Binding Energy of Triplet Excitons in Nonfullerene Acceptors: The Effects of Fluorination and Chlorination.

One strategy to improve the photovoltaic properties of nonfullerene acceptors (NFAs), employed in state-of-art organic solar cells, is the rational fluorination or chlorination of these molecules. Although this modification improves important acceptor properties, little is known about the effects on the triplet states. Here, we combine the polarizable continuum model with an optimally tuned range-separated hybrid functional to investigate this issue. We find that fluorination or chlorination of NFAs decreases the degree of the highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) overlap along these molecules. Consequently, the energy gap between T1 and S1 states, ΔEST = ES1 - ET1, also decreases. This effect reduces the binding energy of triplet excitons, which favors their dissociation into free charges. Furthermore, the reduction of ΔEST can contribute to mitigating the losses produced by the nonradiative deactivation of the T1 excitons. Interestingly, although Cl has a lower electronegativity than F, chlorination is more effective to reduce ΔEST. Since the chlorination of NFAs is easier than fluorination, Cl substitution can be a useful approach to enhance solar energy harvesting using triplet excitons.

Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial-PEARL.

BACKGROUND: Palbociclib plus endocrine therapy (ET) is the standard treatment of hormone receptor-positive and human epidermal growth factor receptor 2-negative, metastatic breast cancer (MBC). However, its efficacy has not been compared with that of chemotherapy in a phase III trial. PATIENTS AND METHODS: PEARL is a multicentre, phase III randomised study in which patients with aromatase inhibitor (AI)-resistant MBC were included in two consecutive cohorts. In cohort 1, patients were randomised 1 : 1 to palbociclib plus exemestane or capecitabine. On discovering new evidence about estrogen receptor-1 (ESR1) mutations inducing resistance to AIs, the trial was amended to include cohort 2, in which patients were randomised 1 : 1 between palbociclib plus fulvestrant and capecitabine. The stratification criteria were disease site, prior sensitivity to ET, prior chemotherapy for MBC, and country of origin. Co-primary endpoints were progression-free survival (PFS) in cohort 2 and in wild-type ESR1 patients (cohort 1 + cohort 2). ESR1 hotspot mutations were analysed in baseline circulating tumour DNA. RESULTS: From March 2014 to July 2018, 296 and 305 patients were included in cohort 1 and cohort 2, respectively. Palbociclib plus ET was not superior to capecitabine in both cohort 2 [median PFS: 7.5 versus 10.0 months; adjusted hazard ratio (aHR): 1.13; 95% confidence interval (CI): 0.85-1.50] and wild-type ESR1 patients (median PFS: 8.0 versus 10.6 months; aHR: 1.11; 95% CI: 0.87-1.41). The most frequent grade 3-4 toxicities with palbociclib plus exemestane, palbociclib plus fulvestrant and capecitabine, respectively, were neutropenia (57.4%, 55.7% and 5.5%), hand/foot syndrome (0%, 0% and 23.5%), and diarrhoea (1.3%, 1.3% and 7.6%). Palbociclib plus ET offered better quality of life (aHR for time to deterioration of global health status: 0.67; 95% CI: 0.53-0.85). CONCLUSIONS: There was no statistical superiority of palbociclib plus ET over capecitabine with respect to PFS in MBC patients resistant to AIs. Palbociclib plus ET showed a better safety profile and improved quality of life.

A phase II feasibility study of palbociclib in combination with adjuvant endocrine therapy for hormone receptor-positive invasive breast carcinoma.

BACKGROUND: The CDK4/6 inhibitor palbociclib prolongs progression-free survival in hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer when combined with endocrine therapy. This phase II trial was designed to determine the feasibility of adjuvant palbociclib and endocrine therapy for early breast cancer. PATIENTS AND METHODS: Eligible patients with HR+/HER2- stage II-III breast cancer received 2 years of palbociclib at 125 mg daily, 3 weeks on/1 week off, with endocrine therapy. The primary end point was discontinuation from palbociclib due to toxicity, non-adherence, or events related to tolerability. A discontinuation rate of 48% or higher would indicate the treatment duration of 2 years was not feasible, and was evaluated under a binomial test using a one-sided α = 0.025. RESULTS: Overall, 162 patients initiated palbociclib; over half had stage III disease (52%) and most received prior chemotherapy (80%). A total of 102 patients (63%) completed 2 years of palbociclib; 50 patients discontinued early for protocol-related reasons (31%, 95% CI 24% to 39%, P = 0.001), and 10 discontinued due to protocol-unrelated reasons. The cumulative incidence of protocol-related discontinuation was 21% (95% CI 14% to 27%) at 12 months from start of treatment. Rates of palbociclib-related toxicity were congruent with the metastatic experience, and there were no cases of febrile neutropenia. Ninety-one patients (56%) required at least one dose reduction. CONCLUSION: Adjuvant palbociclib is feasible in early breast cancer, with a high proportion of patients able to complete 2 years of therapy. The safety profile in the adjuvant setting mirrors that observed in metastatic disease, with approximately half of the patients requiring dose-modification. As extended duration adjuvant palbociclib appears feasible and tolerable for most patients, randomized phase III trials are evaluating clinical benefit in this population. CLINICALTRIALS.GOV REGISTRATION: NCT02040857.

[Guidelines of the German Respiratory Society for Diagnosis and Treatment of Adults Suffering from Acute, Subacute and Chronic Cough]. / Leitlinie der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin zur Diagnostik und Therapie von erwachsenen Patienten mit Husten.

The present 2019 S2k consensus guideline of the German Respiratory Society was written - in contrast to the predecessor more general S3 guidelines from 2004 and 2010 - for pneumologists, since 2014 the German College of General Practitioners and Family Physicians (DEGAM) published his own cough guidelines.The guideline contains 48 recommendations agreed by consensus and 16 statements, which are explained in the background text in the following nine chapters: epidemiology, physiology, classification, acute, subacute or chronic cough, diagnostics and therapy; an extra chapter was dedicated to chronic idiopathic cough. Further emphasis of the guideline is the physiology of cough in anticipation of the introduction of new drugs, as well as detailed treatises on cough triggered by affections in the upper respiratory tract or by gastroesophageal reflux. The guideline should provide the pneumologist with the latest knowledge from neighboring disciplines required for diagnosis and therapy of cough. The clinical chapters also contain a short summary, practical recommendations and a bibliography of their own. Three new, simplified algorithms for acute, subacute and chronic cough round off the Diagnostics chapter.

Electronic and structural properties of fluorene-thiophene copolymers as function of the composition ratio between the moieties: a theoretical study.

Through theoretical analysis, we study relevant properties of some molecular structures formed by oligothiophenes (T) and dioctylfluorenes (F) units, commonly employed in the fabrication of different kinds of optical and electronic devices. For so, we first consider F-(T)n-F molecules with different numbers of thiophene rings (n). Among other characteristics, we calculate the dipole moment change between the ground and excited state (Δµge), a quantity that greatly influences the exciton dissociation and charge carrier mobility. We show that the planarity of the ground state geometry correlates Δµge to the exciton binding energy (Eb), with higher Δµge's corresponding to lower Eb's when n > 3. We also unveil a relevant dependence of Δµge with the odd-even parity of n and that Δµge assumes higher values when the molecule is composed by bithiophene (instead of simple thiophenes) moieties in the syn-conformation (with the two heteroatoms pointing in the same direction). From molecules results, we then address larger systems, formed by different oligomers of F-T copolymers containing blocks of dioctylfluorenes and bithiophenes (T2). We systematic investigate their electronic and structural properties as function of the composition ratio between the T2 and F moieties. Similar to the molecules, we deduce that the magnitude of Δµge is higher for the syn conformer of the T2 unit. Moreover, the highest values of Δµge are achieved when the number of the T2 increases relative to a fixed number of the F units in the mer. Such behaviors are in agreement and actually can qualitative explain measurements in the literature on the quantum efficiency of charge carrier generation in F-T copolymers. The present findings can be helpful in designing novel materials with improved photoelectric responses.

Non-invasive evaluation of human mucosal structures by multiphoton laser scanning tomography in vitro.

BACKGROUND: Mucous membranes may be affected by various diseases and the diagnostic accessibility is limited. Multiphoton laser tomography (MPT) is a useful tool for in vivo evaluation of superficial skin structures and might also be useful for the imaging of mucosa. OBJECTIVES: In order to investigate the suitability of MPT for the evaluation of mucous membranes, tissue samples of different donors and anatomical localizations have been imaged. METHODS: Human mucosa samples from the urinary bladder, palatine tonsil and ocular conjunctiva were investigated by MPT and subsequently compared with conventional histology. RESULTS: Horizontal images of the epithelium and the underlying connective tissue were obtained using the autofluorescence and second harmonics generation signals by MPT. The stratification of multilayered epithelium was consistently reproduced. Also inflammatory changes like lymphocytic infiltrates and widened intercellular spaces were imaged in some cases. CONCLUSION: Mucous tissue samples were obtained and MPT imaging was successfully performed. In the direct comparison with histology of the same tissue samples, the characteristic morphology of the epithelia was found. Further studies are necessary in order to compare images of healthy and diseased mucosal epithelium and the use of MPT for its evaluation in vivo.

Itinerant Antiferromagnetism in RuO_{2}.

Bulk rutile RuO_{2} has long been considered a Pauli paramagnet. Here we report that RuO_{2} exhibits a hitherto undetected lattice distortion below approximately 900 K. The distortion is accompanied by antiferromagnetic order up to at least 300 K with a small room temperature magnetic moment of approximately 0.05µ_{B} as evidenced by polarized neutron diffraction. Density functional theory plus U (DFT+U) calculations indicate that antiferromagnetism is favored even for small values of the Hubbard U of the order of 1 eV. The antiferromagnetism may be traced to a Fermi surface instability, lifting the band degeneracy imposed by the rutile crystal field. The combination of high Néel temperature and small itinerant moments make RuO_{2} unique among ruthenate compounds and among oxide materials in general.

Candidate Elastic Quantum Critical Point in LaCu_{6-x}Au_{x}.

The structural properties of LaCu_{6-x}Au_{x} are studied using neutron diffraction, x-ray diffraction, and heat capacity measurements. The continuous orthorhombic-monoclinic structural phase transition in LaCu_{6} is suppressed linearly with Au substitution until a complete suppression of the structural phase transition occurs at the critical composition x_{c}=0.3. Heat capacity measurements at low temperatures indicate residual structural instability at x_{c}. The instability is ferroelastic in nature, with density functional theory calculations showing negligible coupling to electronic states near the Fermi level. The data and calculations presented here are consistent with the zero temperature termination of a continuous structural phase transition suggesting that the LaCu_{6-x}Au_{x} series hosts an elastic quantum critical point.

Epidermal changes during UVB phototherapy assessed by multiphoton laser tomography.

BACKGROUND: Multiphoton laser tomography (MPT) is a non-invasive technique that allows imaging of skin in vivo with very high spatial resolution and contrast. Previous work of our group has demonstrated that known morphological changes due to erythematogenic ultraviolet B (UVB) irradiation may be imaged in vivo by MPT. The present work investigated if morphological skin changes known from experimental erythematogenic UVB irradiation are also demonstrable in the course of a standard phototherapy regime that implies suberythematogenic doses of narrow band UVB. METHODS: Sixteen patients with psoriasis vulgaris receiving a narrow band phototherapy were included. A test field and a light-protected control field were measured with the multiphoton tomograph DermaInspect® at four time points: at baseline, the next day, after 3 days and at the day of the last exposure. RESULTS: In the course of the UVB phototherapy, spongiosis and pleomorphy as parameters of inflammation and cellular damage did not show significant changes. By contrast, an adaptive skin reaction with significant changes of keratosis and pigmentation was observed. CONCLUSION: MPT is a suitable technique for the investigation of qualitative and quantitative skin changes after UVB irradiation. After suberythematogenic UVB irradiation, photoadaptive skin changes, but no cellular damage can be observed with MPT.

Acute UVB-induced epidermal changes assessed by multiphoton laser tomography.

BACKGROUND: In vivo multiphoton tomography (MPT) of human skin has become a valuable tool for non-invasive examination of morphological and biophysical skin properties and their alterations. So far, skin changes after UVB irradiation were mainly evaluated clinically and histologically. The present study aimed at non-invasive imaging of histological changes during acute UVB irradiation by multiphoton laser tomography. METHODS: In 10 volunteers, five areas were irradiated once with an erythematous UVB dose. Multiphoton measurements were performed four times, i.e. before irradiation (baseline), and 24, 48 and 72 h after irradiation, respectively. The data were evaluated for changes of epidermal pleomorphy, spongiosis, pigmentation and thickness. RESULTS: The four parameters were altered significantly by acute UVB irradiation, i.e. epidermal pleomorphy, spongiosis, pigmentation and thickness increased within 72 h after irradiation. CONCLUSION: Thus, the study has shown that typical epidermal changes induced by acute UVB irradiation can be evaluated by MPT.

[Multiphoton tomography]. / Multiphotonentomographie.

In recent years, multiphoton tomography (MPT) and multiphoton microscopy have gained increasing importance as noninvasive examination techniques in dermatology. MPT imaging is based on the specific stimulation of biogenic fluorophores. The induction of second harmonic generation is also used for imaging of particular molecules. Additional fluorescence staining or fluorescence markers are not necessary-an important advantage for the in vivo examination of human skin. Multiphoton techniques are not only appropriate for clinical diagnostics but also for biomedical research. MPT provides an optical biopsy depth up to 200 µm with subcellular resolution depicting cellular and extracellular structures. In combination with fluorescence lifetime imaging, additional information about the microenvironment, the energetic state and the cellular metabolism can be obtained. This review presents recent developments of MPT for the in vivo evaluation of physiological and pathological changes of skin and diagnostics of dermal diseases.

Role of catheter location on local impedance measurements and clinical outcome with the new direct sense technology in cardiac ablation procedures.

Background: A novel catheter technology (direct sense, DS) enables periprocedural local impedance (LI) measurement for estimation of tissue contact during radiofrequency ablation (RFA) for real-time assessment of lesion generation. This measure reflects specific local myocardial conduction properties in contrast to the established global impedance (GI) using a neutral body electrode. Our study aimed to assess representative LI values for the cardiac chambers, to evaluate LI drop in response to RF delivery and to compare those values to established GI measures in patients undergoing RFA procedures. Methods and Results: Seventy-three patients undergoing RFA with the DS technology were included. Within the cardiac chambers, baseline LI was significantly different, with the highest values in the left atrium (LA 107.5 ± 14.3 Ω; RV 104.6 Ω ± 12.9 Ω; LV 100.7 Ω ± 11.7 Ω, and RA 100.5 Ω ± 13.4 Ω). Baseline LI was positively correlated to the corresponding LI drop during RF delivery (R2 = 0.26, p = 0.01) representing a promising surrogate of lesion generation. The observed mean LI drop (15.6 ± 9.5 Ω) was threefold higher as GI drop (4.9 ± 7.4 Ω), p < 0.01. We evaluated the clinical outcome in a subgroup of patients undergoing DS-guided pulmonary vein isolation, which was comparable regarding arrhythmia recurrence to a conventional ablation cohort (57 % vs 50 %, p = 0.2). Conclusion: We provide detailed information on LI measures in electrophysiological procedures with significant differences within the cardiac chambers highlighting that RFA-related LI drop can serve as a promising surrogate for real-time assessment of lesion generation. Guiding the electrophysiologist in RFA procedures, this additional information promises to improve safety profile and success rates in the interventional treatment of arrhythmias.

Keratinocyte morphology of human skin evaluated by in vivo multiphoton laser tomography.

BACKGROUND: Multiphoton tomography (MPT) is a novel non-invasive imaging method in dermatology allowing the depiction of the epidermis with sub-cellular resolution. Here, we present a descriptive characterization of unaffected human epidermis, morphometric data on human keratinocytes and some epidermal parameters in vivo and a morphological characterization of keratinocyte changes in actinic keratoses. METHODS: In a clinical setting, 57 volunteers of different age groups were examined using MPT. RESULTS: The morphological appearance of keratinocytes showed polygonal cells in the horny layer, a granular cytoplasm in the stratum granulosum, smaller prickle cells in the stratum spinosum and hyperpigmented small round basal cells. Actinic keratoses presented remarkable differences including widened inter-cellular spaces, heterogeneity in cellular fluorescence and shape as well as an increased ratio of nuclear to cellular size. Finally, the thickness of the epidermis was significantly increased in actinic keratoses compared with the control. CONCLUSION: In vivo MPT provides high-resolution images allowing the identification and quantification of cellular morphometric parameters. First observations of morphology and morphometry of actinic keratoses are reported.

Actinic damage and its treatments.

Over the last decades, there has been a dramatic increase of skin tumour incidence that results from actinic damage. This increase is mainly due to the current demographic development, but also due to a change in spare time habits. Thus, the treatment and prevention of light induced skin tumours is gaining interest, but also the treatment of photoaged skin. This review will focus on 1) the basic principles of actinic damage including carcinogenesis; 2) treatment options for photoaged skin and 3) an overview of current therapy concepts of light induced skin tumours.

German Respiratory Society guidelines for diagnosis and treatment of adults suffering from acute, subacute and chronic cough.

The present 2019 S2k consensus guideline of the German Respiratory Society was written for pneumologists - in contrast to the more general predecessor's S3 guidelines from 2004 to 2010 -, since 2014 the German College of General Practitioners and Family Physicians (DEGAM) published their own cough guidelines. The guidelines contain 48 recommendations agreed upon the consensus and 16 statements, which are explained in the background text in the following nine chapters: epidemiology, physiology, classification, acute, subacute or chronic cough, diagnostics and therapy; an extra chapter was dedicated to chronic idiopathic/refractory cough. Further emphasis of the guidelines is the physiology of cough in anticipation of the introduction of new drugs, as well as detailed treatment for cough triggered by affectations of the upper respiratory tract or gastroesophageal reflux. The guideline should provide the pneumologist with the latest knowledge for neighboring disciplines required for diagnosis and therapy of cough. The clinical chapters also contain a short summary, practical recommendations and a bibliography of their own. Three new simplified algorithms for acute, subacute and chronic cough, round off the diagnostics chapter.

Analysis of dermatologic events in patients with cancer treated with lapatinib.

PURPOSE: Dermatologic events (DEs) in patients with cancer treated with lapatinib, a small-molecule dual tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR [ErbB1]) and HER2 (ErbB2), were characterized. PATIENTS AND METHODS: Nine clinical trials of metastatic cancer were included in this analysis. Lapatinib was administered at doses ranging from 1000 to 1500 mg/day as monotherapy (n=928) or in combination with paclitaxel or capecitabine (n=491). Patients not treated with lapatinib comprised the control group. Dermatologic events included hand-foot syndrome, rash, hair disorder, dry skin, pruritus/urticaria, skin disorder, skin infection, and nail disorder; DEs were characterized based on type, time to onset, severity, duration, and required interventions. RESULTS: Fifty-eight percent of patients treated with lapatinib monotherapy, 74% treated with lapatinib plus paclitaxel or capecitabine, and 53% in the control group developed DEs. Among patients receiving lapatinib monotherapy, 55% experienced grade 1/2 DEs, 3% had grade 3 DEs, and no grade 4 DEs were observed. The most common DE was rash (43%); all other events occurred in

High-density Mapping Guided Pulmonary Vein Isolation for Treatment of Atrial Fibrillation - Two-year clinical outcome of a single center experience.

Pulmonary vein isolation (PVI) as interventional treatment for atrial fibrillation (AF) aims to eliminate arrhythmogenic triggers from the PVs. Improved signal detection facilitating a more robust electrical isolation might be associated with a better outcome. This retrospective cohort study compared PVI procedures using a novel high-density mapping system (HDM) with improved signal detection vs. age- and sex-matched PVIs using a conventional 3D mapping system (COM). Endpoints comprised freedom from AF and procedural parameters. In total, 108 patients (mean age 63.9 ± 11.2 years, 56.5% male, 50.9% paroxysmal AF) were included (n = 54 patients/group). Our analysis revealed that HDM was not superior regarding freedom from AF (mean follow-up of 494.7 ± 26.2 days), with one- and two-year AF recurrence rates of 38.9%/46.5% (HDM) and 38.9%/42.2% (COM), respectively. HDM was associated with reduction in fluoroscopy times (18.8 ± 10.6 vs. 29.8 ± 13.4 min; p < 0.01) and total radiation dose (866.0 ± 1003.3 vs. 1731.2 ± 1978.4 cGy; p < 0.01) compared to the COM group. HDM was equivalent but not superior to COM with respect to clinical outcome after PVI and resulted in reduced fluoroscopy time and radiation exposure. These results suggest that HDM-guided PVI is effective and safe for AF ablation. Potential benefits in comparison to conventional mapping systems, e.g. arrhythmia recurrence rates, have to be addressed in randomized trials.

Heterogeneity and variability of artificial lung colony-forming ability among clones from mouse fibrosarcoma.

Lung colony-forming ability of clones isolated from a fibrosarcoma was examined by i.v. injection of the cells cultured in vitro. The clones were heterogeneous in their lung colony-forming ability, demonstrating variability of this malignant characteristic.