductor lasers. However, continuous-wave operation has not been achieved so far1–3. ...Here, we demonstrate that optically pumped continuous-wave lasing can be sustained above threshold excitation intensities of ~17 kW cm–2 for over an hour in methylammonium lead iodide (MAPbI3) distributed feedback lasers that are maintained below the MAPbI3 tetragonal-to-orthorhombic phase transition temperature of T ≈ 160 K. In contrast with the lasing death phenomenon that occurs for pure tetragonal-phase MAPbI3 at T > 160 K (ref. 4), we find that continuous-wave gain becomes possible at T ≈ 100 K from tetragonal-phase inclusions that are photogenerated by the pump within the normally existing, larger-bandgap orthorhombic host matrix. In this mixed-phase system, the tetragonal inclusions function as carrier recombination sinks that reduce the transparency threshold, in loose analogy to inorganic semiconductor quantum wells, and may serve as a model for engineering improved perovskite gain media.
Following irradiation, numerous DNA-damage-responsive proteins rapidly redistribute into microscopically visible subnuclear aggregates, termed ionising-radiation-induced foci (IRIF). How the ...enrichment of proteins on damaged chromatin actually relates to DNA repair remains unclear. Here, we use super-resolution microscopy to examine the spatial distribution of BRCA1 and 53BP1 proteins within single IRIF at subdiffraction-limit resolution, yielding an unprecedented increase in detail that was not previously apparent by conventional microscopy. Consistent with a role for 53BP1 in promoting DNA double-strand break repair by non-homologous end joining, 53BP1 enrichment in IRIF is most prominent in the G0/G1 cell cycle phases, where it is enriched in dense globular structures. By contrast, as cells transition through S phase, the recruitment of BRCA1 into the core of IRIF is associated with an exclusion of 53BP1 to the focal periphery, leading to an overall reduction of 53BP1 occupancy at DNA damage sites. Our data suggest that the BRCA1-associated IRIF core corresponds to chromatin regions associated with repair by homologous recombination, and the enrichment of BRCA1 in IRIF represents a temporal switch in the DNA repair program. We propose that BRCA1 antagonises 53BP1-dependent DNA repair in S phase by inhibiting its interaction with chromatin proximal to damage sites. Furthermore, the genomic instability exhibited by BRCA1-deficient cells might result from a failure to efficiently exclude 53BP1 from such regions during S phase.
Organic–inorganic lead halide perovskite semiconductors have recently reignited the prospect of a tunable, solution-processed diode laser, which has the potential to impact a wide range of ...optoelectronic applications. Here, we demonstrate a metal-clad, second-order distributed feedback methylammonium lead iodide perovskite laser that marks a significant step toward this goal. Optically pumping this device with an InGaN diode laser at low temperature, we achieve lasing above a threshold pump intensity of 5 kW/cm2 for durations up to ∼25 ns at repetition rates exceeding 2 MHz. We show that the lasing duration is not limited by thermal runaway and propose instead that lasing ceases under continuous pumping due to a photoinduced structural change in the perovskite that reduces the gain on a submicrosecond time scale. Our results indicate that the architecture demonstrated here could provide the foundation for electrically pumped lasing with a threshold current density J th < 5 kA/cm2 under sub-20 ns pulsed drive.
Summary Background Bisphosphonates reduce the risk of skeletal events in patients with malignant bone disease, and zoledronic acid has shown potential anticancer effects in preclinical and clinical ...studies. We aimed to establish whether bisphosphonates can affect clinical outcomes in patients with multiple myeloma. Methods Patients of age 18 years or older with newly diagnosed multiple myeloma were enrolled from 120 centres in the UK. Computer-generated randomisation sequence was used to allocate patients equally, via an automated telephone service, to receive 4 mg zoledronic acid as an infusion every 3–4 weeks or 1600 mg oral clodronic acid daily. Patients also received intensive or non-intensive induction chemotherapy. No investigators, staff, or patients were masked to treatment allocation, and bisphosphonate and maintenance therapy continued at least until disease progression. The primary endpoints were overall survival, progression-free survival, and overall response rate. We assessed between-group differences with Cox proportional hazards models for progression-free survival and overall survival, and with logistic regression models for overall response rate. Analysis was by intention to treat. This trial is registered, number ISRCTN68454111. Findings 1970 patients were enrolled between May, 2003, and November, 2007, of whom 1960 were eligible for intention-to-treat analysis: 981 in the zoledronic acid group (555 on intensive chemotherapy, 426 on non-intensive chemotherapy); and 979 on clodronic acid (556 on intensive chemotherapy, 423 on non-intensive chemotherapy). The treatment cutoff was Oct 5, 2009, with patients receiving bisphosphonates for a median of 350 days (IQR 137–632) before disease progression, with a median of 3·7 years' follow-up (IQR 2·9–4·7). Zoledronic acid reduced mortality by 16% (95% CI 4–26) versus clodronic acid (hazard ratio HR 0·84, 95% CI 0·74–0·96; p=0·0118), and extended median overall survival by 5·5 months (50·0 months, IQR 21·0 to not reached vs 44·5 months, IQR 16·5 to not reached; p=0·04). Zoledronic acid also significantly improved progression-free survival by 12% (95% CI 2–20) versus clodronic acid (HR 0·88, 95% CI 0·80–0·98; p=0·0179), and increased median progression-free survival by 2·0 months (19·5 months, IQR 9·0–38·0 vs 17·5 months, IQR 8·5–34·0; p=0·07). Rates of complete, very good partial, or partial response did not differ significantly between the zoledronic acid and clodronic acid groups for patients receiving intensive induction chemotherapy (432 patients 78% vs 422 76%; p=0·43) or non-intensive induction chemotherapy (215 50% vs 195 46%; p=0·18). Both bisphosphonates were generally well tolerated, with similar occurrence of acute renal failure and treatment-emergent serious adverse events, but zoledronic acid was associated with higher rates of confirmed osteonecrosis of the jaw (35 4%) than was clodronic acid (3 <1%). Interpretation Consistent with the potential anticancer activity of zoledronic acid, overall survival improved independently of prevention of skeletal-related events, showing that zoledronic acid has treatment benefits beyond bone health. These findings support immediate treatment with zoledronic acid in patients with newly diagnosed multiple myeloma, not only for prevention of skeletal-related events, but also for potential antimyeloma benefits. Funding Medical Research Council (London, UK), with unrestricted educational grants from Novartis, Schering Health Care, Chugai, Pharmion, Celgene, and Ortho Biotech.
Abstract Background People with schizophrenia experience increased rates of osteoporosis and may be at heightened risk of fractures. We conducted a systematic review and meta-analysis to investigate ...fractures among people with schizophrenia compared to people without mental illness. Method We systematically searched major electronic databases from inception until October 2014. Articles were included that reported the number of fractures in people with schizophrenia and a control group. Two independent authors conducted searches, completed methodological assessment and extracted data. Data were narratively synthesized, and a random-effects incidence rate ratio (IRR) meta-analysis was performed. Results Eight studies were included encompassing 48,384 people with schizophrenia (49.9–75.2 years, 41%–100% female) and 3,945,783 controls. The pooled adjusted rate of fractures per 1000 person-years was 5.54 95% confidence interval (CI)=4.92–5.57 in people with schizophrenia and 3.48 (95% CI=3.39–3.64) in control participants. The comparative meta-analysis showed that people with schizophrenia experience an increased rate of fractures compared to control participants (IRR 1.72, 95% CI=1.24–2.39, I2 = 49%; n = 168,914). There were insufficient data to conduct moderation analysis, but the narrative review consistently highlighted that antipsychotic medication was an important risk factor for fractures. Conclusion People with schizophrenia are at significantly increased risk of fractures. Future research is required to understand the mechanisms and should seek to validate fracture prediction algorithms used in the general population. Importantly, there is a need to develop preventative strategies to improve bone health and reduce fracture risk involving the wider multidisciplinary team and incorporating falls-prevention strategies.
First metatarsophalangeal joint arthrodesis with isolated dorsal plating without a lag screw and without a compressive mechanism incorporated into the plate is not well studied. Although surface area ...for bony fusion is increased, there is concern for lower fusion rates and progressive loss of sagittal plane positioning. We present fusion rates and progressive sagittal plane deviation with isolated dorsal plate fixation.
A retrospective review was performed of 41 patients (43 feet) who underwent first metatarsophalangeal joint arthrodesis with isolated dorsal plate fixation. Patients were excluded if another form of fixation was used, if there was a compressive feature to the dorsal plate, or if a lag screw was used. Preoperative, immediate postoperative, and final postoperative radiographs were reviewed to assess radiographic alignment and fusion about the first metatarsophalangeal joint. Specific attention was placed on hallux dorsiflexion in relation to the first metatarsal. Statistical significance was set at P ≤ .05 a priori.
Patients were followed for an average of 55.7 weeks. Overall union rate was 97.62%. The average time to union was 42.55 days. Reoperation rate was 4.65%, with one patient requiring revisional arthrodesis with a lag screw construct. Hallux abduction and first-second intermetatarsal angle correction reached significance (P < .00001). Hallux dorsiflexion increased by 1.05° between initial postoperative and final postoperative radiographs (P = .542).
Although fusion rates and progressive loss of sagittal plane position have been concerns for first metatarsophalangeal joint arthrodesis with an isolated dorsal plate construct, these results suggest this to be a stable construct without loss of positioning over time.
Summary Background Bisphosphonates are the standard of care for reducing the risk of skeletal-related events in patients with bone lesions from multiple myeloma. The MRC Myeloma IX study was designed ...to compare the effects of zoledronic acid versus clodronic acid in newly diagnosed patients with multiple myeloma. Here, we report the secondary outcomes relating to skeletal events. Methods Patients (≥18 years) with newly diagnosed multiple myeloma were enrolled from 120 centres in the UK and received intensive or non-intensive antimyeloma treatment. A computer-generated randomisation sequence was used to allocate patients in a 1:1 ratio, through an automated telephone service to intravenous zoledronic acid (4 mg every 21–28 days) or oral clodronic acid (1600 mg/day), and the drugs were continued at least until disease progression. No investigators, staff, or patients were masked to treatment allocation. The primary endpoints—overall survival, progression-free survival, and overall response rate—and adverse events have been reported previously. We assessed between-group differences with Cox proportional hazards models for time to first skeletal-related event and incidence of skeletal-related events. These were defined as fractures, spinal cord compression, radiation or surgery to bone, and new osteolytic lesions. Data were analysed until disease progression. Analyses were by intention to treat. This trial is registered, number ISRCTN68454111. Findings 1960 patients were randomly assigned and analysed—981 in the zoledronic acid group and 979 in the clodronic acid group. This trial is fully enrolled, and follow-up continues. At a median follow-up of 3·7 years (IQR 2·9–4·7), patients in the zoledronic acid group had a lower incidence of skeletal-related events than did those in the clodronic acid group (265 27% vs 346 35%, respectively; hazard ratio 0·74, 95% CI 0·62–0·87; p=0·0004). Zoledronic acid was also associated with a lower risk of any skeletal-related event in the subsets of patients with (233 35% of 668 vs 292 43% of 682 with clodronic acid; 0·77, 0·65–0·92; p=0·0038) and without bone lesions at baseline (29 10% of 302 vs 48 17% of 276 with clodronic acid; 0·53, 0·33–0·84; p=0·0068). Fewer patients in the zoledronic acid group had vertebral fractures than did those in the clodronic acid group (50 5% in the zoledronic acid group vs 88 9% in the clodronic acid group; p=0·0008), other fractures (45 5% vs 66 7%; p=0·04), and new osteolytic lesions (46 5% vs 95 10%; p<0·0001). Interpretation The results of this study support the early use of zoledronic acid rather than clodronic acid in patients with newly diagnosed multiple myeloma for the prevention of skeletal-related events, irrespective of bone disease status at baseline. Funding Medical Research Council (London, UK), Novartis, Schering Health Care, Chugai, Pharmion, Celgene, and Ortho Biotech.
Ecological communities are increasingly exposed to multiple interacting stressors. For example, warming directly affects the physiology of organisms, eutrophication stimulates the base of the food ...web, and harvesting larger organisms for human consumption dampens top‐down control. These stressors often combine in the natural environment with unpredictable results. Bacterial communities in coastal ecosystems underpin marine food webs and provide many important ecosystem services (e.g. nutrient cycling and carbon fixation). Yet, how microbial communities will respond to a changing climate remains uncertain. Thus, we used marine mesocosms to examine the impacts of warming, nutrient enrichment, and altered top‐predator population size structure (common shore crab) on coastal microbial biofilm communities in a crossed experimental design. Warming increased bacterial α‐diversity (18% increase in species richness and 67% increase in evenness), but this was countered by a decrease in α‐diversity with nutrient enrichment (14% and 21% decrease for species richness and evenness, respectively). Thus, we show some effects of these stressors could cancel each other out under climate change scenarios. Warming and top‐predator population size structure both affected bacterial biofilm community composition, with warming increasing the abundance of bacteria capable of increased mineralization of dissolved and particulate organic matter, such as Flavobacteriia, Sphingobacteriia, and Cytophagia. However, the community shifts observed with warming depended on top‐predator population size structure, with Sphingobacteriia increasing with smaller crabs and Cytophagia increasing with larger crabs. These changes could alter the balance between mineralization and carbon sequestration in coastal ecosystems, leading to a positive feedback loop between warming and CO2 production. Our results highlight the potential for warming to disrupt microbial communities and biogeochemical cycling in coastal ecosystems, and the importance of studying these effects in combination with other environmental stressors.
Coastal ecosystems are increasingly exposed to multiple anthropogenic stressors, including warming, nutrient enrichment, and changes in population size structure. Microbial communities underpin marine food webs, but how bacteria will respond to the combined effects of these stressors remains uncertain. We found that bacterial diversity increased with warming and decreased with nutrient enrichment. However, these effects cancelled out when the stressors were combined. Compositional changes with warming depended on top‐predator population size structure. Notably, warming increased abundance of degraders of complex biomolecules, such as Bacteroidetes. This could divert carbon from long‐term storage in the oceans.
Metal halide perovskites are a promising platform for solution‐processed semiconductor lasers but have so far only achieved continuous‐wave (cw) operation at low temperature. Here, the origin of this ...limitation is investigated in prototypical methylammonium lead iodide (MAPbI3) distributed feedback (DFB) lasers and is found to stem from a combination of pump‐induced heating and the accumulation of photoinduced defects. A temperature rise of more than 30 K in the first few hundred ns following pump turn‐on is observed, which leads to a dynamic increase in threshold owing to the strong temperature dependence of stimulated emission in MAPbI3 thin films. In parallel, it is found that the Shockley–Read–Hall rate coefficient increases by an order of magnitude on a similar timescale, suppressing the carrier density generated by the pump. The combined impact of both effects is understood using a comprehensive model that quantitatively explains the duration of lasing as a function of pump intensity and predicts that the threshold of current DFB lasers must be decreased by an order of magnitude to achieve cw operation at room temperature.
The origin of lasing death in hybrid perovskite semiconductors is explored and found to result from a combination of pump‐induced heating and the accumulation of photoinduced defects. Modeling quantitatively explains the observed lasing duration and predicts the material and device parameters needed to achieve continuous‐wave operation at room temperature.
Anodyspareunia may be an adverse outcome of prostate cancer (PCa) treatment for gay, bisexual, and other men who have sex with men (GBM).
The aims of this study were to (1) describe the clinical ...symptoms of painful receptive anal intercourse (RAI) in GBM following PCa treatment, (2) estimate the prevalence of anodyspareunia, and (3) identify clinical and psychosocial correlates.
This was a secondary analysis of baseline and 24-month follow-up data from the Restore-2 randomized clinical trial of 401 GBM treated for PCa. The analytic sample included only those participants who attempted RAI during or since their PCa treatment (N = 195).
Anodyspareunia was operationalized as moderate to severe pain during RAI for ≥6 months that resulted in mild to severe distress. Additional quality-of-life outcomes included the Expanded Prostate Cancer Index Composite (bowel function and bother subscales), the Brief Symptom Inventory-18, and the Functional Assessment of Cancer Therapy-Prostate.
Overall 82 (42.1%) participants reported pain during RAI since completing PCa treatment. Of these, 45.1% experienced painful RAI sometimes or frequently, and 63.0% indicated that the pain was persistent. The pain at its worst was moderate to very severe for 79.0%. The experience of pain was at least mildly distressing for 63.5%. Painful RAI worsened for a third (33.4%) of participants after completing PCa treatment. Of the 82 GBM, 15.4% were classified as meeting criteria for anodyspareunia. Antecedents of anodyspareunia included a lifelong history of painful RAI and bowel dysfunction following PCa treatment. Those reporting symptoms of anodyspareunia were more likely to avoid RAI due to pain (adjusted odds ratio, 4.37), which was negatively associated with sexual satisfaction (mean difference, -2.77) and self-esteem (mean difference, -3.33). The model explained 37.2% of the variance in overall quality of life.
Culturally responsive PCa care should include the assessment of anodyspareunia among GBM and explore treatment options.
This is the largest study to date focused on anodyspareunia among GBM treated for PCa. Anodyspareunia was assessed with multiple items characterizing the intensity, duration, and distress related to painful RAI. The external validity of the findings is limited by the nonprobability sample. Furthermore, the cause-and-effect relationships between the reported associations cannot be established by the research design.
Anodyspareunia should be considered a sexual dysfunction in GBM and investigated as an adverse outcome of PCa treatment.
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